Single amino acid exchanges in separate domains of the Drosophila serendipity delta zinc finger protein cause embryonic and sex biased lethality.

The Drosophila serendipity (sry) delta (delta) zinc finger protein is a sequence-specific DNA binding protein, maternally inherited by the embryo and present in nuclei of transcriptionally active cells throughout fly development. We report here the isolation and characterization of four ethyl methanesulfate-induced zygotic lethal mutations of different strengths in the sry delta gene. For the stronger allele, all of the lethality occurs during late embryogenesis or the first larval instar. In the cases of the three weaker alleles, most of the lethality occurs during pupation; moreover, those adult escapers that emerge are sterile males lacking partially or completely in spermatozoa bundles. Genetic analysis of sry delta thus indicates that it is an essential gene, whose continued expression throughout the life cycle, notably during embryogenesis and pupal stage, is required for viability. Phenotypic analysis of sry delta hemizygote escaper males further suggests that sry delta may be involved in regulation of two different sets of genes: genes required for viability and genes involved in gonadal development. All four sry delta alleles are fully rescued by a wild-type copy of sry delta, but not by an additional copy of the sry beta gene, reinforcing the view that, although structurally related, these two genes exert distinct functions. Molecular characterization of the four sry delta mutations revealed that these mutations correspond to single amino acid replacements in the sry delta protein. Three of these replacements map to the same (third out of seven) zinc finger in the carboxy-terminal DNA binding domain; interestingly, none affects the zinc finger consensus residues. The fourth mutation is located in the NH2-proximal part of the protein, in a domain proposed to be involved in specific protein-protein interactions.


Evolution of multilocus genetic structure in an experimental barley population.

Data from 311 selfed families isolated from four generations (F8, F13, F23, F45) of an experimental barley population were analyzed to determine patterns of change in character expression for seven quantitative traits, and in single-locus allelic frequencies, and multilocus genetic structure, for 16 Mendelian loci that code for discretely recognizable variants. The analyses showed that large changes in single-locus allelic frequencies and major reorganizations in multilocus genetic structure occurred in each of the generation-to-generation transitions examined. Although associations among a few traits persisted over generations, dynamic dissociations and reassociations occurred among several traits in each generation-transition period. Overall, the restructuring that occurred was characterized by gradual decreases in the number of clusters of associated traits and increases in the number of traits within each cluster. The observed changes in single-locus frequencies and in multilocus genetic structure were attributed to interplay among various evolutionary factors among which natural selection acting in a temporally heterogeneous environment was the guiding force.


Estimating polygenic models for multivariate data on large pedigrees.

We have developed algorithms for the likelihood estimation of additive genetic models for quantitative traits on large pedigrees. The approach uses the expectation L-maximization (EM) algorithm, but avoids intensive computation. In this paper, we focus on extensions of previous work to the case of multivariate data. We exemplify the approach by analyses of bivariate data on a four-generation, 949-member pedigree of the snail Lymnaea elodes, and on a three-generation pedigree of the guppy Poecilia reticulata containing about 400 individuals.


On the theory of partially inbreeding finite populations. III. Fixation probabilities under partial selfing when heterozygotes are intermediate in viability.

In a previous paper by the senior author, an approximation to the probability of survival was given for a mutant, which is originally present in a single heterozygote, in a population that reproduces partly by selfing and partly by random mating. The population was assumed to be very large, but the result obtained is general with regard to the level of dominance in viability. In this paper two errors which were made in that earlier work are corrected. A general approximate expression is then derived for the probability that an allele A is fixed in a partially self fertilizing population of size N, if its initial frequency is p, selection is weak and heterozygotes with the allele are exactly intermediate in viability compared with genotypes AA and AA. A rigorous proof is given for a special case that is a generalization of the classical binomial sampling model. In this case, but not in general, the approximate fixation probability is independent of the probability of reproduction by selfing. Some implications are discussed.


Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis.

BSAP has been identified previously as a transcription factor that is expressed at early, but not late, stages of B-cell differentiation. Biochemical purification and cDNA cloning has now revealed that BSAP belongs to the family of paired domain proteins. BSAP is encoded by the Pax-5 gene and has been highly conserved between human and mouse. An intact paired domain was shown to be both necessary and sufficient for DNA binding of BSAP. Binding studies with several BSAP recognition sequences demonstrated that the sequence specificity of BSAP differs from that of the distantly related paired domain protein Pax-1. During embryogenesis, the BSAP gene is transiently expressed in the mesencephalon and spinal cord with a spatial and temporal expression pattern that is distinct from that of other Pax genes in the developing central nervous system (CNS). Later, the expression of the BSAP gene shifts to the fetal liver where it correlates with the onset of B lymphopoiesis. BSAP expression persists in B lymphocytes and is also seen in the testis of the adult mouse. All of this evidence indicates that the transcription factor BSAP may not only play an important role in B-cell differentiation but also in neural development and spermatogenesis.


Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia.

Oncogenic conversion of transcription factors by chromosomal translocations is implicated in leukemogenesis. We report that the t(17;19) in acute lymphoblastic leukemia produces a chimeric transcription factor consisting of the amino-terminal portion of HLH proteins E12/E47 (products of the E2A gene) fused to the basic DNA-binding and leucine zipper dimerization motifs of a novel hepatic protein called hepatic leukemia factor (Hlf). Hlf, which is not normally transcribed in lymphoid cells, belongs to the recently described PAR subfamily of basic leucine zipper (bZIP) proteins, which also includes Dbp and Tef/Vbp. Wild-type Hlf is able to bind DNA specifically as a homodimer or as a heterodimer with other PAR factors. Structural alterations of the E2a-Hlf fusion protein markedly impair its ability to bind DNA as a homodimer compared with wild-type Hlf. However, E2a-Hlf can bind DNA as a heterodimer with other PAR proteins, suggesting a novel mechanism for leukemogenic conversion of a bZIP transcription factor.


Ras mediates translation initiation factor 4E-induced malignant transformation.

Translation initiation factor eIF-4E binds to the eukaryotic mRNA 5' cap structure (m7 GpppN, where N is any nucleotide). eIF-4E is a limiting factor in translation and plays a key role in regulation of translation. We have shown previously that overexpression of eIF-4E in rodent fibroblasts results in tumorigenic transformation. eIF-4E also exhibits mitogenic activity when microinjected into serum-starved NIH-3T3 cells. To understand the mechanisms by which eIF-4E exerts its mitogenic property, we examined the involvement of the Ras signaling pathway in this activity. Here, we report that Ras is activated in eIF-4E-overexpressing cells, as the proportion of GTP-bound Ras is increased. Overexpression of the negative effector of cellular Ras, GTPase activating protein, causes reversion of the transformed phenotype. Furthermore, we show that neutralizing antibodies to Ras, or a dominant-negative mutant of Ras, inhibit the mitogenic activity of eIF-4E. We conclude that eIF-4E exerts its mitogenic and oncogenic activities by the activation of Ras.


Stable synapsis of homologous DNA molecules mediated by the Escherichia coli RecA protein involves local exchange of DNA strands.

