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4,854 | 400 | 24449200 | Which is the protein encoded by the human gene GRIK? | 1p34.3 deletion involving GRIK3: Further clinical implication of GRIK family glutamate receptors in the pathogenesis of developmental delay. A growing body of evidence suggests an association between microdeletion/microduplication and schizophrenia/intellectual disability. Abnormal neurogenesis and neurotransmission have been implicated in the pathogenesis of these neuropsychiatric and neurodevelopmental disorders. The kainate/AMPA-type ionotropic glutamate receptor (GRIK = glutamate receptor, ionotropic, kainate) plays a critical role in synaptic potentiation, which is an essential process for learning and memory. Among the five known GRIK family members, haploinsufficiency of GRIK1, GRIK2, and GRIK4 are known to cause developmental delay, whereas the roles of GRIK3 and GRIK5 remain unknown. Herein, we report on a girl who presented with a severe developmental delay predominantly affecting her language and fine motor skills. She had a 2.6-Mb microdeletion in 1p34.3 involving GRIK3, which encodes a principal subunit of the kainate-type ionotropic glutamate receptor. Given its strong expression pattern in the central nervous system and the biological function of GRIK3 in presynaptic neurotransmission, the haploinsufficiency of GRIK3 is likely to be responsible for the severe developmental delay in the proposita. A review of genetic alterations and the phenotypic effects of all the GRIK family members support this hypothesis. The current observation of a microdeletion involving GRIK3, a kainate-type ionotropic glutamate receptor subunit, and the neurodevelopmental manifestation in the absence of major dysmorphism provides further clinical implication of the possible role of GRIK family glutamate receptors in the pathogenesis of developmental delay. |
4,856 | 401 | 22232559 | Which residue of alpha-synuclein was found to be phosphorylated in Lewy bodies? | Phosphorylation of α-synuclein protein at Ser-129 reduces neuronal dysfunction by lowering its membrane binding property in Caenorhabditis elegans. α-Synuclein is causative for autosomal dominant familial Parkinson disease and dementia with Lewy bodies, and the phosphorylation of α-synuclein at residue Ser-129 is a key posttranslational modification detected in Parkinson disease/dementia with Lewy bodies lesions. However, the role of Ser-129 phosphorylation on the pathogenesis of Parkinson disease/dementia with Lewy bodies remains unclear. Here we investigated the neurotoxicity of Ser-129-substituted α-synuclein in the transgenic Caenorhabditis elegans (Tg worm) model of synucleinopathy. Tg worms pan-neuronally overexpressing nonphosphorylatable (S129A) α-synuclein showed severe defects including motor dysfunction, growth retardation, and synaptic abnormalities. In contrast, Tg worms expressing phosphorylation mimic (S129D) α-synuclein exhibited nearly normal phenotypes. Biochemical fractionation revealed that the level of membrane-bound α-synuclein was significantly increased in S129A-α-synuclein Tg worms, whereas S129D- as well as A30P-α-synuclein displayed lower membrane binding properties. Furthermore, A30P/S129A double mutant α-synuclein did not cause neuronal dysfunction and displayed low membrane binding property. In human neuroblastoma SH-SY5Y cells, localization of S129A-α-synuclein to membranes was significantly increased. Finally, gene expression profiling of S129A-Tg worms revealed a dramatic up-regulation of Daf-16/FOXO pathway genes, which likely act against the dysfunction caused by S129A-α-synuclein. These results imply a role of Ser-129 phosphorylation of α-synuclein in the attenuation of α-synuclein-induced neuronal dysfunction and downstream stress response by lowering the membrane binding property. |
4,863 | 402 | 16633152 | Is paroxetine effective for treatment of premenstrual dysphoric disorder? | Symptom-onset treatment for women with premenstrual dysphoric disorder. UNLABELLED: Symptoms of premenstrual dysphoric disorder (PMDD) respond to serotonin reuptake inhibitors when treatment is limited to 14 days of the menstrual cycle. Many women have less than a week of symptoms, and shorter treatment intervals would further reduce medication exposure and costs. METHODS: Twenty women with PMDD were randomly assigned to either paroxetine CR or placebo for 1 cycle and crossed over to the other condition for a second cycle. Subjects initiated treatment when premenstrual symptoms began and stopped within 3 days of beginning menses. RESULTS: Women took capsules for an average of 9 days (range, 3-15 days), including the first few days of menses. Moderate "PMDD level" symptoms occurred in 1 subject (6%) for 2 days and 4 subjects (24%) for 1 day before starting paroxetine or placebo. Daily Record of Severity of Problems scores were lower in the paroxetine group compared with the placebo group, although the differences were not statistically significant. However, the mean on-treatment Inventory of Depressive Symptomatology (clinician-rated) score for the paroxetine group was 17.9 +/- 8.3 compared with 31.5 +/- 11.2 in the placebo group (adjusted mean difference = 13.6, P = 0.009). Response (Clinical Global Impressions Scale score of 1 or 2) occurred in 70% of subjects randomized to paroxetine CR and 10% of those assigned to placebo (chi2(1) = 7.5, P = 0.006). Discontinuation symptoms did not differ in the groups. CONCLUSION: These data suggest the need to further evaluate symptom-onset treatment in a larger randomized clinical trial. |
4,888 | 403 | 10673511 | What is known about thalidomide therapy and survival of glioblastoma patients? | Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth. |
4,906 | 404 | 11301401 | Is endostatin a proangiogenic factor? | Serum endostatin levels are elevated in patients with soft tissue sarcoma. BACKGROUND: Solid tumors are angiogenesis dependent, and elevated levels of proangiogenic cytokines have been reported in a variety of histologies. Endostatin is an antiangiogenic fragment of the basement membrane protein, collagen XVIII. Because antiangiogenic protein fragments may be generated by tumor-derived proteases, the authors sought to determine whether circulating levels of endostatin were elevated in patients with localized soft tissue sarcoma. METHODS: The authors analyzed preoperative serum levels of endostatin, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in 25 patients (14 males and 11 females; mean age, 44 years) with soft tissue sarcoma. For each serum sample, two aliquots were assayed in duplicate using a competitive enzyme immunoassay. Serum levels were compared with levels from 34 age-matched and gender-matched volunteer blood donors. RESULTS: Endostatin levels were significantly higher in sera from sarcoma patients than in sera from healthy controls (43.0 ng/mL vs. 25.8 ng/mL, respectively; P = 0.0002; Mann-Whitney U test). Significant elevations also were noted in VEGF and bFGF levels (P = 0.0002 and P = 0.0001, respectively). Furthermore, endostatin levels > 2 standard deviations above the control mean (55 ng/mL) were associated with an increased risk of tumor recurrence after resection (P = 0.047; log-rank test). CONCLUSIONS: Serum endostatin, VEGF, and bFGF levels are elevated in patients with soft tissue sarcoma. Elevated endostatin levels appear to be associated with tumor aggressiveness. The role of these cytokines in sarcoma angiogenesis and as potential targets for therapy warrants further study. |
4,941 | 405 | 17632395 | List Genes associated with adolescent idiopathic scoliosis | Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis. STUDY DESIGN: A genetic association study to comprehensively investigate variations of melatonin receptor 1B gene polymorphism by a set of tagging single nucleotide polymorphisms (tagSNPs) derived from the International Hapmap project. OBJECTIVES: To determine whether melatonin receptor 1B (MTNR1B) gene polymorphisms are associated with the predisposition and/or disease severity of adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Linkage studies suggested a genetic predisposition for AIS. In addition, evidence showed that AIS might be related to melatonin deficiency and dysfunction of melatonin signaling pathway. Locating in one of the chromosomal regions linked to AIS, MTNR1B gene is a potential candidate gene for AIS. METHODS: This study was carried out in 2-stage case-control analysis: 1) initial screening (472 cases and 304 controls) and 2) separate replication test (342 cases and 347 controls) to confirm results in the screening. In the first screening stage, 5 tagSNPs were selected to cover most of the genetic variation in the MTNR1B gene. In the second stage, SNPs showing association in the screening stage were studied in a separate replication sample set to confirm the association. Genotyping was performed by PCR-RFLP. RESULTS: The first stage showed a putative association between rs4753426 and AIS, which was confirmed in the replication sample set. By meta-analysis, the frequency of C allele of this SNP locating in the promoter was significantly higher in the cases than controls (P = 0.006 aftermeta-analysis). Subjects with the CC genotype had an odds ratio of 1.29 for AIS. Another SNP rs741837 in promoter region, being moderate linkage disequilibrium with rs4753426, was also marginally associated with AIS. CONCLUSION: Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene. |
5,032 | 406 | 23735780 | Can botulism poisoning of a pregnant woman harm her fetus? | Foodborne botulism in Canada, 1985-2005. During 1985-2005, a total of 91 laboratory-confirmed outbreaks of foodborne botulism occurred in Canada; these outbreaks involved 205 cases and 11 deaths. Of the outbreaks, 75 (86.2%) were caused by Clostridium botulinum type E, followed by types A (7, 8.1%) and B (5, 5.7%). Approximately 85% of the outbreaks occurred in Alaska Native communities, particularly the Inuit of Nunavik in northern Quebec and the First Nations population of the Pacific coast of British Columbia. These populations were predominantly exposed to type E botulinum toxin through the consumption of traditionally prepared marine mammal and fish products. Two botulism outbreaks were attributed to commercial ready-to-eat meat products and 3 to foods served in restaurants; several cases were attributed to non-Native home-prepared foods. Three affected pregnant women delivered healthy infants. Improvements in botulism case identification and early treatment have resulted in a reduction in the case-fatality rate in Canada. |
5,034 | 407 | 22473248 | List the off-label use of SSRIs | Endpoints of drug discovery for menopausal vasomotor symptoms: interpretation of data from a proxy of disease. OBJECTIVE: Estrogen supplementation is considered a reliable therapeutic approach to symptoms of vasomotor dysregulation (hot flashes) associated with the menopausal transition and sex hormone deprivation. Implication of changes in central neurotransmission in the pathogenesis of hot flashes has prompted the off-label use of serotonergic and γ-aminobutyric acid-ergic drugs as a therapeutic alternative, claiming similarity of outcomes to those of estrogen treatment. METHODS: Using telemetric recordings in a rat model of estrogen deficit-induced vasomotor dysregulation, we compared the long- and short-term effects of estrogen supplementation and treatment with neuropharmaceuticals (venlafaxine, desvenlafaxine, fluoxetine, agomelatine, gabapentin) on endpoints of thermoregulation. RESULTS: Among the tested drugs, only fluoxetine was capable to emulate the restorative action of estradiol on the diurnal oscillations in skin temperature and control of heat dissipation. Unlike estradiol, several of the tested compounds produced marked transient decreases in skin temperature within the first 2 hours of application while being unable to restore physiological diurnal patterns of thermoregulation. CONCLUSIONS: Our findings suggest that in this animal model of impaired thermoregulation, neuropharmaceuticals may simulate therapeutic effects by eliciting immediate but transient hypothermia, which is not associated with the recovery of physiological control of heat dissipation. Therefore, short-term monitoring of drug actions in this disease model may considerably bias readouts of drug discovery for menopausal vasomotor symptoms. |
5,053 | 408 | 16636294 | Which is the definition of pyknons in DNA? | Short blocks from the noncoding parts of the human genome have instances within nearly all known genes and relate to biological processes. Using an unsupervised pattern-discovery method, we processed the human intergenic and intronic regions and catalogued all variable-length patterns with identically conserved copies and multiplicities above what is expected by chance. Among the millions of discovered patterns, we found a subset of 127,998 patterns, termed pyknons, which have additional nonoverlapping instances in the untranslated and protein-coding regions of 30,675 transcripts from 20,059 human genes. The pyknons arrange combinatorially in the untranslated and coding regions of numerous human genes where they form mosaics. Consecutive instances of pyknons in these regions show a strong bias in their relative placement, favoring distances of approximately 22 nucleotides. We also found pyknons to be enriched in a statistically significant manner in genes involved in specific processes, e.g., cell communication, transcription, regulation of transcription, signaling, transport, etc. For approximately 1/3 of the pyknons, the intergenic/intronic instances of their reverse complement lie within 380,084 nonoverlapping regions, typically 60-80 nucleotides long, which are predicted to form double-stranded, energetically stable, hairpin-shaped RNA secondary structures; additionally, the pyknons subsume approximately 40% of the known microRNA sequences, thus suggesting a possible link with posttranscriptional gene silencing and RNA interference. Cross-genome comparisons reveal that many of the pyknons have instances in the 3' UTRs of genes from other vertebrates and invertebrates where they are overrepresented in similar biological processes, as in the human genome. These unexpected findings suggest potential unique functional connections between the coding and noncoding parts of the human genome. |
5,059 | 409 | 22586276 | Does a linker histone exist in the yeast genome? | The linker histone plays a dual role during gametogenesis in Saccharomyces cerevisiae. The differentiation of gametes involves dramatic changes to chromatin, affecting transcription, meiosis, and cell morphology. Sporulation in Saccharomyces cerevisiae shares many chromatin features with spermatogenesis, including a 10-fold compaction of the nucleus. To identify new proteins involved in spore nuclear organization, we purified chromatin from mature spores and discovered a significant enrichment of the linker histone (Hho1). The function of Hho1 has proven to be elusive during vegetative growth, but here we demonstrate its requirement for efficient sporulation and full compaction of the spore genome. Hho1 chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed increased genome-wide binding in mature spores and provides novel in vivo evidence of the linker histone binding to nucleosomal linker DNA. We also link Hho1 function to the transcription factor Ume6, the master repressor of early meiotic genes. Hho1 and Ume6 are depleted during meiosis, and analysis of published ChIP-chip data obtained during vegetative growth reveals a high binding correlation of both proteins at promoters of early meiotic genes. Moreover, Ume6 promotes binding of Hho1 to meiotic gene promoters. Thus, Hho1 may play a dual role during sporulation: Hho1 and Ume6 depletion facilitates the onset of meiosis via activation of Ume6-repressed early meiotic genes, whereas Hho1 enrichment in mature spores contributes to spore genome compaction. |
5,070 | 410 | 15247430 | What is the role of deadenylases in the cell? | mRNA deadenylation by PARN is essential for embryogenesis in higher plants. Deadenylation of mRNA is often the first and rate-limiting step in mRNA decay. PARN, a poly(A)-specific 3' --> 5' ribonuclease which is conserved in many eukaryotes, has been proposed to be primarily responsible for such a reaction, yet the importance of the PARN function at the whole-organism level has not been demonstrated in any species. Here, we show that mRNA deadenylation by PARN is essential for viability in higher plants (Arabidopsis thaliana). Yet, this essential requirement for the PARN function is not universal across the phylogenetic spectrum, because PARN is dispensable in Fungi (Schizosaccharomyces pombe), and can be at least severely downregulated without any obvious consequences in Metazoa (Caenorhabditis elegans). Development of the Arabidopsis embryos lacking PARN (AtPARN), as well as of those expressing an enzymatically inactive protein, was markedly retarded, and ultimately culminated in an arrest at the bent-cotyledon stage. Importantly, only some, rather than all, embryo-specific transcripts were hyperadenylated in the mutant embryos, suggesting that preferential deadenylation of a specific select subset of mRNAs, rather than a general deadenylation of the whole mRNA population, by AtPARN is indispensable for embryogenesis in Arabidopsis. These findings indicate a unique, nonredundant role of AtPARN among the multiple plant deadenylases. |
5,091 | 411 | 25093016 | What molecule is targeted by brodalumab? | Brodalumab: an evidence-based review of its potential in the treatment of moderate-to-severe psoriasis. Advances in knowledge regarding the pathogenesis of psoriasis have allowed the development of a new class of agents known as biologic drugs. Data confirm that T helper (Th)17 and interleukin (IL)-17 signaling has a crucial role in the pathogenesis of the disease. High levels of IL-17 and Th17-related cytokines have been reported in psoriasis, leading to the suggestion of agents targeting IL-17 as a potential therapeutic strategy in psoriasis. Brodalumab is a human monoclonal antibody that targets IL-17 receptor A, blocking the effects of IL-17A, IL-17F, and IL-17E. Data from Phase I and Phase II clinical trials indicate that brodalumab has a favorable safety and tolerability profile, with strong clinical activity, suggesting that it is a potential tool for use in the treatment of moderate-to-severe psoriasis. |
5,101 | 412 | 11810275 | How long, in kb (kilobases), is a "Long interspersed nuclear element"? | A full-length and potentially active LINE element is integrated polymorphically within the IGL locus in a genomically unstable region of chromosome 22. Leukemic cells of a patient diagnosed with chronic myeloid leukemia (CML) showed a complex BCR-ABL1 rearrangement hidden within a normal appearing karyotype. Previous molecular studies had established that the 3' BCR had recombined at a novel site within the variable region of the immunoglobulin lambda locus ( IGL). A segment of DNA mapping very close to the site of the IGL/3' BCR recombination recognized a previously undescribed insertion polymorphism. A combination of molecular hybridization studies and long-range polymerase chain reaction was used to isolate a 6-kb full-length long interspersed nuclear element (LINE or L1), here designated L1(IGL), which occupies 19% of alleles in the general population. Although unclonable, DNA sequence analysis by a primer walking approach established that L1(IGL) has features characteristic of an actively retrotransposing element. The L1(IGL) element has a 5' untranslated region, two open reading frames (ORF-1 and ORF-2), a 3' untranslated region and terminates in a poly-A tail. We compared the DNA sequence and the predicted amino acid sequence of L1(IGL) with a consensus sequence compiled from seven reported active L1 elements. This analysis indicated that L1(IGL) has high potential for involvement in as yet undetermined somatically and constitutionally acquired disease, not only through recombination mechanisms, but also through retrotransposition events. This full-length L1 element maps close within the IGLlocus to L1.2, one of only nine active L1 elements that have been reported so far. L1(IGL) and L1.2 map within a wider and well-recognized region of genomic instability on chromosome 22. |