Escherichia coli RecA protein promotes stable synapsis between a single-stranded DNA and a homologous duplex DNA, resulting in the formation of a complex of RecA with three DNA strands. To gain insight into the molecular interactions responsible for DNA synapsis, the base-pairing status within the synaptic complex was analyzed by using dimethylsulfate and potassium permanganate as probes. The results indicate that the original base pairs in the parental duplex are disrupted; one strand is displaced and the other strand appears to be involved in Watson-Crick base-pairing with the incoming single-stranded DNA. The state of base-pairing thus resembles that of the end products of strand exchange and not a canonical DNA triple helix involving non-Watson-Crick base-pairing. The results also indicate that this local strand exchange can occur without homology at the ends of the DNA substrates (i.e., when axial rotation of the product heteroduplex with respect to the axis of the parental duplex is obstructed). Taken together, these results suggest that exchange of DNA strands mediated by RecA occur at or before the stage of stable DNA synapsis by a process that does not require DNA rotation.


Yeast SNF2/SWI2, SNF5, and SNF6 proteins function coordinately with the gene-specific transcriptional activators GAL4 and Bicoid.

The SNF2 (SWI2), SNF5, and SNF6 genes are required for transcription of many diversely regulated genes in Saccharomyces cerevisiae. Previously, we showed that SNF2, SNF5, and SNF6 function interdependently in transcriptional activation, possibly forming a heteromeric complex. Here, we present evidence that SNF6 has a more direct role in stimulating transcription than SNF2 and SNF5. The global effects of mutations in SNF2, SNF5, and SNF6 suggested that these SNF proteins may function coordinately with many gene-specific activators. We show that LexA-GAL4 and LexA-Bicoid fusion proteins are both dependent on SNF2, SNF5, and SNF6 for activation of target genes containing one or multiple lexA operators. The stringency of the requirement for the SNF proteins varies with the activator, the number of binding sites for the activator, and the target promoter. Thus, these SNF proteins appear to represent a class of intermediary proteins that facilitate transcriptional activation by gene-specific regulatory proteins.


The acidic activator GAL4-AH can stimulate polymerase II transcription by promoting assembly of a closed complex requiring TFIID and TFIIA.

The assembly of activated RNA polymerase II (pol II) transcription complexes has been investigated by assaying whether pre-assembly of intermediate complexes reduces the extended time required for start-site melting. The results show that a closed complex requiring factors IIA, IID, and the acidic activator GAL4-AH forms in a rate-limiting step. This directs the templates into a productive assembly pathway. Factor TFIIB is then added rapidly, affording further protection against diversion into nonproductive pathways. These events are followed by a series of rapid steps in which the remaining general factors are assembled onto the template, which is then melted using the energy of ATP hydrolysis.


The Drosophila gene Hairless encodes a novel basic protein that controls alternative cell fates in adult sensory organ development.

The mechanosensory bristles of adult Drosophila are composed of four cells that, in most cases, are progeny of a single sensory organ precursor (SOP) cell. Two sister cells in this lineage, the trichogen and tormogen, produce the external shaft and socket of the bristle, respectively. Loss-of-function mutations of Hairless (H) confer two distinct mutant phenotypes on adult bristles. The bristle loss phenotype results from the failure to specify and/or execute the SOP cell fate; the double socket phenotype results from the transformation of the trichogen (shaft) cell into a second tormogen (socket) cell. We have found that the H gene encodes a novel basic protein with a predicted molecular mass of 109 kD. Basal levels of expression of a transgene (P[Hs-H]) in which the H protein-coding region is under the control of the Hsp70 promoter are sufficient to provide full rescue of H mutant phenotypes. Heat shock treatment of P[Hs-H] transgenic animals as late larvae and early pupae produces a tormogen-to-trichogen (double shaft) cell fate transformation, as well as bristle multiplication and loss phenotypes very similar to those caused by loss-of-function mutations in the neurogenic gene Notch. Our results indicate that the SOP cell fate requires H to antagonize the activity of the neurogenic group of genes and that the expression of distinct cell fates by the trichogen/tormogen sister cell pair depends on an asymmetry in their levels of H+ activity or in their thresholds for response to H.


StuA is required for cell pattern formation in Aspergillus.

The stunted (stuA) gene product is required for the orderly differentiation and spatial organization of cell types of the Aspergillus nidulans conidiophore. Expression of the stuA gene is complex. Two transcripts, stuA alpha and stuA beta, are initiated from separate promoters. Transcription of both RNAs increases approximately 50-fold during the establishment of developmental competence. Induction-dependent transcriptional and post-transcriptional regulatory mechanisms further enhance expression 15-fold. Consistent with the latter observation, both transcripts have structural features characteristic of RNAs subject to translational control. Conidiophore morphogenesis requires regulatory interactions between the products of the stuA, bristle (brlA), and abacus (abaA) genes. Enhanced stunted expression is cell type specific and dependent on a functional BrlA protein. StuA affects the spatial localization of AbaA by acting directly, or indirectly, to repress abaA expression.


Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors.

The MEF2 site is an essential element of muscle enhancers and promoters that is bound by a nuclear activity found, so far, only in muscle and required for tissue-specific transcription. We have cloned a group of transcription factors from human muscle that are responsible for this activity: They are present in muscle-specific DNA-binding complexes, have a target sequence specificity identical to that of the endogenous activity, and are MEF2 site-dependent transcriptional activators. These MEF2 proteins comprise several alternatively spliced isoforms from one gene and a related factor encoded by a second gene. All share a conserved amino-terminal DNA-binding domain that includes the MADS homology. MEF2 transcripts are ubiquitous but accumulate preferentially in skeletal muscle, heart, and brain. Specific alternatively spliced isoforms are restricted to these tissues, correlating exactly with the presence of endogenous MEF2 activity. Furthermore, MEF2 protein is detected only in skeletal and cardiac muscle nuclei and not in myoblast and nonmuscle cells. Thus, post-transcriptional regulation is important in the generation of tissue-specific MEF2 activity. Cardiac and smooth, as well as skeletal, muscles contain functionally saturating levels of MEF2 trans-activating factors that are absent in nonmuscle cells. Moreover, MEF2 is induced in nonmuscle cells by MyoD; however, MEF2 alone is insufficient to produce the full muscle phenotype. Implications for the molecular mechanisms of myogenesis are considered.


Yeast GCN4 as a probe for oncogenesis by AP-1 transcription factors: transcriptional activation through AP-1 sites is not sufficient for cellular transformation.

The Jun and Fos oncoproteins belong to the AP-1 family of transcriptional activators and are believed to induce cellular transformation by inappropriately activating genes involved in cell replication. To determine whether transcriptional activation through AP-1 sites is sufficient for transforming activity, we examined the properties of an autonomous and heterologous AP-1 protein, yeast GCN4, in rat embryo fibroblasts. GCN4 induces transcriptional activation through AP-1 sites but, unlike Jun and Fos, fails to induce cellular transformation, in cooperation with Ha-ras. Jun-GCN4 and Fos-GCN4 homodimers independently induce cellular transformation indicating that the amino-terminal regions of Jun and Fos each contain regulatory functions that are required for oncogenesis but are distinct from generic transcriptional activation domains. In addition, these observations have implications for the nature of the oncogenically relevant target genes that respond to Jun and Fos.


Conserved motifs in Fos and Jun define a new class of activation domain.

Fos and Jun form a tight heterodimeric complex that activates transcription by AP1 sites. We have recognized that two adjacent regions of the Jun A1 activation domain are conserved in the Fos protein, and we refer to these two homologous regions as homology box 1 (HOB1) and homology box 2 (HOB2). Using GAL4 chimeras, we show that the HOB1/HOB2 region of Fos and Jun is an independent activation domain in which HOB1 and HOB2 act cooperatively to activate transcription. This cooperativity is retained after the replacement of Fos HOB1 or HOB2 with the equivalent domain of Jun or when duplicated HOB1/HOB1 and HOB2/HOB2 combinations are generated. In the Fos protein, HOB1 or HOB2 can also cooperate with a distinct domain at the carboxyl terminus of the protein. Using the HOB2 consensus sequence as a guide, we identified a HOB2-containing activation domain in the CCAAT/enhancer binding protein (C/EBP) protein. This HOB2 motif can cooperate with as yet undefined sequences in C/EBP and will function even when linked to Jun HOB1. Thus, HOB1 and HOB2 represent inert "cooperating modules" that are combined to generate a functional activation domain. Each of these modules has the potential to cooperate with both distinct and identical domains. The presence of HOB-like modules in three different transcription factors indicates that the HOB motifs characterize a new class of activation domain. These motifs can be used now to identify other transcription factors with such modular characteristics.


Lead-induced lipid peroxidation and antioxidant defense components of developing chick embryos.

Administration of lead (1.25 and 2.5 mumol/kg egg weight) to 14-day-old chick embryos enhanced the level of lipid peroxides (LPO) in tissues of liver, brain, and heart. Accumulation of LPO was maximum at 9 h after treatment with lead and returned to normal level by 72 h. Further, we have studied the levels of glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. At 9 h posttreatment, the hepatic GR was reduced significantly with the induction of GST and considerable depletion of GSH. However, in brain and heart, both GR and GST activities were unaltered with significant reduction of GSH. Further, an increase of non-Se-dependent GPx and SOD activities were observed in liver, brain, and heart. Similarly, at 72 h, although the GPx activity was found decreased in liver and brain, the GST, catalase, and SOD activities were significantly increased in all the three tissues alike, suggesting tissue-specific changes of antioxidant defense components in response to lead treatment. Our results suggests that the elevated levels of GST, SOD, and catalase at 72 h were successful in bringing LPO levels back to normal.


Antioxidant mechanism of Mn(II) in phospholipid peroxidation.

Antioxidant action of Mn2+ on radical-mediated lipid peroxidation without added iron in microsomal lipid liposomes and on iron-supported lipid peroxidation in phospholipid liposomes or in microsomes was investigated. High concentrations of Mn2+ above 50 microM inhibited 2,2'-azobis (2-amidinopropane) (ABAP)-supported lipid peroxidation without added iron at the early stage, while upon prolonged incubation, malondialdehyde production was rather enhanced as compared with the control in the absence of Mn2+. However, in a lipid-soluble radical initiator, 2,2'-azobis (2,4-dimethyl-valeronitrile) (AMVN)-supported lipid peroxidation of methyl linoleate in methanol Mn2+ apparently did not scavenge lipid radicals and lipid peroxyl radicals, contrary to a previous report. At concentrations lower than 5 microM, Mn2+ competitively inhibited Fe(2+)-pyrophosphate-supported lipid peroxidation in liposomes consisting of phosphatidylcholine with arachidonic acid at the beta-position and phosphatidylserine dipalmitoyl, and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-supported lipid peroxidation in the presence of iron complex in microsomes. Iron reduction responsible for lipid peroxidation in microsomes was not influenced by Mn2+.


8-Hydroxydeoxyguanosine in vitro: effects of glutathione, ascorbate, and 5-aminosalicylic acid.

Oxidative DNA damage, as expressed by 8-hydroxydeoxyguanosine (8-OHdG), was investigated in calf thymus DNA exposed to either ultraviolet radiation or to FeCl2/H2O2 in a Fenton-like reaction. The influence of iron (absent in the UV system and present in the FeCl2/H2O2 system) and pH (7.4 and 4.0) on the effect of glutathione (GSH), ascorbate, and 5-aminosalicylic acid (5-ASA, a drug used in the treatment of chronic inflammatory bowel diseases) was examined in these systems. Without iron, all three compounds considerably reduced 8-OHdG formation (i.e., acted as scavengers), while in the presence of iron salts, 8-OHdG formation was accelerated (except for GSH at pH 7.4), i.e., the compounds acted as prooxidants. This effect was augmented at low pH. The prooxidant property of 5-ASA may have implications for its clinical use. Maximum scavenging effect for all the compounds investigated was obtained at much lower doses than the maximum enhancing effect. This demonstrates that to the end of oxy-radical scavenging, the concentration of the GSH, ascorbate, and 5-ASA, respectively, should be chosen to obtain maximum antioxidant effect and minimum prooxidant effects. The significance of this finding for the selection of antioxidant dose is important but remains to be investigated further.


Effects of beta-carotene and alpha-tocopherol on radical-initiated peroxidation of microsomes.

Rat liver microsomal membranes were exposed to either beta-nicotinamide adenine dinucleotide phosphate (NADPH), adenosine 5'-diphosphate (ADP), and Fe+3 or to azocompounds, and the antioxidant activities of beta-carotene and alpha-tocopherol were studied. Lipid peroxidation was monitored either by malondialdehyde (MDA) formation in the thiobarbituric acid assay at 535 nm or by hydroperoxide formation at 234 nm, after high-pressure liquid chromatography (HPLC) separation of phospholipid hydroperoxides. The radical initiators, water-soluble 2,2'-azobis(2-amidinopropane) (AAPH) and lipid-soluble 2,2'-azobis(2,4-dimethylvaleronitrile (AMVN), when thermally decomposed at 37 degrees C under air, produced a constant rate of lipid peroxidation in microsomes and lag times inversely related to their concentrations. Using 25 mM AAPH, beta-carotene suppressed lipid peroxidation at a concentration of 50 nmol/mg protein; using 24 mM AMVN, an inhibition of MDA formation was observed at a concentration of only 5 nmol/mg protein. Inhibition by beta-carotene did not produce a clearly defined lag phase. During AAPH-induced lipid peroxidation, beta-carotene was consumed linearly, and high levels of the antioxidant were still present at the end of 45 min of incubation. Using NADPH/ADP/Fe+3, protection by beta-carotene was observed at 10 nmol/mg protein. alpha-Tocopherol effectively suppressed both MDA and hydroperoxide formation in a dose-dependent manner when either NADPH/ADP/Fe+3 or azocompounds were used. These effects were observed at very low concentrations of the added alpha-tocopherol, ranging from 2 to 3 nmol/mg protein. When the lag times were measurable (AAPH and AMVN), they were directly proportional to the concentration of alpha-tocopherol and revealed the presence of endogenous antioxidants in the microsomal membranes. Different temporal relationships between the loss of alpha-tocopherol and lipid peroxidation were observed in relation to the prooxidant used. A substantial depletion of about 70% of endogenous alpha-tocopherol preceded the propagation phase when induced by the azocompounds, while only 20% of antioxidant disappeared at the beginning of the peroxidation when induced by NADPH/ADP/Fe+3. Although our results show that both beta-carotene and alpha-tocopherol suppress the peroxidation of microsomal membranes, their antioxidant efficacy is influenced by several factors, including the type of radical initiator involved and the site and rate of radical production.


Effects of recombinant human extracellular-superoxide dismutase type C on myocardial reperfusion injury in isolated cold-arrested rat hearts.