5,104 | 413 | 20442305 | Which is the gene mutated in type 1 neurofibromatosis? | Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner. Neurofibromatosis type 1 (NF1) is the most common genetic disease affecting the nervous system. Patients typically develop many tumors over their lifetime, leading to increased morbidity and mortality. The NF1 gene, mutated in NF1, is also commonly mutated in sporadic glioblastoma multiforme (GBM). Because both NF1 and GBM are currently incurable, new therapeutic approaches are clearly needed. Natural products represent an opportunity to develop new therapies, as they have been evolutionarily selected to play targeted roles in organisms. Schweinfurthin A is a prenylated stilbene natural product that has previously shown specific inhibitory activity against brain and hematopoietic tumor lines. We show that patient-derived GBM and NF1 malignant peripheral nerve sheath tumor (MPNST) lines, as well as tumor lines derived from the Nf1-/+;Trp53-/+ (NPcis) mouse model of astrocytoma and MPNST are highly sensitive to inhibition by schweinfurthin A and its synthetic analogs. In contrast, primary mouse astrocytes are resistant to the growth inhibitory effects of schweinfurthin A, suggesting that schweinfurthin A may act specifically on tumor cells. Stable transfection of the GTPase-activating protein related domain of Nf1 into Nf1-/-;Trp53-/- astrocytoma cells confers resistance to schweinfurthin A. In addition, the profound effect of schweinfurthin A on dynamic reorganization of the actin cytoskeleton led us to discover that schweinfurthin A inhibits growth factor-stimulated Rho signaling. In summary, we have identified a class of small molecules that specifically inhibit growth of cells from both central and peripheral nervous system tumors and seem to act on NF1-deficient cells through cytoskeletal reorganization correlating to changes in Rho signaling. |
5,129 | 414 | 22517378 | List receptors of the drug Cilengitide | Cyclic RGD peptidomimetics containing bifunctional diketopiperazine scaffolds as new potent integrin ligands. The synthesis of eight bifunctional diketopiperazine (DKP) scaffolds is described; these were formally derived from 2,3-diaminopropionic acid and aspartic acid (DKP-1-DKP-7) or glutamic acid (DKP-8) and feature an amine and a carboxylic acid functional group. The scaffolds differ in the configuration at the two stereocenters and the substitution at the diketopiperazinic nitrogen atoms. The bifunctional diketopiperazines were introduced into eight cyclic peptidomimetics containing the Arg-Gly-Asp (RGD) sequence. The resulting RGD peptidomimetics were screened for their ability to inhibit biotinylated vitronectin binding to the purified integrins α(v)β(3) and α(v)β(5), which are involved in tumor angiogenesis. Nanomolar IC(50) values were obtained for the RGD peptidomimetics derived from trans DKP scaffolds (DKP-2-DKP-8). Conformational studies of the cyclic RGD peptidomimetics by (1)H NMR spectroscopy experiments (VT-NMR and NOESY spectroscopy) in aqueous solution and Monte Carlo/Stochastic Dynamics (MC/SD) simulations revealed that the highest affinity ligands display well-defined preferred conformations featuring intramolecular hydrogen-bonded turn motifs and an extended arrangement of the RGD sequence [Cβ(Arg)-Cβ(Asp) average distance ≥8.8 Å]. Docking studies were performed, starting from the representative conformations obtained from the MC/SD simulations and taking as a reference model the crystal structure of the extracellular segment of integrin α(v)β(3) complexed with the cyclic pentapeptide, Cilengitide. The highest affinity ligands produced top-ranked poses conserving all the important interactions of the X-ray complex. |
5,158 | 415 | 15328599 | Can protein coding exons originate from ALU sequences? | From "junk" to gene: curriculum vitae of a primate receptor isoform gene. Exonization of Alu retroposons awakens public opinion, particularly when causing genetic diseases. However, often neglected, alternative "Alu-exons" also carry the potential to greatly enhance genetic diversity by increasing the transcriptome of primates chiefly via alternative splicing.Here, we report a 5' exon generated from one of the two alternative transcripts in human tumor necrosis factor receptor gene type 2 (p75TNFR) that contains an ancient Alu-SINE, which provides an alternative N-terminal protein-coding domain. We follow the primate evolution over the past 63 million years to reconstruct the key events that gave rise to a novel receptor isoform. The Alu integration and start codon formation occurred between 58 and 40 million years ago (MYA) in the common ancestor of anthropoid primates. Yet a functional gene product could not be generated until a novel splice site and an open reading frame were introduced between 40 and 25 MYA on the catarrhine lineage (Old World monkeys including apes). |
5,175 | 416 | 22362925 | How could U1 small nuclear RNA be used in therapeutics? | An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. A significant proportion of disease-causing mutations affect precursor-mRNA splicing, inducing skipping of the exon from the mature transcript. Using F9 exon 5, CFTR exon 12 and SMN2 exon 7 models, we characterized natural mutations associated to exon skipping in Haemophilia B, cystic fibrosis and spinal muscular atrophy (SMA), respectively, and the therapeutic splicing rescue by using U1 small nuclear RNA (snRNA). In minigene expression systems, loading of U1 snRNA by complementarity to the normal or mutated donor splice sites (5'ss) corrected the exon skipping caused by mutations at the polypyrimidine tract of the acceptor splice site, at the consensus 5'ss or at exonic regulatory elements. To improve specificity and reduce potential off-target effects, we developed U1 snRNA variants targeting non-conserved intronic sequences downstream of the 5'ss. For each gene system, we identified an exon-specific U1 snRNA (ExSpeU1) able to rescue splicing impaired by the different types of mutations. Through splicing-competent cDNA constructs, we demonstrated that the ExSpeU1-mediated splicing correction of several F9 mutations results in complete restoration of secreted functional factor IX levels. Furthermore, two ExSpeU1s for SMA improved SMN exon 7 splicing in the chromosomal context of normal cells. We propose ExSpeU1s as a novel therapeutic strategy to correct, in several human disorders, different types of splicing mutations associated with defective exon definition. |
5,183 | 417 | 21738055 | What is the influence of patent expiry on ACE inhibitor prescribing. | Generic switch after ramipril patent expiry is not associated with decreased pharmacy refill compliance: a retrospective study using the DAPI database. OBJECTIVE: For treatment success in chronic diseases such as hypertension, adequate adherence to long-term pharmacotherapy is a prerequisite. The purpose of this study was to evaluate whether switching from brand name ramipril to a generic product after patent expiry may negatively affect patients' refill compliance. METHODS: Claims data for ambulatory prescriptions within the statutory health insurance system were evaluated. Patients were included if they had filled a ramipril prescription (index) for either brand name or generic ramipril products between September 2003 and June 2004. Patients had to be continuously treated with ramipril for at least 12 months before and after the index date. Patients with a change from brand name to generic product or vice versa during follow-up after the index date were excluded from the analyses, as were patients who could not be unequivocally allocated to characteristics of covariates. Refill compliance was analysed by calculating the medication possession ratio (MPR), assuming that patients were prescribed one unit dose per day (MPR(UD)). RESULTS: In total, 142,690 and 79,191 patients were classified as brand name or generic therapy, respectively. Median MPR(UD) values were 0.95 and 0.96 (P < 0.001). In a logistic regression model adjusting for covariates, the probability for noncompliance (MPR(UD) < 0.8) was marginally lower in the generic compared with the brand name group (odds ratio 0.926, 99% confidence interval 0.901-0.951, P < 0.001). CONCLUSION: These results suggest that refill compliance is not negatively affected by a physician-induced switch from brand name to generic ramipril products after patent expiry. |
5,186 | 418 | 22098224 | Is there evidence that tomato juice lowers cholesterol levels? | Bioavailability of phytochemical constituents from a novel soy fortified lycopene rich tomato juice developed for targeted cancer prevention trials. Studies suggest that tomato and soy foods may contribute to a lower risk of certain cancers. We developed a novel soy germ tomato juice to be used in controlled cancer prevention trials. This study describes an initial test of compliance, phytochemical bioavailability, and effects on biomarkers of blood lipids. Healthy men and women (n = 18) consumed a soy germ-fortified juice daily (300 mL supplying 66 mg isoflavones and 22 mg lycopene) for 8 wk. A single-dose bioavailability study was completed on day 1 and isoflavones in plasma and urine, and lycopene in the plasma, were measured. All subjects completed the trial, with 97.7% ± 3.5% (mean ± SD) of the scheduled juice consumed. No adverse effects were documented. The postprandial study indicated that 3.1% ± 2.3% of lycopene was absorbed and that 49.3% ± 12.1% isoflavones ingested were recovered in 24-h urines. Lycopene plasma concentration changed from 0.60 ± 0.22 to 1.24 ± 0.30 μmol/L during 8 wk of consumption. Juice consumption significantly improved resistance of LDL+VLDL-C to Cu(2+)-mediated oxidation (P = 0.039), HDL-C (47.3 ± 15.8 to 51.7 ± 14.8 mg/dL, P < 0.001), and the ratio of total-C/HDL-C (4.25 ± 1.59 to 3.63 ± 1.16, P < 0.001) at 8 wk. A well-characterized soy-fortified tomato juice can be produced in large scale for multiinstitutional long-term cancer prevention trials and showed excellent compliance with no toxicity, while demonstrating absorption of biologically active phytochemicals. |
5,191 | 419 | 18093339 | Are there transposon-free regions in mammalian genomes? | Maintenance of transposon-free regions throughout vertebrate evolution. BACKGROUND: We recently reported the existence of large numbers of regions up to 80 kb long that lack transposon insertions in the human, mouse and opossum genomes. These regions are significantly associated with loci involved in developmental and transcriptional regulation. RESULTS: Here we report that transposon-free regions (TFRs) are prominent genomic features of amphibian and fish lineages, and that many have been maintained throughout vertebrate evolution, although most transposon-derived sequences have entered these lineages after their divergence. The zebrafish genome contains 470 TFRs over 10 kb and a further 3,951 TFRs over 5 kb, which is comparable to the number identified in mammals. Two thirds of zebrafish TFRs over 10 kb are orthologous to TFRs in at least one mammal, and many have orthologous TFRs in all three mammalian genomes as well as in the genome of Xenopus tropicalis. This indicates that the mechanism responsible for the maintenance of TFRs has been active at these loci for over 450 million years. However, the majority of TFR bases cannot be aligned between distantly related species, demonstrating that TFRs are not the by-product of strong primary sequence conservation. Syntenically conserved TFRs are also more enriched for regulatory genes compared to lineage-specific TFRs. CONCLUSION: We suggest that TFRs contain extended regulatory sequences that contribute to the precise expression of genes central to early vertebrate development, and can be used as predictors of important regulatory regions. |
5,194 | 420 | 26121403 | Are messenger RNA molecules epigenetically methylated? | Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. N(6)-methyladenosine (m6A) is the most abundant modified base in eukaryotic mRNA and has been linked to diverse effects on mRNA fate. Current mapping approaches localize m6A residues to transcript regions 100-200 nt long but cannot identify precise m6A positions on a transcriptome-wide level. Here we developed m6A individual-nucleotide-resolution cross-linking and immunoprecipitation (miCLIP) and used it to demonstrate that antibodies to m6A can induce specific mutational signatures at m6A residues after ultraviolet light-induced antibody-RNA cross-linking and reverse transcription. We found that these antibodies similarly induced mutational signatures at N(6),2'-O-dimethyladenosine (m6Am), a modification found at the first nucleotide of certain mRNAs. Using these signatures, we mapped m6A and m6Am at single-nucleotide resolution in human and mouse mRNA and identified small nucleolar RNAs (snoRNAs) as a new class of m6A-containing non-coding RNAs (ncRNAs). |
5,201 | 421 | 19367498 | Which genes are more frequently affected by somatic mutations in Chronic Lymphocytic Leukemia | BCL6: somatic mutations and expression in early-stage chronic lymphocytic leukemia. BCL6 somatic mutations affect normal and tumoral post germinal center B-lymphocytes. Our objective was to analyse expression, mutations and polymorphisms in the BCL6 gene and to correlate those variables with the clinical outcome in early-stage chronic lymphocytic leukemia (CLL). CLL samples were used for characterisation of the mutational status of BCL6/ immunoglobulin variable heavy chain (IGHV) genes, and expression of BCL6 was determined by real time PCR and immunoblot. Out of 68 cases, 29% show somatic mutations on BCL6 which occur exclusively in IGHV mutated cases. They are single nucleotide substitutions located mainly in two short mutational hot spots. CLL cells express different levels of BCL6 regardless of the mutational status, the number of mutations and polymorphisms. CLL cases expressing high levels of BCL6 have significantly shorter treatment-free interval. In conclusion, in early-stage patients with CLL, we found no correlation between expression and the mutations or polymorphism in BCL6, but high levels of BCL6 can discriminate patients with a worse prognosis. |
5,207 | 422 | 11022098 | How effective is the dentritic cells treatment on cancer? | [Dendritic cells: orchestration of the immune response]. Dendritic cells are critical initiators of immune responses. They not only activate pathogen-specific T and B lymphocytes, they also stimulate cells of the innate immune system. Furthermore, dentritic cells are involved in immunological tolerance induction through the elimination of autoreactive T lymphocytes. Over the last ten years, understanding of the development, biology and physiopathology of dentritic cells has progressed considerably which has lead to the use of dentritic cells in immunotherapy protocols to treat tumors, infections and auto-immune diseases. |
5,219 | 423 | 17846275 | What is the mode of inheritance of nemaline myopathy? | Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2). OBJECTIVE: To describe the clinical, morphologic, and genetic findings in a family in which one woman had nemaline myopathy, whereas her daughter showed features of cap disease. PATIENTS: A 66-year-old woman and her 35-year-old daughter had congenital, slowly progressive muscle weakness. They had weakness in both proximal and distal muscles and facial diplegia with bilateral ptosis, a long narrow face, a high arched palate, and micrognathia. RESULTS: Muscle biopsy specimens in the mother at age 57 years had shown nemaline myopathy, whereas a biopsy specimen at age 32 years had demonstrated no rods. Muscle biopsy specimens in the daughter at age 26 years had shown features of cap disease and no apparent nemaline rods. A missense mutation, Glu41Lys, in the beta-tropomyosin gene TPM2 was identified in both patients but was absent in their healthy relatives. CONCLUSIONS: The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. These disorders may thus be phenotypic variants of the same genetic defect. |
5,222 | 424 | 24630051 | Which syndrome is NHE6 associated with? | A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES). |
5,226 | 425 | 20608882 | What is known about the reimbursement of Viagra | Treatment patterns and resource utilization and costs among patients with pulmonary arterial hypertension in the United States. OBJECTIVE: To explore treatment patterns and resource utilization and cost for subjects with pulmonary arterial hypertension (PAH). RESEARCH DESIGN: Retrospective claims database analysis of 706 patients with PAH enrolled in a large, geographically diverse US managed-care organization. RESULTS: In the final sample of PAH patients treated with bosentan (n=251) or sildenafil (n=455), average age was 57 years, 86% of patients were commercially insured, and 52% of patients were male. Gender distribution varied significantly across subgroups, with a lower proportion of males in the bosentan (30%) subgroup compared with the sildenafil group (64%) (p<0.001). Average baseline Charlson comorbidity score was 2.4. Average numbers of fills per month were 0.8 and 0.4 for bosentan and sildenafil patients, respectively (p<0.001). Over 80% of patients received only one PAH treatment in the first 90 days following the index date, with 28% of bosentan and 13% of sildenafil patients receiving combination therapy (p<0.001). Over one-third of bosentan patients and one-quarter of sildenafil patients experienced a dose increase in the follow-up period (p=0.009). Sixteen percent of sildenafil patients experienced a dose decrease in the follow-up period, while a smaller proportion of patients receiving bosentan (4%) experienced a dose decrease (p<0.001). On average, number of PAH-related per subject per month (PSPM) inpatient stays and emergency department visits and PSPM length of inpatient stays were statistically similar between the subgroups. PAH-related PSPM healthcare costs were high for both subgroups, with average monthly costs of $5,332 and $3,632 among bosentan and sildenafil patients, respectively (p=0.003). Differences in total costs were driven mainly by differences in pharmacy expenditures. CONCLUSIONS: Of the oral agents approved for treating PAH at the time of this study, sildenafil was most commonly prescribed as index therapy and was also associated with the lowest costs, largely due to significantly lower pharmacy costs. This study is characterized by limitations inherent to claims database analyses, such as the potential for coding errors and lack of information on whether a drug was taken as prescribed. Furthermore, PAH severity (WHO functional class) was not assessed. |