The efficacy of recombinant human extracellular-superoxide dismutase type C (EC-SOD C) on myocardial reperfusion injury was explored in hypothermically arrested rat hearts, as was its site of action. Forty isolated working rat hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion. The hearts were arrested by the administration of 10 mL of cold perfusate at the onset of ischemia. At the same time, they were randomly assigned to one of five groups; A: cold perfusate only; B: cold perfusate + EC-SOD C 10.4 mg/L (30,000 U/L); C: cold perfusate+bovine CuZn-SOD 7.5 mg/L (30,000 U/L); D: cold perfusate + EC-SOD C 10.4 mg/L + heparin 50,000U/L; E: cold perfusate + heparin 50,000 U/L. Heparin was given to prevent binding of EC-SOD C to endothelial cell surfaces. Left ventricular function was studied before ischemia and at the end of reperfusion. Percent recovery of maximal left ventricular dP/dt after reperfusion was more pronounced in group B (109 +/- 24%; p less than .05) than in groups A (42 +/- 40%), C (47 +/- 36%), D (44 +/- 33%) and E (58 +/- 25%). Likewise, percent recovery of the double product (heart rate x systolic left ventricular pressure) was better in group B (104 +/- 18%; p less than .05) than in the other groups (A: 47 +/- 37%, C: 49 +/- 36%, D: 50 +/- 35%, E: 69 +/- 31%). Compared to the preischemic level, creatine kinase increased significantly in the coronary effluent after reperfusion in groups A, C, D, and E, but not in group B. The results suggest that EC-SOD C, which attaches to the endothelial cell surfaces, might be particularly effective as protection against myocardial reperfusion injury when given together with cardioplegic solution.


Mechanism(s) involved in meat mutagen formation and inhibition.

The Maillard reaction, which involves Amadori rearrangement as a key step, also results in sugar fragmentation and free radical formation. The imidazoquinoline meat mutagens (2-amino-3-methylimidazo[4,5-f]-quinoline, or IQ, and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, or MeIQ) are formed from a reaction mixture containing alkylpyridine free radicals and creatinine. The imidazoquinoxaline meat mutagens (2-amino-3,4-dimethylimidazo[4,5-f]-quinoxaline, or MeIQx, and 2-amino-3,4,8-trimethylimidazo[4,5-f]-quinoxaline, or 4,8-DiMeIQx) may be produced by reacting a mixture containing dialkylpyrazine free radicals and creatinine. Two different pathways for free radical formation are proposed. One involves bimolecular ring formation from the enaminol form of the glycoaldehyde alkylimine and is followed by oxidative formation of the free radical. The other pathway involves formation of N,N1-dialkylpyrazinium ions from glyoxal monoalkylimine followed by reduction to produce the free radicals. The respective intermediates (glycoaldehyde alkylimine and glyoxal monoalkylamine) are formed by reacting glycoaldehyde and glyoxal with amino compounds. The glycoaldehyde system reacts faster and produces more free radicals than the glyoxal system. The reactions help to explain the formation of imidazoquinoxaline meat mutagens and their predominance in fried fish and why these mutagens are present in larger quantities in fried ground beef than the imidazoquinoline-type meat mutagens. These two pathways may not be the only mechanisms involved in formation of meat mutagens, but other free radical reactions may also contribute to meat mutagenicity and are mentioned briefly.(ABSTRACT TRUNCATED AT 250 WORDS)


Progressive increases in serum catalase activity in advancing human immunodeficiency virus infection.

We found that serum from individuals with Acquired Immunodeficiency Syndrome (AIDS) had more (p less than .05) catalase activity (31.5 +/- 5.2 U/mL) than serum from healthy control subjects (7.3 +/- 0.8 U/mL). Moreover, serum catalase (but not glutathione peroxidase) activity increased progressively with advancing human immunodeficiency virus (HIV) infection (i.e., AIDS greater than symptomatic infection greater than asymptomatic infection greater than controls). Increases in serum catalase activity correlated with increases in serum hydrogen peroxide (H2O2) scavenging ability and reached levels which decreased exogenous H2O2-mediated injury to cultured endothelial cells without altering neutrophil bactericidal activity or mononuclear cell cytotoxicity in vitro. Serum catalase activity correlated with serum lactate dehydrogenase (LDH) activity but did not appear to be a consequence of erythrocyte (RBC) hemolysis since RBC fragility and serum haptoglobin levels were comparable in HIV-infected and control subjects. Increases in serum catalase activity may reflect and/or compensate for systemic glutathione and other antioxidant deficiencies in HIV-infected individuals.


Antioxidant depletion in aortic crossclamping ischemia: increase of the plasma alpha-tocopheryl quinone/alpha-tocopherol ratio.

To assess whether oxidative stress contributes to the ischemia/reperfusion injury of aortic surgery, the contents of alpha-tocopherol, alpha-tocopheryl quinone, ascorbate, lipid-derived malondialdehyde, protein thiols, cholesterol, and lactate were analyzed in plasma samples from 24 patients subjected to aortic crossclamping. alpha-Tocopherol, ascorbate, and protein thiols decreased during ischemia, whereas alpha-tocopheryl quinone increased in all but two cases, doubling on average in proportion to alpha-tocopherol. Upon reperfusion alpha-tocopherol, ascorbate, and protein thiols remained low, whereas alpha-tocopheryl quinone returned to the preischemic level. Lipid-derived malondialdehyde (a measure of lipid hydroperoxides) increased significantly only during reperfusion. The results suggest that oxidative stress occurs simultaneously with ischemia/reperfusion during aortic surgery, and that measurement of the tocopheryl quinone/tocopherol ratio may shed new light on the underlying pathological events.


Clastogenic and mutagenic actions of active species generated in the 6-hydroxydopamine/oxygen reaction: effects of scavengers of active oxygen, iron, and metal chelating agents.

A pro-oxidant triphenol, 6-hydroxydopamine (6-OHDA), induced mutations in the Salmonella typhimurium TA 104 tester strain (over the concentration range to 800 microM), and induced chromosomal aberrations in cultured Chinese hamster ovary (CHO) cells at lower concentrations (up to 90 microM). It was however only marginally mutagenic (up to cytotoxic levels of 200 microM) in the TA102 tester strain. Clastogenicity in the more sensitive CHO cell assay was mediated by activated oxygen. Superoxide dismutase decreased the incidence of chromosomal aberrations by 60% and catalase (or superoxide dismutase plus catalase) decreased the incidence to control levels. The clastogenicity of 6-OHDA was dependent upon unsequestered transition metal ions, since addition of EDTA plus desferrioxamine decreased chromosomal aberrations by 90%. The simplest explanation of the data is that genotoxicity is mediated by active species generated in a Fenton-type reaction between 6-OHDA and H2O2 catalyzed by traces of metals in the medium.


Antioxidant activity of ubiquinone-3 in human low density lipoprotein.

The ability of ubiquinone-3, a short chain ubiquinone homologue, to prevent Cu2+ induced oxidation of human low density lipoprotein was investigated. The results are as follows: in the presence of ubiquinone-3 the extent of peroxidation, as determined by the formation of thiobarbituric acid reactive substances, was only one third of that found in its absence; the quinone can also prevent the fragmentation of apolipoprotein B-100 and the increase of the net negative surface charge of the particle.


Electrochemical characteristics of nitroheterocyclic compounds of biological interest. VIII. Stability of nitro radical anions from cyclic voltammetric studies.

The stability of the one electron addition product of four biologically important nitroheterocyclic compounds has been examined electrochemically. Using cyclic voltammetry the tendency of the nitro radical anion to undergo disproportionation was studied by two methods of analysis. The first was based on determining the voltammetric time-constant required for half of the reduction product, RNO2-., to react further. The second concerned the minimum volume of dimethylformamide which had to be added to the aqueous electrolytic medium to give a specific cyclic voltammetric response. Both methods were found to compare well with the results obtained for RNO2-. stabilities using a theoretically derived procedure for a second order reaction following a charge-transfer step. The use of these alternative approaches for quantifying the reactivity of reduction products is discussed. The time-constant method in particular may be useful in studying complex reaction pathways.


The role of extracellular medium components and specific amino acids in the cytotoxic response of Escherichia coli and Chinese hamster ovary cells to hydrogen peroxide.

A concentration of H2O2 resulting in mode one killing of Escherichia coli is more toxic when exposure to the oxidant is performed in complete medium (K medium), as compared to a saline (M9 salts). Inorganic salts (MgSO4 and CaCl2), thiamine or glucose, when added separately, or combined, to M9 salts had no effect on the cytotoxic response to H2O2. In contrast, the lethality of the oxidant was highly dependent on the presence of the amino acids in the incubation medium. The addition of glucose further enhanced this response. Among the seventeen amino acids which are present in the complete amino acid mixture, only two, i.e. L-histidine and L-cystine, were found to increase the toxicity of H2O2. Again, glucose augmented this response. The effect of these amino acids on the growth inhibitory action of hydrogen peroxide was also tested in Chinese Hamster Ovary cells. It was found that L-histidine was capable of increasing the toxicity of the oxidant whereas all the other amino acids did not affect the toxicity of the oxidant. Glucose only slightly augmented this effect of L-histidine. DNA single strand breakage produced by H2O2 was increased by L-histidine and was not significantly modified by the other amino acids. DNA double strand breakage was also shown to occur in cells exposed to H2O2-L-histidine, and this effect was independent on the presence of glucose. These results demonstrate that the cytotoxic response of bacterial and mammalian cells to challenge with H2O2 is highly dependent on the composition of the extracellular milieu.(ABSTRACT TRUNCATED AT 250 WORDS)


Control of pro-oxidant activity of cupric ions by entrapment in unilamellar lipid vesicles.

As a demonstration of a potential means of delivering and controlling the biochemical and biological activity of metal ions, cupric ions have been trapped in unilamellar phospholipid vesicles. The activity of these cupric ion-containing vesicles as catalysts of the autoxidation of ascorbate and epinephrine has been investigated. A marked increase in autoxidation rate was observed on release of the cupric ion on addition of detergent. When an azobenzene-containing photochromic lipid was incorporated in the bilayer membrane of the vesicles, the release of cupric ions could be initiated by irradiation with ultraviolet light. In the dark, these vesicles remained stable for at least several weeks. Photo-controlled release of liposomally-entrapped species might find application in areas similar to those where 'caged' reagents are presently used.


Ubisemiquinones of the mitochondrial respiratory chain do not interact with molecular oxygen.

The present investigation deals with the suggested role of redox-cycling ubisemiquinones in mitochondrial O2-. generation. Due to the functional complexity of electron-transferring ubiquinones in the respiratory chain, model experiments were designed to study whether ubisemiquinones will directly react with oxygen, thereby generating O2-. radicals. Based on the fact that mitochondrial ubiquinone was reported to operate in an aprotic surrounding of the inner mitochondrial membrane, the reactivity of ubisemiquinones with oxygen was tested in water-free acetonitrile. Our results prove that autoxidation of ubisemiquinones requires the addition of protons to the non-polar reaction system. An experimental evaluation of the validity of this finding with respect to mitochondrial ubiquinones is impeded by the biochemical role that oxygen plays in the establishment of ubisemiquinone populations. To differentiate between a possible direct interaction of oxygen on redox-cycling ubisemiquinones and this indirect biochemical O2 effect, we have successfully introduced ferricyanide instead of oxygen to establish mitochondrial ubisemiquinone pools. Ubisemiquinones in this reaction system were not susceptible to oxygen and no O2-. radicals were released unless the inner mitochondrial membrane was protonated by toluene pretreatment. Since the inner mitochondrial membrane is normally not permeable to protons (which is a prerequisite of the chemiosmotic theory of energy conservation) based on our experiments we can exclude the involvement of redox-cycling ubisemiquinones in mitochondrial O2-. generation.


[Siliconoma and rheumatic symptoms--a familial and a questionable complication of silicone implantation].

Ruptured silicone-gel filled implants after breast augmentation or reconstruction may cause siliconomas. These lesions frequently develop years later and should be surgically excised. Since the use of modern double lumen implants they do not occur anymore. The possibility of a correlation between silicone implants and the incidence of rheumatologic disorders is critically evaluated by case reports from the world literature. Up to now, no statistically significant cumulation of these disorders in women with silicone implants can be observed.


[The status of replantation centers and services in the area served by the German Professional Society of Microsurgery of Peripheral Nerves and Blood Vessels (Commission for Replantation)].

This survey concerns the years 1989 and 1990. While the number of institutions performing replantations remained constant in Austria and Switzerland, there has been a noticeable trend in Germany from around-the-clock replantation centers to simple replantation services, offering emergency microsurgery by arrangement only. The total number of replantations performed decreased from 975 replanted parts (903 microreplantations and 72 macroreplantations) in 1989 to 875 in 1990, with a micro-/macroreplantation ratio of 12.8:1. Based on the results of questionaire received from 34 university and city hospitals in Austria, Switzerland and former West Germany, an analysis of clinical organization and management of replantation services is presented.


Polyotia. A case report.

An extremely rare case of polyotia is presented. A seven-month old male had a congenital deformity of the right auricle, appearing like a large accessory auricular appendage. It had a small helix-like protuberance connecting to a very long helical crus; there was a conchal cavity between the external auditory meatus and the protuberance. Surgery led to good results. The surgical procedure is described and the literature concerning polyotia discussed. Our diagnostic criteria for polyotia and the accessory auricular appendage are presented.


[Advanced carpal collapse (SLAC-wrist) in scaphoid pseudarthrosis. Therapy concept: medio-carpal partial arthrodesis].

Longstanding unstable scaphoid nonunions inevitably lead to carpal collapse and symptomatic secondary arthrotic changes, ruling out reconstructive procedures to the scaphoid itself. Partial mediocarpal fusion, however, can preserve some wrist motion and markedly reduce or even eliminate wrist pain. By correcting the malalignment of the lunate and capitate, carpal height is restored. By excision of the scaphoid, its destroyed articular surfaces are removed. In 26 of 31 patients undergoing mediocarpal fusion, complete or at least significant reduction of wrist pain was observed. Average grip strength increased by 23%, whereas wrist mobility decreased by 33 to 40% with a relatively short follow-up of 14 months. Total wrist fusion remains the last line of defense.


[Indications for and value of kinematography of the wrist joint].

Ruptures of carpal ligaments are frequently overlooked, as they are difficult to diagnose. The authors evaluate 63 wrist kinematographies and include it in their algorithm for the examination of the painful wrist.


[Initial experiences with a new wrist joint fixator in treatment of distal radius fractures].