5,239 | 426 | 21133379 | Why is lock mass used in Orbitrap measurements? | 24-hour lock mass protection. The positive role and application of highly accurate mass measurements in proteomics is well documented. The new generation of hybrid FTMS and Q-TOF instruments, including the LTQ-Orbitrap (OT), is remarkable in their ability to routinely produce single-digit to subppm statistical mass accuracy while maintaining high analytical sensitivity. The use of mass calibrants (lock masses) to reduce the systematic error of mass-to-charge measurements has also been reported and, in some cases, incorporated in the instrument control software by the instrument manufacturers. We evaluated the use of one such calibrant in the OT (e.g., polydimethylcyclosiloxane, PCM) to study its impact on the rate of phosphopeptide annotation and found it to lack robustness under normal laboratory conditions. Therefore, we devised a strategy to improve its performance by increasing the external abundance of calibrant molecules in laboratory air. This resulted in a more robust performance of the preprogrammed lock mass recalibration feature as evidenced by improvements in both statistical mass accuracy and peptide annotation rates. |
5,244 | 427 | 19725597 | Which virus is Cidofovir (Vistide) indicated for? | Antivirals for cytomegalovirus infection in neonates and infants: focus on pharmacokinetics, formulations, dosing, and adverse events. Cytomegalovirus (CMV) infection is very common throughout the world, and has become more of a pediatric clinical concern given the high incidence of congenital CMV infections as well as the increasing numbers of immunocompromised patients. Because of this, the need for antiviral therapies in infants and neonates is growing. Currently, there are four antivirals available that are active against CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. At this time, none have approved indications for use in children. Although there are limited data regarding the dose, pharmacokinetics (PK), safety, and adverse events for some of these antivirals, ganciclovir, and its oral prodrug valganciclovir, have been the best studied in the infant and neonate populations. In general, pharmaceutical PK studies in young children are limited by the constraints of sampling difficulties and blood volume requirements; fewer sampling times and studies may be available for drug evaluation. Given this caveat, ganciclovir and valganciclovir PK in children thus far appears to follow a monocompartmental model, contrary to what has been described in adults. However, when normalized for weight, the volume of distribution, clearance, and half-life of ganciclovir are similar to those found in adults. Given the findings that ganciclovir (and thus valganciclovir) clearance is directly proportionate to renal function, care must be taken when administering the drug to patients with impaired renal function. Recent studies evaluating valganciclovir PK in infants (at a dose of 16 mg/kg every 12 hours) have shown similar areas under the plasma concentration-time curve (AUCs) to intravenous ganciclovir (at a dose of 6 mg/kg every 12 hours), and that these AUCs remain quite stable over a number of weeks. As seen in adults, oral ganciclovir has a low bioavailability (4.8% in a pediatric analysis) and is therefore a poor alternative for treating serious CMV infections. Neutropenia is the most frequent toxicity associated with ganciclovir and valganciclovir therapy, whereas significant (and possibly irreversible) renal toxicity can be seen with cidofovir. Foscarnet administration can also result in renal toxicity as well as significant electrolyte imbalances. Several of these drugs have potential toxicities that are of concern, including carcinogenesis, teratogenesis, and azospermia (ganciclovir, valganciclovir, and cidofovir) and deposition into bone or dentition (foscarnet) that may have significant implications when treating an infant. Given these potential ill effects, careful consideration of the indications for the clinical use of these antivirals is necessary before using them for CMV infection in neonates and infants. |
5,248 | 428 | 17145736 | Have gnotobiotic animal models been used for the study of bowel disease? | Helicobacter bilis triggers persistent immune reactivity to antigens derived from the commensal bacteria in gnotobiotic C3H/HeN mice. BACKGROUND: Infection with Helicobacter species has been associated with the development of mucosal inflammation and inflammatory bowel disease (IBD) in several mouse models. However, consensus regarding the role of Helicobacter as a model organism to study microbial-induced IBD is confounded by the presence of a complex colonic microbiota. AIM: To investigate the kinetics and inflammatory effects of immune system activation to commensal bacteria following H bilis colonisation in gnotobiotic mice. METHODS: C3H/HeN mice harbouring an altered Schaedler flora (ASF) were selectively colonised with H bilis and host responses were investigated over a 10-week period. Control mice were colonised only with the defined flora (DF). Tissues were analysed for gross/histopathological lesions, and bacterial antigen-specific antibody and T-cell responses. RESULTS: Gnotobiotic mice colonised with H bilis developed mild macroscopic and microscopic lesions of typhlocolitis beginning 3 weeks postinfection. ASF-specific IgG responses were demonstrable within 3 weeks, persisted throughout the 10-week study, and presented as a mixed IgG1:IgG2a profile. Lymphocytes recovered from the mesenteric lymph node of H bilis-colonised mice produced increased levels of interferon gamma, tumour necrosis factor alpha (TNFalpha), interleukin 6 (IL6) and IL12 in response to stimulation with commensal- or H bilis-specific bacterial lysates. In contrast, DF mice not colonised with H bilis did not develop immune responses to their resident flora and remained disease free. CONCLUSIONS: Colonisation of gnotobiotic C3H/HeN mice with H bilis perturbs the host's response to its resident flora and induces progressive immune reactivity to commensal bacteria that contributes to the development of immune-mediated intestinal inflammation. |
5,260 | 429 | 15742475 | List chromosomes that have been linked to Arnold Chiari syndrome in the literature. | Interstitial deletion of the long arm of chromosome 5 in a boy with multiple congenital anomalies and mental retardation: Molecular characterization of the deleted region to 5q22.3q23.3. Interstitial deletions of the middle portion of the long arm of chromosome 5 are relatively rare. So far, only 36 cases have been reported. Because of the repetitive banding pattern of this region, the extent and localization of the deleted segment has not been well characterized in the majority of reported cases. This has complicated attempts to establish a definite karyotype-phenotype correlation. We report a further case with a de novo interstitial deletion of the region 5q?15 to 5q?22 identified by standard karyotype analysis. The proband presented with failure to thrive, developmental delay, distinct craniofacial dysmorphic features, and associated structural anomalies (amongst them cleft palate, iris colobomata, and horseshoe kidney, which have previously been reported in 5q deletion cases). In addition, this child had an Arnold-Chiari type I malformation that required surgical decompression. FISH studies using BAC clones spanning the 5q15 to 5q22 region revealed that these were all present in both homologues. Use of more distal clones allowed delineation of the deleted region to 5q22.3q23.3 and to narrow down the breakpoints to approximately 200 kb. The 14 Mb deleted region contains about 60 genes but, with the possible exception of FBN2 and DMXL1, there are no obvious candidate genes for the specific components of the phenotype. This case illustrates the discrepancy between cytogenetic and molecular techniques in trying to delineate 5q interstitial deletions. Molecular studies need to be performed on these patients, to establish genotype-phenotype correlation and to understand the role and influence of genes in this region. |
5,274 | 430 | 22266186 | Which translocation is the hallmark of Ewing sarcoma? | Impairment of p53 acetylation by EWS-Fli1 chimeric protein in Ewing family tumors. The chromosomal translocation t(11;22)(q24;q12) yields the EWS-Fli1 fusion gene, which contributes to the development of Ewing Family Tumors (EFTs). Previous studies have shown the ability of EWS-Fli1 chimeric protein to silence p53 activity. Here we demonstrate that the introduction of EWS-Fli1 significantly inhibited p300-mediated acetylation of p53 at Lys-382 and depletion of EWS-Fli1 protein by small interfering RNAs (siRNA) in EFTs cells facilitated it in response to DNA damage. Furthermore, the deacetylation of p53 by EWS-Fli1 suppressed its transcriptional activity and enhanced mdm2-mediated p53 degradation. On the other hand, immunoprecipitation study shows that N-terminal region of EWS-Fli1 associated with histone deacetylase 1 (HDAC1) to forms a complex with p53. Knockdown of HDAC1, but not HDAC2 or HDAC3 protein restored the expression of p53 Lys-382 in EFTs cells. Overexpression of HDAC1 also significantly inhibited p53 transcriptional activity. Pharmacologic inhibitor of HDAC, trichostatin A (TSA) promoted p53-p300 interaction and recruitment of p53 Lys-382 to promoter regions of its target genes p21 and Puma, consequently inducing apoptosis and stabilizing the acetylation of p53 at Lys-382 together with the upregulation of p21 and Puma, which were impaired in EFTs cells after the knockdown of p53 expression. Our data indicate EWS-Fli1 might deacetylate p53 to inhibit its transcriptional function and protein stability via the recruitment of HDAC1. These results might elucidate a novel molecular mechanism about the abrogation of p53 pathway by EWS-Fli1 in EFTs pathogenesis. |
5,292 | 431 | 19662202 | Is invasion and metastasis one of the hallmarks of cancer? | Expression of cancer-associated molecules in malignant mesothelioma. Malignant mesothelioma (MM) is a malignant tumor derived from mesothelial cells, native cells of the body cavities. Exposure to asbestos is the most strongly established etiologic factor, predominantly for the most common disease form, pleural mesothelioma. The pathogenesis of MM involves the accumulation of extensive cytogenetic changes, as well as cancer-related phenotypic alterations that facilitate tumor cell survival, invasion and metastasis. This review presents current knowledge regarding the biological characteristics of this disease that are linked to the so-called hallmarks of cancer. In addition, data suggesting that the anatomic site (solid tumor vs. effusion) affects the expression of metastasis-associated and regulatory molecules in MM are presented. Finally, recent work in which high-throughput methodology has been applied to MM research is reviewed. The data obtained in the reviewed research may aid in defining new prognostic markers and therapeutic targets for this aggressive disease in the future. |
5,293 | 432 | 22930255 | Is it possible to detect survivin protein expression in normal human adult tissues? | Elevated levels of survivin and livin mRNA in bronchial aspirates as markers to support the diagnosis of lung cancer. Survivin and livin are two members of the inhibitor of apoptosis gene family, which have been found to be expressed in many human cancer tissues. But their expression could not be detected in normal adult tissue. The aim of our study was to evaluate the diagnostic role of survivin and livin mRNA expression in the bronchial aspirates of patients with lung cancer. Seventy lung cancer patients and 26 benign lung disease patients participated in our study. The bronchial aspirates (bronchial wash or bronchoalveolar lavage fluids) obtained during bronchoscopy. Survivin and livin mRNA were determined by reverse transcriptase-polymerase chain reaction. Receiver operating characteristic (ROC) curve was used to analyze diagnostic performance of the two markers. Survivin and livin mRNA levels in patients with lung cancer were significantly higher than in those with benign lung disease (p < 0.001 and p = 0.001, respectively). In lung cancer patients, specimens taken from cancerous bronchi had significantly higher levels of survivin and livin mRNA than specimens from the mirror side bronchi in the same patients (p < 0.001 and p = 0.001, respectively). The best cutoff values of survivin and livin were selected according to ROC curves. The survivin mRNA expression in bronchial aspirates had sensitivity and specificity of 83 and 96% for diagnosis of lung cancer. Livin mRNA detection in bronchial aspirates showed 63% sensitivity and 92% specificity. Our findings suggest that survivin and livin mRNA detection in bronchial aspirates may be valuable diagnostic marker for the early diagnosis of lung cancer. |
5,313 | 433 | 24962423 | List symptoms of Meigs' Syndrome. | Large twisted ovarian fibroma associated with Meigs' syndrome, abdominal pain and severe anemia treated by laparoscopic surgery. BACKGROUND: The Meigs' syndrome is a rare but well-known syndrome defined as the triad of benign solid ovarian tumor, ascites, and pleural effusion. Meigs' syndrome always requires surgical treatment. However, the optimal approach for its management has not been sufficiently investigated. CASE PRESENTATION: We report a patient with a large twisted ovarian fibroma associated with Meigs' syndrome, abdominal pain and severe hemolytic anemia that was treated by laparoscopic surgery. This case highlights the difficulties that may be encountered in the management of patients with Meigs' syndrome, including potential misdiagnosis of the tumor as a malignant ovarian neoplasm that may influence the medical and surgical approach and the adverse impact that Meigs' syndrome can have on the patient's condition, especially if it is associated with acute pain and severe anemia. Considering the patient's serious clinical condition and assuming that she had Meigs' syndrome with a twisted large ovarian mass and possible hemolytic anemia, we first concentrated on effective medical management of our patient and chose the most appropriate surgical treatment after laparoscopic examination. The main aim of our initial approach was preoperative management of the anemia. Blood transfusions and glucocorticoid therapy resulted in stabilization of the hemoglobin level and normalization of the bilirubin levels, which confirmed the appropriateness of this approach. Laparoscopic surgery 4 days after admission enabled definitive diagnosis of the tumor, confirmed torsion and removed the bulky ovarian fibroma, resulting in timely resolution of symptoms, short hospitalization, relatively low morbidity and a rapid return to her social and professional life. CONCLUSIONS: This case highlights the difficulties that may be encountered in the management of patients with Meigs' syndrome, including potential misdiagnosis of the tumor as a malignant ovarian neoplasm that may influence the medical and surgical approach, and the adverse impact that Meigs' syndrome can have on the patient's condition, especially if it is associated with acute pain and severe anemia. The present case suggests that laparoscopic surgery for potentially large malignant tumors is feasible and safe, but requires an appropriate medical and gynecological oncology expertise. |
5,318 | 434 | 17264115 | What is the effect of CRD-BP on the stability of c-myc mRNA? | CRD-BP shields c-myc and MDR-1 RNA from endonucleolytic attack by a mammalian endoribonuclease. The c-myc mRNA coding region determinant-binding protein (CRD-BP) has high affinity for the coding region determinant (CRD) of c-myc mRNA. Such affinity is believed to protect c-myc CRD from endonucleolytic attack. We have recently purified a mammalian endoribonuclease which can cleave within the c-myc CRD in vitro. The availability of this purified endonuclease has made it possible to directly test the interaction between CRD-BP and the endonuclease in regulating c-myc CRD RNA cleavage. In this study, we have identified the coding region of MDR-1 RNA as a new target for CRD-BP. CRD-BP has the same affinity for c-myc CRD nts 1705-1886 and MDR-1 RNA nts 746-962 with K(d) of 500 nM. The concentration-dependent affinity of CRD-BP to these transcripts correlated with the concentration-dependent blocking of endonuclease-mediated cleavage by CRD-BP. In contrast, three other recombinant proteins tested which had no affinity for c-myc CRD did not block endonuclease-mediated cleavage. Finally, we have identified RNA sequences required for CRD-BP binding. These results provide the first direct evidence that CRD-BP can indeed protect c-myc CRD cleavage initiated by an endoribonuclease, and the framework for further investigation into the interactions between CRD-BP, c-myc mRNA, MDR-1 mRNA and the endoribonuclease in cells. |
5,327 | 435 | 1432387 | What is the molecular function of psoralen photobinding on DNA? | Synthesis and photobiological activity of new methylpsoralen derivatives. The synthesis and the photobiological activity of two new derivatives of psoralen (3,4'-dimethylpsoralen and 3,4',8-trimethylpsoralen) has been described. They are congeners of the monofunctional linear furocoumarin 3,4'-dimethyl-8-methoxypsoralen. Both compounds bind very efficiently to DNA, the extent of this process being modulated by the nature of substituents at position 8. The number of photolesions is linearly related to adenine-thymine content of the nucleic acid which indicates lack of specificity for particular sequences of the nucleic acid. The structural arrangement of DNA (single stranded, double stranded, nucleosomes and chromatin) plays an additional role in affecting the photobinding process. Unlike their 8-methoxy congener the new derivatives cross-link DNA to a substantial extent. Their photobiological properties, including erythema formation, reflect very closely those of 8-methoxypsoralen (8-MOP). The conclusion can be drawn that 3,4'-dimethyl-8-MOP represents a unique derivative in its family. |
5,336 | 436 | 17327733 | Is progesterone effective for treatment of patients with traumatic brain injury based on clinical trial data? | Neuroprotection in traumatic brain injury: a complex struggle against the biology of nature. PURPOSE OF REVIEW: Translating the efficacy of neuroprotective agents in experimental traumatic brain injury to clinical benefit has proven an extremely complex and, to date, unsuccessful undertaking. The focus of this review is on neuroprotective agents that have recently been evaluated in clinical trials and are currently under clinical evaluation, as well as on those that appear promising and are likely to undergo clinical evaluation in the near future. RECENT FINDINGS: Excitatory neurotransmitter blockage and magnesium have recently been evaluated in phase III clinical trials, but showed no neuroprotective efficacy. Cyclosporin A, erythropoietin, progesterone and bradykinin antagonists are currently under clinical investigation, and appear promising. SUMMARY: Traumatic brain injury is a complex disease, and development of clinically effective neuroprotective agents is a difficult task. Experimental traumatic brain injury has provided numerous promising compounds, but to date these have not been translated into successful clinical trials. Continued research efforts are required to identify and test new neuroprotective agents, to develop a better understanding of the sequential activity of pathophysiologic mechanisms, and to improve the design and analysis of clinical trials, thereby optimizing chances for showing benefit in future clinical trials. |
5,363 | 437 | 19412431 | Is there a role for the cylindromatosis tumor suppressor (CYLD) in lung cancer? | Truncation of the catalytic domain of the cylindromatosis tumor suppressor impairs lung maturation. Cyld encodes a 956-amino acid deubiquitinating enzyme (CYLD), which is a negative regulator of nuclear factor kappaB and mitogen-activated protein kinase pathways. Mutations that truncate and inactivate the carboxyl-terminal deubiquitinating domain of CYLD underlie the development of skin appendage tumors in humans, whereas down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer. To establish an animal model of human CYLD inactivation and characterize the biological role of CYLD in vivo, we generated mice carrying a homozygous deletion of Cyld exon 9 (Cyld(Delta 9/Delta 9) mice) using a conditional approach. Deletion of exon 9 would cause a carboxyl-terminal truncation of CYLD and inactivation of its deubiquitinating activity. In accordance with previous studies, fibroblasts from Cyld(Delta 9/Delta 9) embryos had hyperactive nuclear factor kappaB and c-Jun kinase pathways compared with control fibroblasts. Cyld(Delta 9/Delta 9) newborn mice were smaller than wild-type littermates with a short and kinky tail and no major developmental defects. However, Cyld(Delta 9/Delta 9) mice died shortly after birth from apparent respiratory dysfunction. Histological examination of E18.5 Cyld(Delta 9/Delta 9) lungs demonstrated an immature phenotype characterized by hyperplasic mesenchyme but apparently normal epithelial, smooth muscle. and endothelial structures. Our study identifies an important role of CYLD in lung maturation, which may underlie the development of many cases of lung cancer. |
5,365 | 438 | 23526674 | Which medical diagnostic tests are used to test kidney function? | Acute kidney injury during vancomycin therapy in critically ill children. STUDY OBJECTIVE: To determine the rate, risk factors, and outcome of vancomycin-associated acute kidney injury (AKI) in critically ill children. DESIGN: Retrospective cohort study. SETTING: Tertiary care children's hospital. PATIENTS: We reviewed the charts of children admitted to the pediatric intensive care unit during a 2-year period who were treated with vancomycin. Courses of vancomycin interrupted by 3 days or more were counted separately. Patients were excluded if they received vancomycin treatment for fewer than 3 days, had preexisting renal failure, or had incomplete serum creatinine (Scr ) data. MEASUREMENTS AND MAIN RESULTS: Demographic and laboratory data; vancomycin dose, duration, and concentrations; and concurrent use of nephrotoxic drugs were recorded. Acute kidney injury was defined as a decrease in estimated glomerular filtration rate of 50% or more from the beginning of vancomycin therapy. Descriptive statistics, step-wise logistic regression, and repeated measures ANOVA were used to analyze the data. A total of 284 patients were included, for a total of 391 courses of vancomycin (272 children and 119 infants). The mean duration of vancomycin therapy was 6.9 ± 4.5 days. Forty nine (17.2%) patients developed AKI during 61 (15.6%) courses. Elevated Scr concentrations returned to baseline after stopping vancomycin in 53 (87%) courses. Mortality was higher in children who developed AKI (p<0.001; Fisher's exact test). Administration of nephrotoxic drugs (odds ratio 2.23, Confidence Interval 1.27-3.93) and presence of high blood urea nitrogen (BUN):Scr ratio before vancomycin therapy (p<0.05) were associated with AKI. The BUN and Scr concentrations significantly increased during vancomycin therapy and decreased after vancomycin was discontinued (p<0.05). CONCLUSIONS: In critically ill children, the development of reversible AKI during vancomycin therapy is associated with administration of nephrotoxic drugs and an elevated BUN: Scr ratio. |
5,378 | 439 | 11005264 | Against which protein is the antibody used for immonostaining of Lewy bodies raised? | Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. Although alpha-synuclein (alpha-syn) has been implicated as a major component of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous and contain full-length alpha-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to defined regions throughout alpha-syn in immunohistochemical epitope mapping studies of GCIs in MSA brains. Although the immunostaining profile of GCIs with these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the alpha-syn epitopes detected in GCIs. Notably, carboxy-terminal alpha-syn epitopes were immunodominant in GCIs, but the entire panel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with LBs brain with similar intensity. While the distribution of alpha-syn labeled GCIs paralleled that previously reported using silver stains, antibodies to carboxy-terminal alpha-syn epitopes revealed a previously undescribed burden of GCIs in the MSA hippocampal formation. Finally, Western blots demonstrated detergent insoluble monomeric and high-molecular weight alpha-syn species in GCI rich MSA cerebellar white matter. Collectively, these data indicate that alpha-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may result from cell type specific conformational or post-translational permutations in alpha-syn. |
5,392 | 440 | 20932506 | Which are the main causes of fetal echogenic bowel? | Focus on cystic fibrosis and other disorders evidenced in fetuses with sonographic finding of echogenic bowel: 16-year report from Brittany, France. OBJECTIVE: Pregnancies medical follow-up and ultrasonography development have enabled detection of fetal echogenic bowel, a sign associated with various pathologies, including cystic fibrosis. Based on the long experience of a region where cystic fibrosis is frequent (Brittany, France), we describe disorders diagnosed in fetal echogenic bowel fetuses and assess ultrasonography ability in detecting cystic fibrosis in utero. STUDY DESIGN: We reviewed the cases of fetal echogenic bowel diagnosed in pregnant women living in Brittany and referred for CFTR gene analysis over the 1992-2007 period (n = 289). RESULTS: A disorder was diagnosed in 32.2% of the fetuses, cystic fibrosis being the most commonly identified (7.6%). We also found digestive malformations (7.0%), chromosomal abnormalities (3.7%), and maternofetal infections (3.7%). Combining these data with our ongoing newborn screening program since 1989 showed that ultrasonography enabled diagnosis of 10.7% of the cystic fibrosis cases. CONCLUSION: This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis. |
5,412 | 441 | 20167841 | How does trimetazidine affect intracellular kinase signaling in the heart? | Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. Trimetazidine [1-(2,3,4-trimethoxybenzyl)piperazine; TMZ] is an anti-ischemic cardiac drug; however, its efficacy and mechanism of cardioprotection upon reperfusion are largely unknown. The objective of this study was to determine whether TMZ, given before reperfusion, could attenuate myocardial reperfusion injury. Ischemia/reperfusion (I/R) was induced in rat hearts by ligating the left anterior descending (LAD) coronary artery for 30 min followed by 48 h of reperfusion. TMZ (5 mg/kg b.wt.) was administered 5 min before reperfusion. The study used three experimental groups: control (-I/R; -TMZ), I/R (+I/R; -TMZ), and TMZ (+I/R; +TMZ). Echocardiography and EPR oximetry were used to assess cardiac function and oxygenation, respectively. The ejection fraction, which was significantly depressed in the I/R group (62 +/- 5 versus 84 +/- 3% in control), was restored to 72 +/- 3% in the TMZ group. Myocardial pO2 in the TMZ group returned to baseline levels (approximately 20 mm Hg) within 1 h of reperfusion, whereas the I/R group showed a significant hyperoxygenation even after 48 h of reperfusion. The infarct size was significantly reduced in the TMZ group (26 +/- 3 versus 47 +/- 5% in I/R). TMZ treatment significantly attenuated superoxide levels in the tissue. Tissue homogenates showed a significant increase in p38 and p-Akt and decrease in caspase-3 levels in the TMZ group. In summary, the results demonstrated that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen-activated protein kinase and Akt signaling. The study emphasizes the importance of administering TMZ before reflow to prevent reperfusion-mediated cardiac injury and dysfunction. |
5,416 | 442 | 15998640 | Which is the enzymatic activity of the myotubularin family of proteins? | The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease type 4B (CMT4B) is a severe, demyelinating peripheral neuropathy characterized by distinctive, focally folded myelin sheaths. CMT4B is caused by recessively inherited mutations in either myotubularin-related 2 (MTMR2) or MTMR13 (also called SET-binding factor 2). MTMR2 encodes a member of the myotubularin family of phosphoinositide-3-phosphatases, which dephosphorylate phosphatidylinositol 3-phosphate (PI(3)P) and bisphosphate PI(3,5)P2. MTMR13 encodes a large, uncharacterized member of the myotubularin family. The MTMR13 phosphatase domain is catalytically inactive because the essential Cys and Arg residues are absent. Given the genetic association of both MTMR2 and MTMR13 with CMT4B, we investigated the biochemical relationship between these two proteins. We found that the endogenous MTMR2 and MTMR13 proteins are associated in human embryonic kidney 293 cells. MTMR2-MTMR13 association is mediated by coiled-coil sequences present in each protein. We also examined the cellular localization of MTMR2 and MTMR13 using fluorescence microscopy and subcellular fractionation. We found that (i) MTMR13 is a predominantly membrane-associated protein; (ii) MTMR2 and MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction; and (iii) MTMR13 membrane association is mediated by the segment of the protein which contains the pseudophosphatase domain. This work, which describes the first cellular or biochemical investigation of the MTMR13 pseudophosphatase protein, suggests that MTMR13 functions in association with MTMR2. Loss of MTMR13 function in CMT4B2 patients may lead to alterations in MTMR2 function and subsequent alterations in 3-phosphoinositide signaling. Such a mechanism would explain the strikingly similar phenotypes of patients with recessive mutations in either MTMR2 or MTMR13. |
5,448 | 443 | 15046306 | Can we detect DNA strand asymmetries using dinucleotide relative abundance "genomic signatures"? | Use of the genomic signature in bacterial classification and identification. In this study we investigated the correlation between dinucleotide relative abundance values (the genomic signature) obtained from bacterial whole-genome sequences and two parameters widely used for bacterial classification, 16S rDNA sequence similarity and DNA-DNA hybridisation values. Twenty-eight completely sequenced bacterial genomes were included in the study. The correlation between the genomic signature and DNA-DNA hybridisation values was high and taxa that showed less than 30% DNA-DNA binding will in general not have dinucleotide relative abundance dissimilarity (delta*) values below 40. On the other hand, taxa showing more than 50% DNA-DNA binding will not have delta* values higher than 17. Our data indicate that the overall correlation between genomic signature and 16S rDNA sequence similarity is low, except for closely related organisms (16S rDNA similarity >94%). Statistical analysis of delta* values between different subgroups of the Proteobacteria indicate that the beta- and gamma-Proteobacteria are more closely related to each other than to the other subgroups of the Proteobacteria and that the alpha- and epsilon-Proteobacteria form clearly separate subgroups. Using the genomic signature we have also predicted DNA-DNA binding values for fastidious or unculturable endosymbionts belonging to the genera Rickettsia, Wigglesworthia and Buchnera. |
5,458 | 444 | 19808991 | What is the percentage of responders to tetrabenazine treatment for dystonia in children? | A case of secondary dystonia responding to levodopa. The authors report a patient with dystonia secondary to bilateral lesions of the basal ganglia, who improved dramatically with levodopa. The patient presented at the age of 4 years with progressive dystonia of the lower extremities and right upper extremity. Magnetic resonance imaging (MRI) of the brain showed bilateral hyperintensities of the globus pallidus that remained stable over the years. Despite extensive investigations, the etiology of her basal ganglia lesions remained nebulous. The patient's dystonia responded to Trihexyphenidyl and to tetrabenazine, but these medications needed to be stopped because of side effects. At the age of 12 years, small doses of levodopa-carbidopa were tried and resulted in dramatic improvement of her dystonia. The authors believe that in the pediatric population with secondary dystonias other than Segawa disease, even though this has been reported only rarely to be effective, a therapeutic trial with levodopa should be considered in some instances. |
5,469 | 445 | 23824326 | Is there any relationship between histone ubiquitylation and splicing? | USP49 deubiquitinates histone H2B and regulates cotranscriptional pre-mRNA splicing. Post-translational histone modifications play important roles in regulating chromatin structure and function. Histone H2B ubiquitination and deubiquitination have been implicated in transcriptional regulation, but the function of H2B deubiquitination is not well defined, particularly in higher eukaryotes. Here we report the purification of ubiquitin-specific peptidase 49 (USP49) as a histone H2B-specific deubiquitinase and demonstrate that H2B deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons. USP49 forms a complex with RuvB-like1 (RVB1) and SUG1 and specifically deubiquitinates histone H2B in vitro and in vivo. USP49 knockdown results in small changes in gene expression but affects the abundance of >9000 isoforms. Exons down-regulated in USP49 knockdown cells show both elevated levels of alternative splicing and a general decrease in splicing efficiency. Importantly, USP49 is relatively enriched at this set of exons. USP49 knockdown increased H2B ubiquitination (uH2B) levels at these exons as well as upstream 3' and downstream 5' intronic splicing elements. Change in H2B ubiquitination level, as modulated by USP49, regulates U1A and U2B association with chromatin and binding to nascent pre-mRNA. Although H3 levels are relatively stable after USP49 depletion, H2B levels at these exons are dramatically increased, suggesting that uH2B may enhance nucleosome stability. Therefore, this study identifies USP49 as a histone H2B-specific deubiquitinase and uncovers a critical role for H2B deubiquitination in cotranscriptional pre-mRNA processing events. |
5,473 | 446 | 25404020 | Which disease can be treated with Delamanid? | Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Delamanid (Deltyba(®)), a nitroimidazo-oxazole derivative, is a new anti-tuberculosis (TB) drug which exhibits potent in vitro and in vivo antitubercular activity against drug-susceptible and -resistant strains of Mycobacterium tuberculosis. It is approved in several countries, including Japan and those of the EU, for use as part of an appropriate combination regimen in adults with multidrug-resistant tuberculosis (MDR-TB) when an effective treatment regimen cannot otherwise be composed due to resistance or tolerability. In a robust phase II trial in adult patients with MDR-TB, oral delamanid 100 mg twice daily for 2 months plus an optimized background regimen improved sputum culture conversion rates to a significantly greater extent than placebo. In a 6-month extension study, long-term (≤8 months) treatment with delamanid was associated with a higher incidence of favourable outcomes (i.e. cured or completed all treatment) than short-term (≤2 months) treatment, with an accompanying reduction inunfavourable outcomes as defined by the WHO (i.e. pre-specified proportion of TB-positive sputum cultures, death or treatment discontinuation for ≥2 months without medical approval). Delamanid was not associated with clinically relevant drug-drug interactions, including with antiretroviral drugs and those commonly used in treating TB. Delamanid was generally well tolerated in patients with MDR-TB, with gastrointestinal adverse events and insomnia reported most commonly. Although the incidence of QT interval prolongation was higher with delamanid-based therapy, it was not associated with clinical symptoms such as syncope and arrhythmia. In conclusion, delamanid is a useful addition to the treatment options currently available for patients with MDR-TB. |
5,478 | 447 | 21772967 | What was the aim of the COSS (Carotid Occlusion Surgery Study) clinical trial? | Intracranial atherosclerotic disease. Intracranial atherosclerotic disease (ICAD) is the most common proximate mechanism of ischemic stroke worldwide. Approximately half of those affected are Asians. For diagnosis of ICAD, intra-arterial angiography is the gold standard to identify extent of stenosis. However, noninvasive techniques including transcranial ultrasound and MRA are now emerging as reliable modalities to exclude moderate to severe (50%-99%) stenosis. Little is known about measures for primary prevention of the disease. In terms of secondary prevention of stroke due to intracranial atherosclerotic stenosis, aspirin continues to be the preferred antiplatelet agent although clopidogrel along with aspirin has shown promise in the acute phase. Among Asians, cilostazol has shown a favorable effect on symptomatic stenosis and is of benefit in terms of fewer bleeds. Moreover, aggressive risk factor management alone and in combination with dual antiplatelets been shown to be most effective in this group of patients. Interventional trials on intracranial atherosclerotic stenosis have so far only been carried out among Caucasians and have not yielded consistent results. Since the Asian population is known to be preferentially effected, focused trials need to be performed to establish treatment modalities that are most effective in this population. |
5,488 | 448 | 17652096 | What are the advantages of the top down mass spectrometric analysis of histones? | Global assessment of combinatorial post-translational modification of core histones in yeast using contemporary mass spectrometry. LYS4 trimethylation correlates with degree of acetylation on the same H3 tail. A global view of all core histones in yeast is provided by tandem mass spectrometry of intact histones H2A, H2B, H4, and H3. This allowed detailed characterization of >50 distinct histone forms and their semiquantitative assessment in the deletion mutants gcn5Delta, spt7Delta, ahc1Delta, and rtg2Delta, affecting the chromatin remodeling complexes SAGA, SLIK, and ADA. The "top down" mass spectrometry approach detected dramatic decreases in acetylation on H3 and H2B in gcn5Delta cells versus wild type. For H3 in wild type cells, tandem mass spectrometry revealed a direct correlation between increases of Lys(4) trimethylation and the 0, 1, 2, and 3 acetylation states of histone H3. The results show a wide swing from 10 to 80% Lys(4) trimethylation levels on those H3 tails harboring 0 or 3 acetylations, respectively. Reciprocity between these chromatin marks was apparent, since gcn5Delta cells showed a 30% decrease in trimethylation levels on Lys(4) in addition to a decrease of acetylation levels on H3 in bulk chromatin. Deletion of Set1, the Lys(4) methyltransferase, was associated with the linked disappearance of both Lys(4) methylation and Lys(14) and Lys(18) or Lys(23) acetylation on H3. In sum, we have defined the "basis set" of histone forms present in yeast chromatin using a current mass spectrometric approach that both quickly profiles global changes and directly probes the connectivity of modifications on the same histone. |