Between January 1989 and October 1991, 56 patients with 57 distal radius fractures were treated with the new Orthofix wrist fixator. This review of 43 patients consists of cases with follow-ups of at least 12 months. One patient had died, and 38 (90.5%) of the remaining 42 fractures were examined 20.3 months after surgery, on average. Radiological findings were classified according to Lidström, and the functional results according to Gartland and Werley in the Sarmiento modification. Functional analysis demonstrated excellent and good results in 73% of the fractures. Although the number of cases studied is too small for statistical analysis, the results do show a trend emphasizing the importance of subtle anatomical restoration, particularly of the radial length. Since this cannot always be obtained by external fixation alone, supplementary Kirschner-wires, screws and bone-grafting can be necessary. The main advantages of the new Orthofix fixator are its light-weight design, simple application, and the possibility of fracture reduction even after the device has been mounted. Early mobilisation has not been evaluated sufficiently, so no general recommendations can be made yet.


[Mycobacterium malmoense infection of the flexor tendon sheath].

Infections of the tendon sheath caused by non-tuberculous mycobacteria are well known. So far, only one case involving Mycobacterium malmoense has been reported. The authors report of a 73-year old patient having undergone carpal tunnel release. In spite of granulomatous inflammation of the flexor tendon sheaths, there was no biopsy cultured for acid-fast bacteria. One year later, symptoms recurred and synovialectomy was repeated. In spite of macroscopic appearance of the synovialis and histological studies, a specific diagnosis was not yet made. Two weeks later, acid-fast bacteria, identified as M. malmoense were cultured in the BACTEC vial. Because specific treatment was not initiated, a further recurrence developed five months later, necessitating further surgery with synovialectomy. Properly treated with Rifampin and Ethambutal for twelve months, the patient has remained asymptomatic for the following two years.


[Modification of the aerobic metabolism of human full skin complexes. An in vitro study].

The effect of increased oxygen supply on oxygen uptake of isolated human full-thickness skin grafts was investigated. Acute hyperoxic conditions led to temporary slight reductions of the cellular oxygen consumption rate, whereas pronounced longer-lasting effects could not be demonstrated. It was concluded that hyperoxic intervention is not suitable to compensate for the complex metabolic disorders arising in transplanted tissue.


[Prevalence of eating disorders among female Israel defence force recruits].

It is assumed that the incidence of anorexia nervosa and bulimia nervosa in the general population has been increasing. Medical personnel in the IDF also believe this to be true with regard to their female soldiers. We administered the eating attitude test (EAT) to 1112 female soldiers at the beginning of their military service and determined weight and height for each. Those whose EAT scores were high or whose weights were low were then interviewed by the study psychiatrist and the author. 2 of them (0.2%) were found to be suffering from anorexia nervosa. Both were identified by their low weights; their EAT scores were both normal. 27 (2.4%) were diagnosed as having a partial eating disorder syndrome, in a third of whom it was severe. The severe cases were also identified by their weights and not by EAT scores. In addition, 4 (0.5%) had bulimia nervosa, all of whom were identified from their EAT scores. These findings are similar to those of some of the most recent studies in the field. The deficiencies of the EAT scale were more apparent in this than in other studies. Because of its relatively low PPV as well as the apparent reluctance of many subjects to answer truthfully, the scale is not effective by itself for screening purposes. As was shown in this study, measuring weight and height in addition considerably improved accuracy of screening.


[Influence of muscle tone and force on ossification in postcomatose patients].

68 post-traumatic brain-injured patients in postcomatose unawareness (PCU) states were admitted during 1982-1987. 32 of them also suffered from fractures of the long bones and pelvis (total of 51 limbs). The muscle tone and force of all limbs were examined and x-rays of the large joints and of the fractures were taken periodically. Periarticular new-bone formation appeared in 32 patients. Normal callus developed in 41 fractured limbs and hypertrophic callus in 18. We found that pathological muscular tone (hypertonus and hypotonus) and pathologically decreased muscle force (paresis and plegia) were closely correlated with the appearance of periarticular new-bone formation. The extent of callus formation was not correlated with muscle tone and force.


[Atrial septal defects and embolic stroke in young adults].

The mechanism of embolic stroke in young adults remains unidentified in about 35% of cases. In recent years defects in the atrial septum have been described as an important route for cerebral and retinal embolism. These include classical atrial septal defect and patent foramen ovale, as well as the less well-recognized entity of atrial septal aneurysm, with or without interatrial communication. The combined incidence of these defects in the general population is between 20-35%. The introduction of transesophageal echocardiography and the use of echogenic contrast have lead to significant improvement in identification. We describe 3 patients in whom atrial defects were identified as possible routes for cerebral embolism: The first presented with recurrent stroke and combined atrial septal aneurysm and patent foramen ovale. In the second, patent foramen ovale was found in a patient with 2 prosthetic values. The third was a soldier in whom patent foramen ovale was found following transient loss of consciousness. Based on our modest experience and review of the literature we believe that transesophageal and contrast echocardiography should be performed in every young patient with unexplained cerebral ischemia.


[Ascaris lumbricoides--a cause of acute abdomen].

Ascaris lumbricoides infestation is the most common helminthic disease in many developing countries and may cause severe surgical complications, especially in children. We present a 3-year-old Ethiopian immigrant brought to hospital directly from the airport because of signs of acute abdomen. It was found to be caused by volvulus and necrosis of a loop of bowel impacted with worms. The necrotic bowel loop was resected and a temporary ileostomy was formed; recovery was uneventful. This disease and its severe complications are rare in Israel and the western world. Awareness of its occurrence is important in view of the present world-wide large-scale immigration from developing countries.


[Traumatic rupture of the diaphragm in an infant].

Traumatic rupture of the diaphragm can be caused by both penetrating and blunt trauma. High kinetic energy applied to the abdomen during blunt abdominal trauma creates pressure differences between the abdominal and chest cavities. These sudden changes in pressure rupture the diaphragm. We present a 13-month-old infant admitted after being injured by a car. In addition to rupture of the diaphragm there were pelvic fractures. Chest x-ray on admission was diagnostic for diaphragmatic rupture. The possibility of congenital diaphragmatic hernia was rejected because of increasing ventilatory embarrassment.


[Training pulse recording--useful or superfluous?].

The setting of an exercise pulse rate has become established in particular in the field of post-infarction rehabilitation. The conditions associated with its establishment, however, vary considerably. As a rule, no differentiation is made for the variations in the muscular work done. Follow-up examinations in 29 post-infarction patients showed that the recommended exercise pulse rate was an average of 10 to 20 beats lower than that established in our office under ergometric conditions. Loading-control via respiration, monitored by lactate measurement, in contrast, has proved superior in our patients, since the respiration is perceived continuously and directly by the patient himself, and is largely independent of the type of exercise involved. Control of physical exercise (loading) via the respiration would appear superior to that by the measurement of the pulse rate. The setting of an exercise pulse rate only if it can be monitored reliably and continuously with the aid of a measuring device.


[The 1990 Bochum cholesterol and blood screening program. Incidence and degree of treatment of cardiovascular risk factors].

Over a four-week period, 1,454 inhabitants of the town of Bochum (567 men = 39%, 887 women = 61%) were screened for cardiovascular risk factors. The sample was recruited from voluntary participants, two-thirds of whom were aged between 50 and 69. Age-adjusted mean total plasma cholesterol levels were 223 mg/dl for women, and 218 mg/dl for men. Age-adjusted mean systolic blood pressure were 136.7 mmHg for women, and 140.8 mmHg for men. The corresponding diastolic levels were 85.0 mmHg for women and 87.8 mmHg for men. The prevalence of hypercholesterolemia (greater than or equal to 250 mg/dl) was 32.8%, that of hypertension (greater than or equal to 160/95 mmHg) was 32.7%. Age- and sex-specific mean figures and prevalences were lower for total cholesterol and markedly higher for blood pressure as compared with representative German studies. Previously unknown hypertension (greater than or equal to 160 mmHg systolic and/or greater than or equal to 95 mmHg diastolic) was detected in 10%, and hypercholesterolemia (total cholesterol greater than or equal to 250 mgdl) in 16%. A reply postcard was received from the family doctors of only 11% of participants with elevated levels. This means that the follow-up rate remained far below the hoped-for level. Population screening can be useful in promoting primary and secondary cardiovascular disease by alerting the population to classical risk factors and informing participants about their own personal situation. In order to motivate individuals with high risk factors to act upon this information, screening should be associated with follow-up.


[Treatment of chronic hepatitis B. Part 2: Effect of glycyrrhizic acid on the course of illness].

Testing of the therapeutic efficacy of Remefa S, a pharmaceutical comprising glycyrrhizinic acid, the major active substance of licorice, on the evolution of the disease in late chronic viral hepatitis B. Prospective evaluation of the biochemical, virus-serological and histomorphological data (blind liver aspiration, laparoscopy) during and following 12 months of application (three times a week, short infusions) of Remefa S, and comparison with the course of the disease (12 months) prior to treatment. Intermediate report on an ongoing multicentre study begun in 1989, with evaluation of 7 subjects receiving the preparation and 3 controls after 12 months of treatment and 10 months of follow-up. During or after treatment, 4 patients experienced a regression of biochemical disease activity. In 2 of the 4 patients, during treatment, an HBe-Ag seroconversion occurred for the first time and has persisted (to date 10 months); in another patient with no detectable HBe-Ag prior to treatment, HBe antibodies were formed under treatment, and have persisted to the present time. In 2 of these responders, histology also revealed an unequivocal reduction in disease activity. In contrast, HBs-Ag seroconversion was observed in none of the patients treated. Since in these three patients the virus genome was already integrated within the chromosome of the host cell (hybridization), this had not been expected from the start. Intravenous chronic application (12 months) of glycyrrhizinic acid in the form of Remefa S in patients with chronic viral hepatitis B, is capable of exercising a positive effect on the evolution of the disease. On the basis of the results obtained so far (30-40% success rate), a comparison with the results obtained with interferon suggests itself.


[Anxiety disorders--syndrome, personality and relationships. Results of multi-methodology diagnosis].

Patients attending the Polyclinic of the Psychiatry Department of the Ludwig Maximilian University in Munich for ambulatory examination and counseling because of panic anxiety states with agoraphobia, were investigated using methods of descriptive-phenomenological diagnostic evaluation of syndromes and personality (structured clinical interviews on the basis of DSM III Criteria) and with methods of empirical married couple and family diagnostic evaluation (Giessen-Paar-Test, Family-Assessment-Measure). On the basis of the findings established on three different observational planes--syndrome, personality and inter-personal relationships--it was shown that anxiety disorders are expressed not merely in the symptomatology (panic disorders) and the behavior (e.g. agoraphobia) of the patient; rather, evidence of co-morbidity involving (concomitant?) personality disorders was found in almost 50% of the patients investigated. In comparison with non-clinical control groups, the patients and their partners also indicated considerable disorders in the emotive field and in their affective relationships and contact with others.


[Need for intensive disability care. Part 3: Classification of nursing care stages--relation to time requirements].

The proviso "a requirement for constant intensive care" in almost all "care-requirement situations" is an extremely strict criterion. It may even exclude some people with an extremely urgent need of care--for example if some of these situations completely fail to apply. In practice, a less strict criterion needs to be applied if the intended sociopolitical aims are to be achieved. On the basis of our experience of the actual situation presenting, orientation to the time-requirement for the services needed in the individual case is recommended as the basis for an assessment of Schwerpflegebedürftigkeit. A minimum requirement of a daily "bodily" care need of about two hours would appear to be necessary. However, an analysis of time requirement must be supplemented by an evaluation of the overall situation.


Effect of probucol on recovery from streptozotocin diabetes in rats.

The present study was conducted to see the effect of probucol on streptozotocin diabetes in rats. After 2 weeks of a 1% probucol diet, 35 or 50 mg/kg of streptozotocin were intravenously injected into male Wistar rats. All the rats became diabetic 2 days after treatment. Thereafter, in order to see the effect of probucol on spontaneous recovery from streptozotocin diabetes, 25 mg/kg of streptozotocin was injected into rats after two weeks of probucol diet and the diet was continued for additional two weeks. All the rats with a standard diet (group CS, n = 13) and 12 of 13 rats with probucol diet (group PS) became diabetic 2 days after streptozotocin injection. One rate from group PS did not develop diabetes. Two weeks after injection, only 4 of 13 rats in groups CS showed recovery, while 11 of 12 rats in group PS showed recovery from streptozotocin diabetes (p less than 0.05). The average blood glucose levels in group PS were significantly lower than group CS (10.5 +/- 4.6 vs 18.5 +/- 0.6 mM, p less than 0.05). In addition, the pancreatic insulin content of group PS was 8 times greater than that of group CS (0.75 +/- 0.24 vs 0.09 +/- 0.03 mmol/pancreas, p less than 0.01). Thus, the in vivo diabetogenic action of streptozotocin could not be reduced by pretreatment with probucol. However, recovery from streptozotocin diabetes was induced by subsequent treatment with probucol. The precise mechanisms for this phenomenon were not known; but the present findings suggest the protective effect of probucol on beta-cell damage induced by small dose of streptozotocin.


Alloxan diabetes blocks noradrenergic tachyphylaxis in the isolated rabbit kidney--effects of insulin.

Normal and alloxan treated diabetic rabbit kidneys were perfused with Krebs-Henseleit solution in a non-recirculating system and the effects of norepinephrine (NOR) 10(-6)M were tested by infusion of this drug for three subsequent periods of 20 min each, with an interval of 10 min for drug wash-out. In the control kidneys the infusion of NOR promoted an intense vasoconstriction, which was less intense during the second and the third periods. This was known as tachyphylaxis. In contrast to the controls, kidneys from diabetic animals did not show tachyphylaxis to NOR, but when insulin was added to the perfusate, tachyphylaxis appeared. Normal kidneys perfused with hyperosmolar solutions show, as in controls, the same phenomenon. The data presented here demonstrate a defect of adrenergic vascular receptors in alloxan treated kidneys, which can be acutely reversed by insulin. These facts are of importance for the understanding of the vascular disease in diabetes.


"In vitro" effects of insulin on the PDH complex of the isolated perfused heart of rats fed a sucrose-rich diet.