5,508 | 449 | 26155517 | What is situs inversus? | Splenic Injury in Situs Inversus Totalis - A Surgical Challenge. Situs inversus totalis is a rare congenital anomaly in which position of the heart and all abdominal viscera is reversed. Situs abnormalities usually go unnoticed but may be recognized by radiography or ultrasonography as an incidental finding or during evaluation for congenital heart diseases. We present such an extremely rare and to the best of our knowledge the third reported case of an injured spleen in the right hypochondrium, following seemingly trivial blunt trauma in a patient with situs inversus totalis who underwent splenectomy. The presence of associated congenital heart defects, visceral anatomical variations and mirror imaging makes the anaesthetic management as well as the surgical exercise a challenging one in such cases. |
5,516 | 450 | 10995744 | Can SUMO affect calcium homeostasis? | Identification and characterization of a SUMO-1 conjugation system that modifies neuronal calcium/calmodulin-dependent protein kinase II in Drosophila melanogaster. Drosophila Uba2 and Ubc9 SUMO-1 conjugation enzyme homologs (DmUba2 and DmUbc9) were isolated as calcium/calmodulin-dependent kinase II (CaMKII) interacting proteins by yeast two-hybrid screening of an adult head cDNA library. We found that at least one isoform of Drosophila neuronal CaMKII is conjugated to DmSUMO-1 in vivo. The interactions observed in the two-hybrid screen may therefore reflect catalytic events. To understand the role of SUMO conjugation in the brain, we undertook a characterization of the system. The other required components of the system, Drosophila Aos1 and SUMO-1 (DmAos1 and DmSUMO-1), were identified in expressed sequence tag data base searches. Purified recombinant DmUba2/DmAos1 dimer can activate DmSUMO-1 in vitro and transfer DmSUMO-1 to recombinant DmUbc9. DmSUMO-1 conjugation occurs in all developmental stages of Drosophila and in the adult central nervous system. Overexpression of a putative dominant negative DmUba2(C175S) mutant protein in the Drosophila central nervous system resulted in an increase in overall DmSUMO-1 conjugates and a base-sensitive p120 species, which is likely to be DmUba2(C175S) linked to endogenous DmSUMO-1 through an oxygen ester bond. Overexpression of DmUba2(wt) protein in vivo also led to increased levels of DmSUMO-1 conjugates. High level overexpression of either DmUba2(wt) or DmUba2(C175S) in the Drosophila central nervous system caused pupal and earlier stage lethality. Expression in the developing eye led to a rough eye phenotype with retinal degeneration. These results suggest that normal SUMO conjugation is essential in the differentiated nervous system and reveal a potential novel mechanism that regulates neuronal calcium/calmodulin-dependent protein kinase II function. |
5,520 | 451 | 12460666 | What is the indication of Daonil (Glibenclamide)? | Opening of potassium channels modulates mitochondrial function in rat skeletal muscle. We have investigated the presence of diazoxide- and nicorandil-activated K+ channels in rat skeletal muscle. Activation of potassium transport in the rat skeletal muscle myoblast cell line L6 caused a stimulation of cellular oxygen consumption, implying a mitochondrial effect. Working with isolated rat skeletal muscle mitochondria, both potassium channel openers (KCOs) stimulate respiration, depolarize the mitochondrial inner membrane and lead to oxidation of the mitochondrial NAD-system in a strict potassium-dependent manner. This is a strong indication for KCO-mediated stimulation of potassium transport at the mitochondrial inner membrane. Moreover, the potassium-specific effects of both diazoxide and nicorandil on oxidative phosphorylation in skeletal muscle mitochondria were completely abolished by the antidiabetic sulfonylurea derivative glibenclamide, a well-known inhibitor of ATP-regulated potassium channels (K(ATP) channels). Since both diazoxide and nicorandil facilitated swelling of de-energised mitochondria in KSCN buffer at the same concentrations, our results implicate the presence of a mitochondrial ATP-regulated potassium channel (mitoK(ATP) channel) in rat skeletal muscle which can modulate mitochondrial oxidative phosphorylation. |
5,526 | 452 | 10748089 | Which is the most typical peptide sequence responsible for retrieval of endoplasmic reticulum (ER) lumenal proteins from the Golgi apparatus? | A single C-terminal peptide segment mediates both membrane association and localization of lysyl hydroxylase in the endoplasmic reticulum. Hydroxylation of lysyl residues is crucial for the unique glycosylation pattern found in collagens and for the mechanical strength of fully assembled extracellular collagen fibers. Hydroxylation is catalyzed in the lumen of the endoplasmic reticulum (ER) by a specific enzyme, lysyl hydroxylase (LH). The absence of the known ER-specific retrieval motifs in its primary structure and its association with the ER membranes in vivo have suggested that the enzyme is localized in the ER via a novel retention/retrieval mechanism. We have identified here a 40-amino acid C-terminal peptide segment of LH that is able to convert cathepsin D, normally a soluble lysosomal protease, into a membrane-associated protein. The same segment also markedly slows down the transport of the reporter protein from the ER into post-ER compartments, as assessed by our pulse-chase experiments. The retardation efficiency mediated by this C-terminal peptide segment is comparable with that of the intact LH but lower than that of the KDEL receptor-based retrieval mechanism. Within this 40-amino acid segment, the first 25 amino acids appear to be the most crucial ones in terms of membrane association and ER localization, because the last 15 C-terminal amino acids did not possess substantial retardation activity alone. Our findings thus define a short peptide segment very close to the extreme C terminus of LH as the only necessary determinant both for its membrane association and localization in the ER. |
5,534 | 453 | 11473953 | What are the clinical trial outcomes of metformin use in polycystic ovary disease? | Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. BACKGROUND: Metformin, an insulin-sensitizing agent, has been used successfully as the first-line drug to induce ovulation in women with polycystic ovary syndrome. There are, however, very few studies evaluating metformin treatment in women with clomiphene citrate (CC)-resistant polycystic ovaries (PCO). METHODS: Twenty infertile Chinese women aged <40 years, who had ultrasound features of PCO and remained anovulatory on CC, were randomized by computer using the sealed envelope method to receive placebo or metformin 500 mg three times a day for 3 months. Hormonal and metabolic profiles were determined before the therapy and were repeated after 3 months for women who failed to become pregnant within this period. Clomiphene was then added for one cycle to those women who did not ovulate after taking placebo or metformin alone. RESULTS: The median ovulation rate in the placebo group was 0% (range: 0--50%) after placebo only and 6.9% (range: 0--50%) after placebo and CC, whereas the corresponding rates in the metformin group were 0% (range: 0--22%) and 0% (range: 0--22%) respectively. There was no improvement in the ovulation rate despite a significant reduction of body mass index, serum testosterone and fasting leptin concentrations in the metformin group. CONCLUSIONS: Metformin treatment may result in successful ovulation only in certain subgroups of these women. |
5,543 | 454 | 23728546 | List the main proteases used for sample digestion in proteomics. | Dried blood spot proteomics: surface extraction of endogenous proteins coupled with automated sample preparation and mass spectrometry analysis. Dried blood spots offer many advantages as a sample format including ease and safety of transport and handling. To date, the majority of mass spectrometry analyses of dried blood spots have focused on small molecules or hemoglobin. However, dried blood spots are a potentially rich source of protein biomarkers, an area that has been overlooked. To address this issue, we have applied an untargeted bottom-up proteomics approach to the analysis of dried blood spots. We present an automated and integrated method for extraction of endogenous proteins from the surface of dried blood spots and sample preparation via trypsin digestion by use of the Advion Biosciences Triversa Nanomate robotic platform. Liquid chromatography tandem mass spectrometry of the resulting digests enabled identification of 120 proteins from a single dried blood spot. The proteins identified cross a concentration range of four orders of magnitude. The method is evaluated and the results discussed in terms of the proteins identified and their potential use as biomarkers in screening programs. |
5,564 | 455 | 18707026 | Which proteins act as factors that promote transcription-coupled repair in bacteria? | Effects of the bacterial transcription-repair coupling factor during transcription of DNA containing non-bulky lesions. Transcription-coupled DNA repair is a mechanism by which bulky DNA lesions that block transcription by RNA polymerase are prioritised for removal by the nucleotide excision repair apparatus. The trigger is thought to be the presence of an irreversibly blocked transcription complex, which is recognised by a transcription-repair coupling factor. Many common DNA lesions do not block transcription, but are bypassed with varying degrees of efficiency and with potentially mutagenic effects on the RNA transcripts that are produced. The effect of the bacterial transcription-repair coupling factor, Mfd, at such lesions is not known: it has been suggested that Mfd may promote mutagenesis by increasing the efficiency with which RNA polymerase bypasses non-bulky lesions, but it has also been reported that 8-oxoguanine, a major product of oxidative DNA damage that is efficiently bypassed by RNA polymerase, is subject to Mfd-dependent transcription-coupled repair in Escherichia coli. We have investigated the effect of Mfd during transcription of templates containing 8-oxoguanine, and various other non-bulky lesions. We show that an 8-oxoguanine in the template strand induces a transient pause in transcription, and that Mfd neither increases nor decreases the efficiency with which RNA polymerase bypasses the lesion. We also show that Mfd can displace a transcription complex stalled at a single strand nick, and that it decreases the efficiency with which RNA polymerase bypasses an abasic site. These activities are not affected by transcription rate, as similar results were obtained using "fast" and "slow" mutant RNA polymerases. Our findings suggest that 8-oxoguanine is unlikely to be directly targeted by the transcription-coupled repair pathway, and identify a potential role for Mfd in reducing the level of transcriptional mutagenesis caused by abasic sites. |
5,585 | 456 | 12947243 | What is the association between Generalized anxiety disorder and mortality risk? | Anxiety disorders in late life: an evolving picture. Although anxiety disorders are the most prevalent group of disorders in the United States, little is known about the efficacy of treatments for these disorders in elderly patients. Anxiety disorders, especially generalized anxiety disorder and phobias, are highly prevalent in older people. Anxiety symptoms and disorders are associated with increased mortality and disability in older people. Risk factors for anxiety disorders include chronic medical illness, disability, low education, low social network, and poor social support. The newer antidepressant medications, in particular the selective serotonin reuptake inhibitors and venlafaxine-extended relief, are recommended as first-line pharmacotherapy of these disorders in elderly. Cognitive-behavioral therapy is recommended as first-line psychotherapy for these disorders. However, these recommendations are based on extrapolation of data from younger adults or retrospective analysis of datasets, the results need to be confirmed with controlled studies in an elderly age group. |
5,596 | 457 | 21824072 | Which molecule is targeted by a monoclonal antibody Mepolizumab? | Current update on eosinophilic lung diseases and anti-IL-5 treatment. Peripheral blood eosinophilia and eosinophilic lung inflammation are common in a variety of pulmonary conditions, including eosinophilic pneumonia and asthma, hypereosinophilic syndrome and Churg-Strauss syndrome. Therapy in most of these clinical entities consists of long-term treatment with systemic corticosteroids, which is not always successful and has substantial side-effects. Interest has increased considerably regarding alternative corticosteroid-sparing "smart" regimens in these diseases that target IL-5, an important regulator of eosinophilic development and function. To date, two humanized monoclonal antibodies, mepolizumab and reslizumab, have been developed that bind to human IL-5. In addition a new monoclonal antibody (MEDI-563) has been recently developed targeting the IL-5 receptor. This review will investigate the current status on IL-5 targeted therapy and related patents regarding eosinophil-driven respiratory diseases, primarily eosinophilic asthma but also CSS and HES. Recent advances and information from clinical trials will be presented in a way that will allow the reader to approach the role of the eosinophil in the lung diseases presented in this review. |
5,640 | 458 | 24696509 | Which is the major symptom of the Doose syndrome? | EEG-fMRI in myoclonic astatic epilepsy (Doose syndrome). OBJECTIVE: To identify neuronal networks underlying generalized spike and wave discharges (GSW) in myoclonic astatic epilepsy (MAE). METHODS: Simultaneous EEG-fMRI recordings were performed in 13 children with MAE. Individual GSW-associated blood oxygenation level-dependent (BOLD) signal changes were analyzed in every patient. A group analysis was performed to determine common syndrome-specific hemodynamic changes across all patients. RESULTS: GSW were recorded in 11 patients, all showing GSW-associated BOLD signal changes. Activation was detected in the thalamus (all patients), premotor cortex (6 patients), and putamen (6 patients). Deactivation was found in the default mode areas (7 patients). The group analysis confirmed activations in the thalamus, premotor cortex, putamen, and cerebellum and deactivations in the default mode network. CONCLUSIONS: In addition to the thalamocortical network, which is commonly found in idiopathic generalized epilepsies, GSW in patients with MAE are characterized by BOLD signal changes in brain structures associated with motor function. The results are in line with animal studies demonstrating that somatosensory cortex, putamen, and cerebellum are involved in the generation of myoclonic seizures. The involvement of these structures might predispose to the typical seizure semiology of myoclonic jerks observed in MAE. |
5,663 | 459 | 17035524 | Have mutations in the GARS gene been identified to cause Charcot-Marie-Tooth Disease Type 2D (CMT2D)? | Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal neuropathies characterized by a phenotype that is more severe in the upper extremities. We previously implicated mutations in the gene encoding glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V. GARS is a member of the family of aminoacyl-tRNA synthetases responsible for charging tRNA with cognate amino acids; GARS ligates glycine to tRNA(Gly). Here, we present functional analyses of disease-associated GARS mutations and show that there are not any significant mutation-associated changes in GARS expression levels; that the majority of identified GARS mutations modeled in yeast severely impair viability; and that, in most cases, mutant GARS protein mislocalizes in neuronal cells. Indeed, four of the five mutations studied show loss-of-function features in at least one assay, suggesting that tRNA-charging deficits play a role in disease pathogenesis. Finally, we detected endogenous GARS-associated granules in the neurite projections of cultured neurons and in the peripheral nerve axons of normal human tissue. These data are particularly important in light of the recent identification of CMT-associated mutations in another tRNA synthetase gene [YARS (tyrosyl-tRNA synthetase gene)]. Together, these findings suggest that tRNA-charging enzymes play a key role in maintaining peripheral axons. |
5,674 | 460 | 7529539 | Which treatment leads to an increase in neutrophil counts in severe congenital neutropenia? | Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias. Congenital neutropenias include a heterogenous group of diseases characterized by a decrease in circulating neutrophils. In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections. We report the effects of long-term safety of subcutaneous r-metHuG-CSF administration in 54 patients (congenital n = 44. cyclic n = 10) treated for 4-6 years. A sustained ANC response was seen in 40/44 severe congenital neutropenia patients and 10/10 cyclic neutropenia patients. Two patients required an increase of > 25% in dose to maintain a clinical response; one patient became refractory to therapy. A significant decrease in the incidence of severe infections and the need for intravenous antibiotics was noted. Significant adverse events noted which may or may not be related to therapy included: osteopenia (n = 15), splenomegaly (n = 12), hypersplenism (n = 1), vasculitis (n = 2), glomerulonephritis (n = 1), BM fibrosis (n = 2), MDS/leukaemia (n = 3), and transient inverted chromosome 5q with excess blasts (n = 1). R-metHuG-CSF has been well tolerated in the majority of patients and resulted in a long-term improvement in their clinical status. |
5,681 | 461 | 10482963 | Which genes are affected in ROMANO-WARD syndrome? | Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene. We describe a Swedish family with the proband and his brother suffering from severe Romano-Ward syndome (RWS) associated with compound heterozygosity for two mutations in the KVLQT1 (also known as KCNQ1 and KCNA9) gene (R518X and A525T). The mutations were found to segregate as heterozygotes in the maternal and the paternal lineage, respectively. None of the heterozygotes exhibited clinical long QT syndrome (LQTS). No hearing defects were found in the proband. The data strongly indicates that the compound heterozygosity for R518X and A525T is the cause of an autosomal recessive form of RWS in this family. Our findings support the implication of a higher frequency of gene carriers than previously expected. We suggest that relatives of 'sporadic RWS' patients should be considered potential carriers, at risk of dying suddenly from drug-induced LQTS. |
5,712 | 462 | 1920508 | Does melanoma occur in people of African origin ? | Primary malignant skin tumors in Nigerians. Skin cancers, although uncommon, do occur in black Africans. Available literature on this subject from black African populations is scant, suggesting diminished interest. Eighteen cases of malignant skin tumors seen at the University of Port Harcourt Teaching Hospital over 3 years (1984 to 1987) were analyzed for diagnoses, site of tumors, sex, and age. Seven patients (39%) had malignant melanomas affecting only the soles of the feet, while the same number had squamous cell carcinomas widely distributed in various parts of the body. Basal cell carcinomas were found in four (22%) patients with face lesions. Only three albinos were in the series, and all three had squamous cell carcinomas. Melanin protection against sun-induced skin cancers gives a false sense of well-being. The need for renewed interest of the subject is emphasized. |
5,731 | 463 | 23272906 | What is the effect of resveratrol on mTOR activity? | Targeting mTOR: evaluating the therapeutic potential of resveratrol for cancer treatment. Resveratrol (3,4',5-trihydroxystilbene; RSV), a natural polyphenol found in a variety of daily food including grapes and red wine, has long been suspected to have multifaceted health beneficial properties, including anti-inflammation, anti-oxidant, and anticancer activities. Over the past few years, numerous studies have suggested that suppressing the activity of mammalian target of rapamycin (mTOR), a critical regulator of cell metabolism, growth, and proliferation, may provide a key mechanism underlying the anticarcinogenic properties of resveratrol. It has been found that resveratrol targets multiple components of the phosphatidylinositol 3- kinase(PI3K)/Akt and mTOR signaling pathways, including PI3K, Akt, PTEN, and DEPTOR, suggesting that this natural compound and its derivatives may offer a promising new cancer treatment. In the current review, we discuss recent findings on the molecular mechanisms regulating mTOR signaling and the therapeutic potential of resveratrol for cancer treatment by targeting mTOR. |
5,749 | 464 | 22771625 | Are people with blood group O protected against severe Malaria? | Differential carbonylation of cytoskeletal proteins in blood group O erythrocytes: potential role in protection against severe malaria. The molecular basis for the prevalence of blood group O in regions where malaria is endemic remains unclear. In some genetic backgrounds oxidative modifications have been linked to a reduced susceptibility to severe malaria disease. Through redox proteomics, we detected differences in carbonylated membrane proteins among the different blood groups, both in Plasmodium-infected and uninfected erythrocytes (RBC). Carbonylation profiles of RBC membrane proteins revealed that group O blood shows a reduced protein oxidation pattern compared to groups A, B and AB. Upon infection with Plasmodium falciparum Dd2, erythrocytes of all blood groups showed increased oxidation of membrane proteins. By examining 4-hydroxy-2-nonenal (4-HNE) modified proteins by LC-MS/MS (liquid chromatography/mass spectrometry) we observed that, upon malaria infection, the protein components of lipid rafts and cytoskeleton were the main targets of 4-HNE carbonylation in all blood groups. Ankyrins and protein bands 4.2 and 4.1 were differentially carbonylated in group O as compared to A and B groups. During trophozoite maturation in group O erythrocytes, a steady increase was observed in the number of 4-HNE-modified proteins, suggesting a parasite-driven 4-HNE-carbonylation process. Our findings indicate a possible correlation between the protection against severe malaria in blood group O individuals and a specific pattern of 4-HNE-carbonylation of cytoskeleton proteins. |
5,754 | 465 | 21117539 | Which eye condition is managed by the athens protocol? | Management of corneal ectasia after LASIK with combined, same-day, topography-guided partial transepithelial PRK and collagen cross-linking: the athens protocol. PURPOSE: To evaluate a series of patients with corneal ectasia after LASIK that underwent the Athens Protocol: combined topography-guided photorefractive keratectomy (PRK) to reduce or eliminate induced myopia and astigmatism followed by sequential, same-day ultraviolet A (UVA) corneal collagen cross-linking (CXL). METHODS: Thirty-two consecutive corneal ectasia cases underwent transepithelial PRK (WaveLight ALLEGRETTO) immediately followed by CXL (3 mW/cm(2)) for 30 minutes using 0.1% topical riboflavin sodium phosphate. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction spherical equivalent, keratometry, central ultrasonic pachymetry, corneal tomography (Oculus Pentacam), and endothelial cell counts were analyzed. Mean follow-up was 27 months (range: 6 to 59 months). RESULTS: Twenty-seven of 32 eyes had an improvement in UDVA and CDVA of 20/45 or better (2.25 logMAR) at last follow-up. Four eyes showed some topographic improvement but no improvement in CDVA. One of the treated eyes required a subsequent penetrating keratoplasty. Corneal haze grade 2 was present in 2 eyes. CONCLUSIONS: Combined, same-day, topography-guided PRK and CXL appeared to offer tomographic stability, even after long-term follow-up. Only 2 of 32 eyes had corneal ectasia progression after the intervention. Seventeen of 32 eyes appeared to have improvement in UDVA and CDVA with follow-up >1.5 years. This technique may offer an alternative in the management of iatrogenic corneal ectasia. |
5,759 | 466 | 16155579 | What is the role of AMPK kinase in myocardial remodeling after myocardial infarction | Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E(2) in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms. |
5,764 | 467 | 24101429 | What is the mechanism of action of solanezumab? | [The DIAN study]. The DIAN study compared the pathophysiological markers between carriers and non-carriers of mutation for autosomal dominant Alzheimer's disease (AD). They used the participant's age at baseline assessment and the parent's age at the onset of symptoms of AD to calculate the estimated delay in symptom onset. The study revealed that the biomarker change, which is the reduction of Aβ42 in the CSF of the carrier's brain, started approximately 15-20 years prior to the onset of symptoms. Subsequently, a chronological series of events took place: deposition of fibrillar Aβ as measured by positron emission tomography with the use of Pittsburgh compound B, increase in tau protein in the CSF, hippocampal atrophy and hypometabolism of FDG-PET, and cognitive and clinical changes. The researchers planned to start the prevention trial with 2 monoclonal antibodies and a BACE inhibitor. In contrast, the API study is the clinical trial of the anti-amyloid monoclonal antibody therapy associated with the early-onset familial AD (EOAD), which carries the PSEN1 E280A mutation. This study also showed changes in the same biomarker as reported in the DIAN study. Anti-amyloid treatment in asymptomatic AD (A4) is a prevention trial aimed at treating older individuals with normal cognition but at risk of developing AD dementia on the basis of having biomarker evidence of amyloid (preclinical AD). They selected solanezumab for the anti-amyloid treatment for A4. |
5,793 | 468 | 22696272 | What are the major clinical Villefranche criteria for classic Ehlers-Danlos syndrome? | Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major--if not only--cause of classic EDS. |
5,794 | 469 | 22401313 | What is the treatment of neuropathic pain in children? | Continuous intravenous infusion of ketamine and lidocaine as adjuvant analgesics in a 5-year-old patient with neuropathic cancer pain. For difficult to treat neuropathic pain from cancer, adjuvant analgesics are often used with opioids. We present the case of a 5-year-old girl who was diagnosed with meningitis caused by malignant T-cell lymphoma. She had severe neuropathic pain not relieved by increasing doses of a fentanyl infusion. Intravenous administration of ketamine and lidocaine in combination with fentanyl provided excellent analgesia without significant side effects. Ketamine and lidocaine can be safely infused together with concomitant opioids for the treatment of refractory neuropathic pain caused by cancer. |
5,804 | 470 | 16901476 | Which phenomenon is known as the "calcium paradox" in the isolated perfused heart? | MAPK activation and apoptotic alterations in hearts subjected to calcium paradox are attenuated by taurine. OBJECTIVE: The Ca2+ -paradox is an important phenomenon to study cell injury induced by Ca2+ -overload in myocardium. Although intracellular Ca2+ -overload acts as a trigger and modulator of cell death due to apoptosis under various pathophysiological conditions, the presence of apoptosis in hearts subjected to Ca2+ -paradox has not been demonstrated. Since taurine attenuates the changes in cardiac function due to Ca2+ -paradox, this study investigated the occurrence and mechanisms of apoptosis in Ca2+ -paradoxic hearts treated in the absence and presence of taurine. METHODS: Ca2+ -paradox was induced by perfusing the isolated rat heart with Ca2+ -free medium for 5 min followed by reperfusion with Ca2+ -containing medium for 30 min. Apoptosis related signal transduction mechanisms were determined in Ca2+ -paradoxic hearts perfused with or without 10 mM taurine. RESULTS: Marked alterations in cardiac function and the presence of apoptosis were seen in Ca2+ -paradoxic hearts reperfused for 30 min. Unlike the total protein contents in hearts subjected to Ca2+ -paradox, the contents of phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase (ERK)1, ERK2 and c-jun amino-terminal kinase were increased by 125 +/- 8.6%, 296 +/- 14.3%, 213 +/- 8.5% and 133 +/- 4.2%, respectively vs. control. Caspase-3 and phosphorylated Bcl-2 contents were also increased by 193 +/- 10.2% and 134 +/- 5.0% vs. control whereas phosphorylated Bad and the ratio of Bcl-2/Bad were depressed by 32 +/- 10.8% and 0.23 +/- 0.5% vs. control in Ca2+ -paradoxic hearts. The apoptosis as seen in Ca2+ -paradoxic hearts reperfused for 30 min was not evident in hearts at 10 min Ca2+ -repletion but was similar to hearts subjected to 60 min Ca2+ -repletion. These changes in the apoptotic pathway in cardiomyocytes subjected to Ca2+ -paradox were prevented by taurine. Furthermore, taurine attenuated the KCl- or ATP-induced increase in intracellular concentration of Ca2+ in cardiomyocytes. CONCLUSIONS: This study suggests that cardiac dysfunction due to Ca2+ -paradox may be associated with apoptosis. In addition, the beneficial effects of taurine on cardiac function may be related to the attenuation of changes in MAPK and apoptotic signal transduction mechanisms in Ca2+ -paradoxic hearts. |
5,813 | 471 | 22365326 | Is there a crystal structure of the full-length of the flaviviridae NS5(Methyltransferase - RNA depended RNA Polymerase) ? | Point mutations in the West Nile virus (Flaviviridae; Flavivirus) RNA-dependent RNA polymerase alter viral fitness in a host-dependent manner in vitro and in vivo. The West Nile virus (WNV) genome contains a single RNA-dependent RNA polymerase (RdRp) gene, which is responsible for replication of the viral genome and, as such, is an important target for antiviral therapy. Viral RdRps are known to lack proofreading capabilities and as a result viruses such as WNV exist as a mixture of viral genotypes within an infection, enabling the virus to readily emerge and adapt to new host environments. To test the consequences of subtle structural alterations remote from the RdRp active-site, the following single point mutations were engineered in the WNV NS5 RdRp coding region: T363N, A365N, and T537I; these mutations were selected in an effort to stabilize the secondary structural elements near the rNTP binding pocket of the RdRp. Mutant viruses were tested in vitro on Vero, C6/36, Culex tarsalis and DF-1 cell types and in vivo in one day old chickens and Culex pipiens mosquitoes. Plaque morphology was affected by each mutation and growth and RNA replication kinetics were altered as well. Our results demonstrate that subtle alteration of the RdRp protein away from the active site can have a significant overall biological effect on WNV fitness, and that this effect can be host-dependent. |
5,819 | 472 | 10358092 | How do Hsp70 and Hsp110 affect mRNA stability? | Mammalian Hsp70 and Hsp110 proteins bind to RNA motifs involved in mRNA stability. In this study, in vitro RNA binding by members of the mammalian 70-kDa heat shock protein (Hsp) family was examined. We show that Hsp/Hsc70 and Hsp110 proteins preferentially bound AU-rich RNA in vitro. Inhibition of RNA binding by ATP suggested the involvement of the N-terminal ATP-binding domain. By using deletion mutants of Hsp110 protein, a diverged Hsp70 family member, RNA binding was localized to the N-terminal ATP-binding domain of the molecule. The C-terminal peptide-binding domain did not bind RNA, but its engagement by a peptide substrate abrogated RNA binding by the N terminus of the protein. Interestingly, removal of the C-terminal alpha-helical structure or the alpha-loop domain unique to Hsp110 immediately downstream of the peptide-binding domain, but not both, resulted in considerably increased RNA binding as compared with the wild type protein. Finally, a 70-kDa activity was immunoprecipitated from RNA-protein complexes formed in vitro between cytoplasmic proteins of human lymphocytes and AU-rich RNA. These findings support the idea that certain heat shock proteins may act as RNA-binding entities in vivo to guide the appropriate folding of RNA substrates for subsequent regulatory processes such as mRNA degradation and/or translation. |
5,820 | 473 | 17076904 | What is Prudent Diet? | Dietary patterns and associated lifestyles in individuals with and without familial history of obesity: a cross-sectional study. BACKGROUND: Familial history of obesity (FHO) and certain dietary habits are risk factors for obesity. The objectives of this cross-sectional study were 1) to derive dietary patterns using factor analysis in a population of men and women with and without FHO; 2) to compare mean factor scores for each dietary pattern between individuals with and without FHO; and 3) to examine the association between these patterns and anthropometric, lifestyle and sociodemographic variables. METHODS: A total of 197 women and 129 men with a body mass index <30 kg/m2 were recruited. A positive FHO (FHO+) was defined as having at least one obese first-degree relative and a negative FHO (FHO-) as no obese first-degree relative. Dietary data were collected from a food frequency questionnaire. Factor analysis was performed to derive dietary patterns. Mean factor scores were compared using general linear model among men and women according to FHO. Regression analyses were performed to study the relationship between anthropometric, lifestyle and sociodemographic variables, and each dietary pattern. RESULTS: Two dietary patterns were identified in both men and women : the Western pattern characterized by a higher consumption of red meats, poultry, processed meats, refined grains as well as desserts, and the Prudent pattern characterized by greater intakes of vegetables, fruits, non-hydrogenated fat, and fish and seafood. Similar Western and Prudent factor scores were observed in individual with and without FHO. In men with FHO+, the Western pattern is negatively associated with age and positively associated with physical activity, smoking, and personal income. In women with FHO-, the Prudent pattern is negatively associated with BMI and smoking and these pattern is positively associated with age and physical activity. CONCLUSION: Two dietary patterns have been identified among men and women with and without FHO. Although that FHO does not seem to influence the adherence to dietary patterns, results of this study suggest that anthropometric, lifestyle and sociodemographic variables associated with dietary patterns differ according to FHO and gender. |
5,850 | 474 | 23875666 | What is the role of necroptosis in cancer therapy? | The role of necroptosis, an alternative form of cell death, in cancer therapy. Programmed cell death plays an important role in animal development, tissue homeostasis and eliminating harmful or virally infected cells. Necroptosis, a novel form of programmed cell death, is caspase independent but RIPK and RIPK3 dependent. Moreover, it is suggested that necroptosis can be specifically inhibited by small molecular inhibitors such as necrostatin-1. Its signaling pathways have something in common with apoptosis, although the molecular mechanisms of necroptosis need to be further elucidated. Previous evidences suggest that necroptosis has significant effects in regulating various physiological processes and disease, such as ischemic brain injury, immune system disorders and cancer. In this review, the molecular mechanism of necroptosis is described and how it could be manipulated in the treatment of cancer is summarized. |
5,854 | 475 | 10490914 | Can venlafaxine block NET and SERT? | Mechanism of sodium channel block by venlafaxine in guinea pig ventricular myocytes. Venlafaxine is a newly introduced antidepressant agent. The drug causes selective inhibition of neuronal reuptake of serotonine and norepinephrine with little effect on other neurotransmitter systems. Cases of seizures, tachycardia, and QRS prolongation have been observed following drug overdose in humans. The clinical manifestations of cardiac toxicity suggest that venlafaxine may exhibit cardiac electrophysiological effects on fast conducting cells. Consequently, studies were undertaken to characterize effects of venlafaxine on the fast inward sodium current (I(Na)) of isolated guinea pig ventricular myocytes. Currents were recorded with the whole-cell configuration of the patch-clamp technique in the presence of Ca(2+) and K(+) channel blockers. Results obtained demonstrated that venlafaxine inhibits peak I(Na) in a concentration-dependent manner with an estimated IC(50) of 8. 10(-6) M. Inhibition was exclusively of a tonic nature and rate-independent. Neither kinetics of inactivation (tau(inac)= 0.652 +/- 0.020 ms, under control conditions; tau(inac)= 0.636 +/- 0.050, in the presence of 10(-5) M venlafaxine; n = 5 cells isolated from five animals) nor kinetics of recovery from inactivation of the sodium channels (tau(re)= 58.7 +/- 1.6 ms, under control conditions; tau(re)= 54.4 +/- 1.8, in the presence of 10(-5) M venlafaxine; n = 10 cells isolated from six animals) were significantly altered by 10(-5) M venlafaxine. These observations led us to conclude that venlafaxine blocks I(Na) following its binding to the resting state of the channel. Thus, the characteristics of block of I(Na) by venlafaxine are different from those usually observed with most tricyclic antidepressants or conventional class I antiarrhythmic drugs. |
5,867 | 476 | 21340496 | Is Rheumatoid Arthritis more common in men or women? | Association of anticyclic citrullinated peptide antibodies with extra-articular manifestations, gender, and tabagism in rheumatoid arthritis patients from southern Brazil. Gender and environmental factors are known to influence the clinical heterogeneity and outcome of rheumatoid arthritis (RA). Some variables have been suggested to be associated with the severity of the disease, which can be of great value in the correct management of RA patients. The purpose of this study was to investigate the associations among anticyclic citrullinated antibody (anti-CCP2) positivity, extra-articular manifestations (EAM), gender, and tobacco exposure in a Brazilian RA population. We performed a transversal study comprising 156 RA patients which were investigated for EAM, functional class, presence of anti-CCP2, and IgM rheumatoid factor (IgM-RF). The determination of anti-CCP2 was performed using enzyme immunoassay (ELISA) kits and IgM-RF by latex agglutination test. Clinical and demographical data were obtained through review of charts. Anti-CCP positivity intensity was directly correlated with tobacco smoking, sex, and the development of rheumatoid nodules. Intense anti-CCP2 reaction was 19.8-fold higher in females vs. males, 2.7-fold higher in tobacco vs. non-tobacco users, 7.7-fold higher in female vs. male tobacco users, and 5.15-fold higher in patients with rheumatoid nodules. Tobacco smoking, gender, and rheumatoid nodules are significantly correlated with anti-CCP2 positivity in Brazilian RA patients. |
5,879 | 477 | 21113021 | What is FINDbase? | FINDbase: a worldwide database for genetic variation allele frequencies updated. Frequency of INherited Disorders database (FIND base; http://www.findbase.org) records frequencies of causative genetic variations worldwide. Database records include the population and ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related external resources and the genetic variation together with its frequency in that population. In addition to the regular data content updates, we report the following significant advances: (i) the systematic collection and thorough documentation of population/ethnic group-specific pharmacogenomic markers allele frequencies for 144 markers in 14 genes of pharmacogenomic interest from different classes of drug-metabolizing enzymes and transporters, representing 150 populations and ethnic groups worldwide; (ii) the development of new data querying and visualization tools in the expanded FINDbase data collection, built around Microsoft's PivotViewer software (http://www.getpivot.com), based on Microsoft Silverlight technology (http://www.silverlight.net) that facilitates querying of large data sets and visualizing the results; and (iii) the establishment of the first database journal, by affiliating FINDbase with Human Genomics and Proteomics, a new open-access scientific journal, which would serve as a prime example of a non-profit model for sustainable database funding. |
5,883 | 478 | 9279523 | Can vitamin B1 deficiency cause encephalopathy? | Gestational thyrotoxicosis manifesting as wernicke encephalopathy: a case report. The thyroid gland is physiologically stimulated in normal early pregnancy. This stimulated thyroid function is occasionally termed "gestational transient thyrotoxicosis". The cause of this thyrotoxicosis has been clarified to closely it associate with human chorionic gonadotropin (hCG). We encountered a pregnant patient with hyperemesis and thyrotoxicosis, who manifested symptoms of Wernicke encephalopathy. Although her serum hCG concentration transiently increased in accordance with the thyrotoxicosis, it was within normal limits for the gestational week. Both the thyrotoxicosis and a catabolic state due to the hyperemesis were thought to have induced a vitamin B1 deficiency, causing the Wernicke encephalopathy. This case suggests that pregnant patients with hyperemesis should undergo careful endocrinological and neurological evaluations. |
5,905 | 479 | 18534925 | Which methyl-CpG-binding protein when mutant becomes the hallmark for Rett syndrome? | Breathing dysfunction in Rett syndrome: understanding epigenetic regulation of the respiratory network. Severely arrhythmic breathing is a hallmark of Rett syndrome (RTT) and profoundly affects quality of life for patients and their families. The last decade has seen the identification of the disease-causing gene, methyl-CpG-binding protein 2 (Mecp2) and the development of mouse models that phenocopy many aspects of the human syndrome, including breathing dysfunction. Recent studies have begun to characterize the breathing phenotype of Mecp2 mutant mice and to define underlying electrophysiological and neurochemical deficits. The picture that is emerging is one of defects in synaptic transmission throughout the brainstem respiratory network associated with abnormal expression in several neurochemical signaling systems, including brain-derived neurotrophic factor (BDNF), biogenic amines and gamma-amino-butyric acid (GABA). Based on such findings, potential therapeutic strategies aimed at improving breathing by targeting deficits in neurochemical signaling are being explored. This review details our current understanding of respiratory dysfunction and underlying mechanisms in RTT with a particular focus on insights gained from mouse models. |
5,909 | 480 | 22773406 | Are epigenetic modifications implicated in cardiovascular development and disease? | Epigenetic programming and risk: the birthplace of cardiovascular disease? Epigenetics, through control of gene expression circuitries, plays important roles in various physiological processes such as stem cell differentiation and self renewal. This occurs during embryonic development, in different tissues, and in response to environmental stimuli. The language of epigenetic program is based on specific covalent modifications of DNA and chromatin. Thus, in addition to the individual identity, encoded by sequence of the four bases of the DNA, there is a cell type identity characterized by its positioning in the epigenetic "landscape". Aberrant changes in epigenetic marks induced by environmental cues may contribute to the development of abnormal phenotypes associated with different human diseases such as cancer, neurological disorders and inflammation. Most of the epigenetic studies have focused on embryonic development and cancer biology, while little has been done to explore the role of epigenetic mechanisms in the pathogenesis of cardiovascular disease. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodeling and histone modifications play key roles in the pathogenesis of cardiovascular disease through (re)programming of cardiovascular (stem) cells commitment, identity and function. |
5,924 | 481 | 19293265 | Which deiodinases are present in skeletal muscle? | Type 2 iodothyronine deiodinase in skeletal muscle: effects of hypothyroidism and fasting. CONTEXT: The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T3 production. OBJECTIVE: We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia. DESIGN: This was a prospective study. SETTING: The study was conducted at a university hospital. PATIENTS: We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T4( replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting. MEAN OUTCOME MEASURES: D2 activity and D2 mRNA levels were measured in skeletal muscle samples. RESULTS: No differences were observed in muscle D2 mRNA levels in DTC patients on and off T4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting. CONCLUSION: Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle. |
5,928 | 482 | 23208322 | Which genes are involved in patient response to warfarin? | Influence of ORM1 polymorphisms on the maintenance stable warfarin dosage. PURPOSE: ORM1 is a plasma drug binding protein. Its polymorphism rs17650 (S>F) has been reported to be an important factor affecting the binding ability and effect of antiretroviral protease inhibitors. The aim of this study was to determine whether the ORM1 rs17650 polymorphism also influences warfarin therapy. METHODS: A total of 191 Chinese patients with steady-dose warfarin therapy were enrolled in this study. The patients were studied for warfarin maintenance dose, the ORM1 rs17650 polymorphism, and two polymorphisms previously demonstrated to affect warfarin response [CYP2C9 rs1057910 (3) and VKORC1 rs7294 (-1639 G>A)]. RESULTS: Warfarin dose was partially correlated with the VKORC1 rs7294, CYP2C9 rs1057910 and ORM1 rs17650 polymorphisms. Patients carrying the wild-type of these three genes (n = 96) took a mean dose of 3.0 ± 1.1 mg warfarin, which was significantly higher than that taken by the 52 S patients (2.7 ± 0.7) and 11 S S patients (2.5 ± 0.6 mg) (p = 0.048). CONCLUSION: We identified ORM1 as another polymorphic gene affecting warfarin dose requirements. ORM1 S carriers require lower maintenance doses to achieve and maintain an optimal level of anticoagulation. |
5,952 | 483 | 7585697 | Which is the molecular weight of the protein angiogenin? | Utility of non-covalent complexes in the matrix-assisted laser desorption ionization mass spectrometry of heparin-derived oligosaccharides. Molecular weights of heparin-derived oligosaccharides ranging from disaccharides to hexadecasaccharides have been determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. While these compounds ionize poorly or not at all when used as such, a strong signal can be obtained of their ionic complexes formed with a basic peptide or protein. The molecular weight of the sulfated oligosaccharide is determined by subtracting the mass of the basic component from that of the complex. Optimization of the experimental conditions resulted in sub-picomole sensitivity, in the elimination of sulfate loss and of the interference from attachment of inorganic cations. Synthetic peptides (Arg-Gly)10 and (Arg-Gly)15 were specifically designed as complexing agents for synthetic and natural heparin fragments up to decasaccharides. Accurate molecular weight determination on chemically homogeneous oligosaccharides (+/- 0.05%) unambiguously identified the number of saccharide units, and the number of O,N-sulfate and N-acetyl groups. For oligosaccharides larger than decasaccharides, a small basic protein, angiogenin (M(r) = 14,120), was used to form the complex (an inhomogeneous hexadecasaccharide fraction was the largest available for this study). For inhomogeneous samples larger than decasaccharides, the mass accuracy is lower (+/- 0.2-0.3%) but still suffices to determine the number of saccharide units present and to estimate the number of sulfate groups, except it is no longer possible to differentiate one sulfate from two N-acetyl groups (delta = 4 Da). However, taking into account known regularities of sulfation and acetylation, the specificity of heparin lyases and chemical degradation steps, the method promises to contribute significantly to the determination of the primary structure of heparin and other sulfated glycosaminoglycans. |
5,961 | 484 | 24040872 | List sodium glucose co-transporter-2 (SGLT2) inhibitors that have been FDA approved for type 2 diabetes mellitus treatment. | Sodium-glucose co-transporter 2 inhibition in diabetes treatment: current evidence and future perspectives. Sodium-glucose co-transporters (SGLT2) are mainly expressed in the kidneys and are responsible for the renal handling of glucose load. SGLT2 inhibitors represent the latest oral agents for diabetes treatment. Their unique mechanism of action, which practically spares the insulin secretion or insulin utilization, differentiates the SGLT2 inhibitors from any existing antidiabetic agent. Thus, it is hypothesized that SGLT2 inhibitors can be effectively (and probably safely) combined with any existing antidiabetic agent (including insulin), either as monotherapy, or in dual or triple combinations. All these hypotheses are currently tested in many clinical trials. Currently dapagliflozin, one of the three most advanced SGLT2 inhibitors in the development (along with canagliflozin and empagliflozin), is already in the market in few European countries and canagliflozin has been approved from the Food and Drug Administration (FDA) in US. The evidence so far shows that SGLT2 inhibitors are equally effective to established antidiabetic agents such as metformin or sulfonylureas in their ability to lower HbA1c. On the other hand, SGLT2 inhibitors increase the possibility of genitourinary infections in type 2 diabetic individuals. Their potency in different populations and with different background therapy, but more importantly their short and long term safety remains to be seen. |
5,985 | 485 | 8213821 | What is the gene mutated in the Gaucher disease? | Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients. The frequency of nine different mutated alleles known to occur in the glucocerebrosidase gene was determined in 247 Gaucher patients, of whom 176 were of Jewish extraction, 2 were Jewish with one converted parent, and 69 were of non-Jewish origin. DNA was prepared from peripheral blood, active glucocerebrosidase sequences were amplified by using the PCR technique, and the mutations were identified by using the allele-specific oligonucleotide hybridization method. The N37OS mutation appeared in 69.77% of the mutated alleles in Jewish patients and in 22.86% of the mutated alleles in non-Jews. The 84GG mutation, which has not been found so far among non-Jewish patients, existed in 10.17% of the disease alleles among Jewish patients. The IVS + 1 mutation constituted 2.26% of the disease alleles among Jewish patients and 1.43% among the non-Jewish patients. RecTL, a complex allele containing four single-base-pair changes, occurred in 2.26% of the alleles in Jewish patients and was found in two (1.43%) of the patients of non-Jewish extraction. Another complex allele, designated "RecNciI" and containing three single-point mutations, appeared in 7.8% of alleles of non-Jewish patients and in only two (0.56%) of the Jewish families. The prevalence of the L444P mutation among non-Jewish Gaucher patients was 31.43%, while its prevalence among Jewish patients was only 4.24%. The prevalence of two other point mutations--D409H and R463C--was 5.00% and 3.57%, respectively, among non-Jewish patients and was not found among the Jewish Gaucher patient population. The prevalence of the R496H mutation, found so far only among Jewish patients, was 1.13%. The results presented demonstrate that seven mutations identify 90.40% of the mutations among Jewish patients and that these seven mutations allow diagnosis of only 73.52% of the non-Jewish patients. Identification of additional mutant alleles will enhance the accuracy of carrier detection. |
6,009 | 486 | 17852557 | Why does the prodrug amifostine (ethyol) create hypoxia? | Hypoxia inducible factor (HIf1alpha and HIF2alpha) and carbonic anhydrase 9 (CA9) expression and response of head-neck cancer to hypofractionated and accelerated radiotherapy. PURPOSE: Tumor hypoxia and low intrinsic radiosensitivity may counteract the efficacy of standard radiotherapy for locally advanced head and neck cancer (HNC). We investigated the involvement of hypoxia-regulated proteins (Hypoxia inducible factors HIF1alpha, HIF2alpha and carbonic anhydrase CA9) in HNC resistance to accelerated and hypofractionated radiotherapy. MATERIALS AND METHODS: Thirty-nine patients with locally advanced HNC received 15 daily fractions of 3.4 Gy amounting to a total tumor dose of 51 Gy (equivalent to 63 Gy in four weeks--one week split); this was combined with platinum chemotherapy and amifostine cytoprotection administered subcutaneously. Immunohistochemical analysis of hypoxia-regulated proteins, namely HIF1alpha, HIF2alpha and CA9, was performed in formalin-fixed paraffin-embedded tissues obtained prior to radio-chemotherapy. RESULTS: HIF1alpha and HIF2alpha were expressed in the nuclei and cytoplasm of cancer cells, while CA9 had a membrane reactivity. A high expression of HIF1alpha, HIF2alpha and CA9 was noted in 21/39 (53.8%), 20/39 (51.3%) and 23/39 (58.9%) cases, respectively. Complete response was obtained in 85.2% of patients and HIF1alpha was marginally related with persistent disease after RT (p = 0.05). HIF1alpha was significantly associated with poor local relapse free survival (LRFS) (p = 0.006) and overall survival (p = 0.008), whilst HIF2alpha was not. A significant association of CA9 expression with poor LRFS was noted (p = 0.01). CONCLUSION: In accord with previously reported studies, high levels of the hypoxia regulated proteins HIF1alpha and CA9 in HNC predict resistance to platinum based radio-chemotherapy. Whether HIF2alpha expressing tumors are more sensitive to larger radiotherapy fractions, compared to standard radiotherapy fractionation, is an issue that deserves further investigation. |
6,022 | 487 | 19278965 | What is considered a reliable technique for the definitive cytogenetic diagnosis of Fanconi anemia homozygosity? | Diagnosis of Fanconi anemia in patients with bone marrow failure. BACKGROUND: Patients with bone marrow failure and undiagnosed underlying Fanconi anemia may experience major toxicity if given standard-dose conditioning regimens for hematopoietic stem cell transplant. Due to clinical variability and/or potential emergence of genetic reversion with hematopoietic somatic mosaicism, a straightforward Fanconi anemia diagnosis can be difficult to make, and diagnostic strategies combining different assays in addition to classical breakage tests in blood may be needed. DESIGN AND METHODS: We evaluated Fanconi anemia diagnosis on blood lymphocytes and skin fibroblasts from a cohort of 87 bone marrow failure patients (55 children and 32 adults) with no obvious full clinical picture of Fanconi anemia, by performing a combination of chromosomal breakage tests, FANCD2-monoubiquitination assays, a new flow cytometry-based mitomycin C sensitivity test in fibroblasts, and, when Fanconi anemia was diagnosed, complementation group and mutation analyses. The mitomycin C sensitivity test in fibroblasts was validated on control Fanconi anemia and non-Fanconi anemia samples, including other chromosomal instability disorders. RESULTS: When this diagnosis strategy was applied to the cohort of bone marrow failure patients, 7 Fanconi anemia patients were found (3 children and 4 adults). Classical chromosomal breakage tests in blood detected 4, but analyses on fibroblasts were necessary to diagnose 3 more patients with hematopoietic somatic mosaicism. Importantly, Fanconi anemia was excluded in all the other patients who were fully evaluated. CONCLUSIONS: In this large cohort of patients with bone marrow failure our results confirmed that when any clinical/biological suspicion of Fanconi anemia remains after chromosome breakage tests in blood, based on physical examination, history or inconclusive results, then further evaluation including fibroblast analysis should be made. For that purpose, the flow-based mitomycin C sensitivity test here described proved to be a reliable alternative method to evaluate Fanconi anemia phenotype in fibroblasts. This global strategy allowed early and accurate confirmation or rejection of Fanconi anemia diagnosis with immediate clinical impact for those who underwent hematopoietic stem cell transplant. |
6,026 | 488 | 24250247 | Can exosomes be detected in urine? | Isolation and quantification of microRNAs from urinary exosomes/microvesicles for biomarker discovery. Recent studies indicate that microRNA (miRNA) is contained within exosome. Here we sought to optimize the methodologies for the isolation and quantification of urinary exosomal microRNA as a prelude to biomarker discovery studies. Exosomes were isolated through ultracentrifugation and characterized by immunoelectron microscopy. To determine the RNA was confined inside exosomes, the pellet was treated with RNase before RNA isolation. The minimum urine volume, storage conditions for exosomes and exosomal miRNA was evaluated. The presence of miRNAs in patients with various kidney diseases was validated with real-time PCR. The result shows that miRNAs extracted from the exosomal fraction were resistant to RNase digestion and with high quality confirmed by agarose electrophoresis. 16 ml of urine was sufficient for miRNA isolation by absolute quantification with 4.15×10(5) copies/ul for miR-200c. Exosomes was stable at 4℃ 24h for shipping before stored at -80℃ and was stable in urine when stored at -80°C for 12 months. Exosomal miRNA was detectable despite 5 repeat freeze-thaw cycles. The detection of miRNA by quantitative PCR showed high reproducibility (>94% for intra-assay and >76% for inter-assay), high sensitivity (positive call 100% for CKD patients), broad dynamic range (8-log wide) and good linearity for quantification (R(2)>0.99). miR-29c and miR-200c showed different expression in different types of kidney disease. In summary, the presence of urinary exosomal miRNA was confirmed for patients with a diversity of chronic kidney disease. The conditions of urine collection, storage and miRNA detection determined in this study may be useful for future biomarker discovery efforts. |
6,036 | 489 | 19497860 | What is the role of lysine-specific demethylase 1 (LSD1) in hematopoiesis? | LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. TAL1 is a critical transcription factor required for hematopoiesis. However, perturbation of its activity often leads to T cell leukemia. Whether and how its transcriptional activities are regulated during hematopoiesis remains to be addressed. Here, we show that TAL1 is associated with histone demethylase complexes containing lysine-specific demethylase 1 (LSD1), RE1 silencing transcription factor corepressor (CoREST), histone deacetylase 1 (HDAC1), and histone deacetylase 2 in erythroleukemia and T cell leukemia cells. The enzymatic domain of LSD1 plays an important role in repressing the TAL1-directed transcription of GAL4 reporter linked to a thymidine kniase minimal promoter. Furthermore, we demonstrate that the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation. Consistent with the rapid changes of TAL1-corepressor complex during differentiation, TAL1 recruits LSD1 to the silenced p4.2 promoter in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells. Finally, shRNA-mediated knockdown of LSD1 in MEL cells resulted in derepression of the TAL1 target gene accompanied by increasing dimeH3K4 at the promoter region. Thus, our data revealed that histone lysine demethylase LSD1 may negatively regulate TAL1-mediated transcription and suggest that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs. |
6,044 | 490 | 16625511 | For the treatment of which conditions can atypical neuroleptic drugs be used? | [Treatment of non cognitive symptoms of Alzheimer's disease]. INTRODUCTION AND DEVELOPMENT: Owing to their functional repercussions, the secondary or non-cognitive symptoms displayed by patients with Alzheimer's disease (AD) are very important both for the patients themselves and for the work of the caregiver. In this article we review the treatment of some of them, such as psychotic disorders and depressive symptoms. Atypical neuroleptic drugs are the preferred treatment for symptoms such as delusions, hallucinations, agitation and aggressive behaviour. The most widely used are olanzapine and risperidone. Their pharmacological characteristics, therapeutic effectiveness and side effects are reviewed. CONCLUSIONS: Broader and better designed clinical studies are required to evaluate their usefulness. Recent reports, from 2004, have described a significant increase in the mortality rate (3.5 vs. 1.5%) and in the risk of suffering a stroke (1.3 vs. 0.4%) in elderly demented patients associated to the use of olanzapine and risperidone. The good tolerance and absence of anticholinergic effects of the serotonin reuptake inhibitors, fluoxetin and paroxetine, make them the first-choice medication for the treatment of the depressive symptoms in AD. Despite their widespread use, the evidence currently available with respect to their therapeutic effectiveness is not very convincing and clinical trials with a wider scope and a better design need to be carried out. |
6,056 | 491 | 12689820 | Which are the characteristics of Andersen syndrome? | Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen's syndrome. Andersen's syndrome (AS) (which is characterized by periodic paralysis, cardiac arrhythmias and dysmorphic features), a hereditary disease, and missense mutations of KCNJ2 (which encodes an inward rectifying potassium channel) have been reported recently. We performed clinical and molecular analyses of a patient with AS, and found a novel mutation (G215D) of KCNJ2. Twelve-lead electrocardiography revealed a long QT interval and frequent premature ventricular contractions, and polymorphic ventricular tachycardia was induced by programmed electrical stimulation. Use of a conventional whole-cell patch-clamp system with COS7 cells demonstrated that the G215D mutant was non-functional, and that co-expression of wild type (WT)- and mutant-KCNJ2 shows a dominant negative effect on both inward and outward currents. We performed confocal laser scanning microscopy to assess the cellular trafficking of WT- and mutant-KCNJ2 subunits tagged with yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP), respectively. Tagging with the YFP did not affect the channel function of WT-KCNJ2 and both proteins showed similar plasma membrane fluorescence patterns. Furthermore, the result of fluorescence resonance energy transfer (FRET) studies at the plasma membrane region suggested that both YFP-tagged WT- and CFP-tagged mutant-KCNJ2 combine to construct a hetero-multimer of the potassium channel. In conclusion, the G215D mutant of KCNJ2 is distributed normally in the plasma membrane, but exhibits a dominant-negative effect and reduces the Kir2.1 current, presumably due to hetero-multimer construction. |
6,085 | 492 | 21919874 | How are induced pluripotent stem cells used in the study and treatment of cardiovascular diseases? | Stem cells in cardiovascular regeneration: from preservation of endogenous repair to future cardiovascular therapies. Cardiovascular disease remains the leading cause of morbidity and mortality in the developed countries. This review summarizes current pre-clinical and clinical evidence for the potential role and mechanisms of action of stem and progenitor cells in vascular and cardiac repair and regeneration. Apart from cell transplantation strategies, approaches to maintain stem cell niche function and targeting mobilization/recruitment of specific stem/progenitor cell populations may aid in preserving vascular and cardiac function. Moreover, with the use of patient-derived induced pluripotent stem cells, the field of regenerative medicine is entering a new era. Potential applications of induced pluripotent stem cells and direct reprogrammed cells as well as recent developments in tissue engineering are discussed. |
6,099 | 493 | 12878302 | Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome? | Neurocristopathies presenting with neurologic abnormalities associated with Hirschsprung's disease. Neurocristopathies are a group of diverse disorders resulting from defective growth, differentiation, and migration of the neural crest cells. Hirschsprung's disease, namely aganglionic megacolon, is the consequence of defective migration of neural crest cells on to the colonic submucosa and is therefore considered a neurocristopathy. We report on four children in whom was diagnosed a neurocristopathy, associating Hirschsprung's disease with a wide spectrum of neurologic abnormalities. The patients included two children presenting the phenotypic features of the Goldberg-Shprintzen syndrome: distinct dysmorphic facial features, microcephaly, and mental retardation, along with agenesis of the corpus callosum and cortical malformations associated with intractable seizures in one child. The third newborn presented with the Haddad syndrome: short-segment Hirschsprung's disease associated with the congenital central hypoventilation syndrome requiring permanent artificial ventilation. In the fourth child, absence of the corpus callosum was associated with mild dysmorphic features, borderline cognitive abilities, and attention-deficit disorder. Therefore, awareness of a possible neurocristopathy associated with neurologic abnormalities should be taken into account in any patient newly diagnosed with Hirschsprung's disease to detect the abnormalities early and promptly manage them. A thorough neurologic examination and a developmental assessment, including magnetic resonance imaging of the brain and electroencephalography, should be performed for any child presenting with an aganglionic megacolon, especially those presenting with seizures, developmental delay, or even congenital hypoventilation. |
6,125 | 494 | 23344365 | Which protein is causing Netherton syndrome? | Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect and constant allergic manifestations. NS is caused by loss-of-function mutations in SPINK5 (serine protease inhibitor of kazal type 5) encoding LEKTI-1 (lympho-epithelial kazal type related inhibitor type 5) expressed in stratified epithelia. In vitro and in vivo studies in murine models and in NS patients have cast light on the pathogenesis of the disease and shown that LEKTI deficiency results in unopposed kallikrein-related peptidase 5 (KLK5) and KLK7 activities and to the overactivity of a new epidermal protease, elastase 2 (ELA2). Two main cascades initiated by KLK5 activity have emerged. One results in desmoglein 1 degradation and desmosome cleavage leading to stratum corneum detachment. KLK5 also activates KLK7 and ELA2, which contribute to a defective skin barrier. This facilitates allergen and microbe penetration and generates danger signals leading to caspase 1 activation and the production of active interleukin-1β. In parallel, KLK5 activates a specific cascade of allergy and inflammation by activating protease-activated receptor-2 (PAR-2) receptors. PAR-2 activation triggers the production of the major pro-Th2 cytokine TSLP (thymic stromal lymphopoietin) and several inflammatory cytokines, including tumour necrosis factor-α. Levels of thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) also contribute to allergy in a PAR-2-independent manner. Patient investigations have confirmed these abnormalities and revealed a wide spectrum of disease expression, sometimes associated with residual LEKTI expression. These results have demonstrated that the tight regulation of epidermal protease activity is essential for skin homeostasis and identified new targets for therapeutic intervention. They also provide a link with atopic dermatitis through deregulated protease activity, as recently supported by functional studies of the E420K LEKTI variant. |
6,135 | 495 | 22377713 | Mutations in which gene and which protein are associated with Netherton syndrome? | A synonymous mutation in SPINK5 exon 11 causes Netherton syndrome by altering exonic splicing regulatory elements. Netherton syndrome (NS) is a rare, life-threatening ichthyosiform syndrome caused by recessive loss-of-function mutations in SPINK5 gene encoding lymphoepithelial Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor expressed in the most differentiated epidermal layers and crucial for skin barrier function. We report the functional characterization of a previously unrecognized synonymous variant, c.891C>T (p.Cys297Cys), identified in the SPINK5 exon 11 of an NS patient. We demonstrated that the c.891C>T mutation is associated with abnormal pre-mRNA splicing and residual LEKTI expression in the patient's keratinocytes. Subsequent minigene splicing assays and in silico predictions confirmed the direct role of the synonymous mutation in inhibiting exon 11 inclusion by a mechanism that involves the activity of exonic regulatory sequences, namely splicing enhancer and silencer. However, this deleterious effect was not complete and a residual amount of normal mRNA and LEKTI protein could be detected, correlating with the relatively mild patient's phenotype. Our study represents the first identification of a disease-causing SPINK5 mutation that alters splicing without affecting canonical splice sites. |
6,151 | 496 | 2085926 | Which disease of the central nervous system is characterized by the presence of Lewy bodies? | [Nosological correlation between autonomic failure with Lewy bodies and Parkinson's disease--comparative assessment of clinical features in both diseases]. Autonomic failure with Lewy bodies (AF-LB) was first described by Fichefet et al. in 1965, and more than ten cases have been reported to date. AF-LB and Parkinson's disease (PD) share the neuropathological findings characterized by widely distributed Lewy bodies in the central nervous system including the substantia nigra and locus coeruleus. However, clinical manifestations of AF-LB are far different from PD in which autonomic dysfunction, if present, is not a predominant feature. In the present study, clinical features were comparatively analysed in AF-LB and PD to investigate the nosological relation between PD and AF-LB. The subjects were 94 patients with PD and 11 reported cases of AF-LB in the literature. A test of 70 degrees passive head-up tilt was performed upon the patients with PD in our laboratory. Based on the results in tilting test, the patients with PD were divided into two groups; PD-I (69 cases) with an orthostatic fall of systolic blood pressure less than 30 mmHg, and PD-II (25 cases) with a fall of 30 mmHg or more. Autonomic dysfunctions were more extent in PD-II than in PD-I, because the incidences of anhidrosis, impotence, neurogenic bladder and constipation were higher in PD-II. All of the cases of AF-LB were contained in the previous literatures with reasonably full clinical descriptions. Mean age at onset of the disease was 62.1 +/- 8.7 (mean +/- SD) years old in PD-I, 64.5 +/- 7.5 years old in PD-II and 63.9 +/- 9.0 years old in AF-LB, and no significant differences were found among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS) |
6,168 | 497 | 9389494 | Which deiodinase is known to be present in liver? | Expression of chicken hepatic type I and type III iodothyronine deiodinases during embryonic development. In embryonic chicken liver (ECL) two types of iodothyronine deiodinases are expressed: D1 and D3. D1 catalyzes the activation as well as the inactivation of thyroid hormone by outer and inner ring deiodination, respectively. D3 only catalyzes inner ring deiodination. D1 and D3 have been cloned from mammals and amphibians and shown to contain a selenocysteine (Sec) residue. We characterized chicken D1 and D3 complementary DNAs (cDNAs) and studied the expression of hepatic D1 and D3 messenger RNAs (mRNAs) during embryonic development. Oligonucleotides based on two amino acid sequences strongly conserved in the different deiodinases (NFGSCTSecP and YIEEAH) were used for reverse transcription-PCR of poly(A+) RNA isolated from embryonic day 17 (E17) chicken liver, resulting in the amplification of two 117-bp DNA fragments. Screening of an E17 chicken liver cDNA library with these probes led to the isolation of two cDNA clones, ECL1711 and ECL1715. The ECL1711 clone was 1360 bp long and lacked a translation start site. Sequence alignment showed that it shared highest sequence identity with D1s from other vertebrates and that the coding sequence probably lacked the first five nucleotides. An ATG start codon was engineered by site-directed mutagenesis, generating a mutant (ECL1711M) with four additional codons (coding for MGTR). The open reading frame of ECL1711M coded for a 249-amino acid protein showing 58-62% identity with mammalian D1s. An in-frame TGA codon was located at position 127, which is translated as Sec in the presence ofa Sec insertion sequence (SECIS) identified in the 3'-untranslated region. Enzyme activity expressed in COS-1 cells by transfection with ECL1711M showed the same catalytic, substrate, and inhibitor specificities as native chicken D1. The ECL1715 clone was 1366 bp long and also lacked a translation start site. Sequence alignment showed that it was most homologous with D3 from other species and that the coding sequence lacked approximately the first 46 nucleotides. The deduced amino acid sequence showed 62-72% identity with the D3 sequences from other species, including a putative Sec residue at a corresponding position. The 3'-untranslated region of ECL1715 also contained a SECIS element. These results indicate that ECL1711 and ECL1715 are near-full-length cDNA clones for chicken D1 and D3 selenoproteins, respectively. The ontogeny of D1 and D3 expression in chicken liver was studied between E14 and 1 day after hatching (C1). D1 activity showed a gradual increase from E14 until C1, whereas D1 mRNA level remained relatively constant. D3 activity and mRNA level were highly significantly correlated, showing an increase from E14 to E17 and a strong decrease thereafter. These results suggest that the regulation of chicken hepatic D3 expression during embryonic development occurs predominantly at the pretranslational level. |
6,174 | 498 | 20972443 | Which proteins participate in the formation of the Notch transcriptional activation complex? | Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes. Ligand-induced proteolysis of Notch produces an intracellular effector domain that transduces essential signals by regulating the transcription of target genes. This function relies on the formation of transcriptional activation complexes that include intracellular Notch, a Mastermind co-activator and the transcription factor CSL bound to cognate DNA. These complexes form higher-order assemblies on paired, head-to-head CSL recognition sites. Here we report the X-ray structure of a dimeric human Notch1 transcription complex loaded on the paired site from the human HES1 promoter. The small interface between the Notch ankyrin domains could accommodate DNA bending and untwisting to allow a range of spacer lengths between the two sites. Cooperative dimerization occurred on the human and mouse Hes5 promoters at a sequence that diverged from the CSL-binding consensus at one of the sites. These studies reveal how promoter organizational features control cooperativity and, thus, the responsiveness of different promoters to Notch signaling. |
6,184 | 499 | 12072528 | How is the sequence variability defined in antibodies? | The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. We have analyzed the unique epitope for the broadly neutralizing human monoclonal antibody (MAb) 2G12 on the gp120 surface glycoprotein of human immunodeficiency virus type 1 (HIV-1). Sequence analysis, focusing on the conservation of relevant residues across multiple HIV-1 isolates, refined the epitope that was defined previously by substitutional mutagenesis (A. Trkola, M. Purtscher, T. Muster, C. Ballaun, A. Buchacher, N. Sullivan, K. Srinivasan, J. Sodroski, J. P. Moore, and H. Katinger, J. Virol. 70:1100-1108, 1996). In a biochemical study, we digested recombinant gp120 with various glycosidase enzymes of known specificities and showed that the 2G12 epitope is lost when gp120 is treated with mannosidases. Computational analyses were used to position the epitope in the context of the virion-associated envelope glycoprotein complex, to determine the variability of the surrounding surface, and to calculate the surface accessibility of possible glycan- and polypeptide-epitope components. Together, these analyses suggest that the 2G12 epitope is centered on the high-mannose and/or hybrid glycans of residues 295, 332, and 392, with peripheral glycans from 386 and 448 on either flank. The epitope is mannose dependent and composed primarily of carbohydrate, with probably no direct involvement of the gp120 polypeptide surface. It resides on a face orthogonal to the CD4 binding face, on a surface proximal to, but distinct from, that implicated in coreceptor binding. Its conservation amidst an otherwise highly variable gp120 surface suggests a functional role for the 2G12 binding site, perhaps related to the mannose-dependent attachment of HIV-1 to DC-SIGN or related lectins that facilitate virus entry into susceptible target cells. |
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