We have recently reported that the "in situ" myocardial concentrations of the active form of the Pyruvate Dehydrogenase Complex (PDHa) were significantly decreased in hearts obtained from normal rats fed for 3 weeks on an isocaloric sucrose rich (63%) diet (SRD) when compared to age matched controls fed on the standard laboratory chow (STD). Since, on the one hand SRD rats present glucose intolerance and impaired "in vivo" insulin action and, on the other hand the effects of insulin on the interconversion of heart PDH remains a controversial matter, we found it relevant to study the effects of insulin on the PDH complex in the "in vitro" perfused (Langendorff technique) heart preparations obtained from SRD rats. After a 35 minute perfusion period with 5.5 mM glucose as the only nutrient in the perfusate, PDHa as a percentage of total PDH was found to remain significantly lower in SRD hearts (M +/- SEM 32.6 +/- 2.3) when compared to STD hearts (68.3 +/- 4.6, P less than 0.05) in spite of comparable total PDH activities in both groups of animals. Although the addition of insulin to the perfusate (20 mu/ml) resulted in a significant increase in the percentage of PDHa (45.8 +/- 3.4) of SRD heart, values attained still remained significantly lower than those obtained in STD controls (67.5 +/- 3.6; P less than 0.05). Simultaneously, the addition of insulin to the perfusate, significantly reduced the Acetyl-CoA/CoASH ratio in SRD hearts although this ratio remained still much higher than those observed in STD controls under the same experimental conditions.


Suppression of thyroid cell growth by serum IgG in Graves' disease.

To determine whether serum immunoglobulin in addition to epidermal growth factor (EGF) augment growth in human thyroid cells, effects of these factors on thyrocytes were tested using IgG derived from 34 patients with Graves' disease and 12 normal subjects. The cell growth was estimated by [3H]-thymidine uptake, cell cycle determined by FACS analysis and the expression of c-fos mRNA in monolayer thyrocytes enzymatically prepared from Graves' thyroid. The addition of IgG taken from patients with Graves' disease inhibited the [3H]-thymidine uptake compared to that taken from control subjects. IgG taken from Graves' disease suppressed EGF-induced increase of S + G2/M phase in cell cycle and the expression of c-fos mRNA, while those taken from normal subjects did not affect at all. [3H]-thymidine uptake was more suppressed by IgG from patients with a smaller-sized goiter than by those with a larger-sized one. There was a negative correlation between the suppression of [3H]-thymidine uptake and levels of TBII (p less than 0.05). There was no correlation between the degree of suppression and the levels of T3, T4, TSAb, TSBAb or MCHA. Thus, in conclusion, IgG derived from sera of Graves' may inhibit the growth of Graves' thyrocytes, leading to the determination of the goiter size.


3,5-T2 stimulates oxygen consumption, but not glucose uptake in human mononuclear blood cells.

L-thyroxine (T4), L-triiodothyronine (T3) and 3,5-di-iodothyronine (T2) rapidly (within 30 min) stimulated oxygen consumption in human mononuclear blood cells, whereas the D isomers of T4 and T3 and Triac had no stimulatory effect. Oxygen consumption was stimulated by the same magnitude by equimolar concentrations (5-500 nmol/l) of L-T4, L-T3 and 3,5-T2 reaching a plateau at 100 nmol/l of 0.025 umol/mg DNA x h. The stimulatory effects of T4 and T3, but not of T2 were inhibited by PTU. Glucose uptake was stimulated only by L-T4 and L-T3, whereas 3,5-T2, Triac and the D-isomers of T4 and T3 had no effect. The dose response curve reached an apparent maximum at 100 nmol/l of 0.30 mmol/l x mg DNA x h and PTU had no effect on iodothyronine stimulated glucose uptake. We conclude that 3,5-T2 is a significant intracellular stimulator of oxygen consumption, whereas T3 and T4 stimulate glucose uptake.


Electrophysiological changes of Sertoli cells produced by the acute administration of amino acid and FSH.

Electrophysiological studies were carried out using seminiferous tubules of "Sertoli cell enriched testes" of rats irradiated in utero. Sertoli cells were inserted with glass microelectrodes in a superfusion chamber continuously perfused with KRb buffer. The topical application of FSH (4.0 mU/ml) produced a biphasic effect characterized by a rapid hyperpolarization (less than 3 s) followed by depolarization. The depolarizing effect of FSH was prolonged and potentiated in the presence of 5 mmol/l alpha-methylamino-isobutyric acid in the bath medium of the superfusion chamber. Verapamil, at a dose (250 mumol/l) that nullified the stimulatory action of FSH in the amino acid transport, suppressed the depolarizing effect of FSH. It was concluded that in immature rat testes FSH produces electrophysiological changes that mediate the stimulatory action of the amino acid transport.


The effect of the somatostatin analogue octreotide on growth hormone secretion in insulin-dependent diabetics without residual insulin secretion.

Growth hormone (GH) hypersecretion is well documented in insulin-dependent diabetes mellitus (IDDM). Somatostatin inhibits GH in acromegalics and healthy subjects although data on its inhibitory effects on high GH levels in IDDM patients are controversial. The effect of treatment with the somatostatin analogue octreotide ("Sandostatin") on GH secretion, IGF1 levels and metabolic control was investigated in insulin-dependent diabetics. Growth hormone and blood glucose were measured at hourly intervals whilst IGF-I was measured every 6 hours during the 24-h period before and after 7 days' treatment with octreotide (200 micrograms subcutaneously three times daily) in 10 C-peptide negative diabetics. Octreotide significantly reduced mean 24 h GH profile (7.2 +/- 0.7 mU/L before; 5.2 +/- 0.5 mU/L on octreotide, p less than 0.01), IGF-I levels (0.62 +/- 0.06 before; 0.47 +/- 0.05 on octreotide, p less than 0.005) mean 24 h blood glucose (14.4 +/- 0.5 mmol/L before; 12.6 +/- 0.4 mmol/L on octreotide, p less than 0.001) and daily insulin requirements (44.8 +/- 3.0 IU before; 37.2 +/- 3.0 IU on octreotide, p less than 0.02). The shape of 24 h GH profile curve changed significantly on octreotide treatment (p less than 0.05) when it consisted of three nadirs and three peaks closely linked with the time of octreotide administration. Moderate (abdominal discomfort) to severe hypoglycaemia) transient side effects have been observed in all treated patients. The results of this study showed that short-term treatment with octreotide given s. c. every eight hours modulates the pattern of GH secretion in C-peptide negative insulin-dependent patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of deflazacort on growth hormone response to insulin tolerance test.

Deflazacort (DF) has been claimed to be provided with a reduced distribution into the central nervous system, therefore it is conceivable that this glucocorticoid holds a lower inhibitory effect on GH secretion. To test this hypothesis we studied the GH response to insulin tolerance test (ITT) in two matched groups of patients given equivalent doses of DF and prednisone (PN). The serum glucose changes induced by ITT were similar in the two groups and in control subjects; the mean increase in plasma GH, in particular the peak and the area under the curve (delta AUC), were not different in control subjects and DF-treated patients (25 +/- 12.5 ng/ml and 1790 +/- 904 ng/ml/min versus 27.7 +/- 21.5 ng/ml and 1578 +/- 1242 ng/ml/min) but were significantly reduced in PN-treated patients (8.8 +/- 9.7 ng/ml and 431.6 +/- 451 ng/ml/min). Our study demonstrates that DF does not interfere with the GH response to ITT as PN does.


Relationship between the changes in placental blood flow resistance assessed by Doppler technique and maternal serum placental aminopeptidases, which degrade vaso-active peptides, in pre-eclampsia.

Our study showed that there were statistically significant correlations between the systolic and diastolic ratio (S/D) of maternal uterine or umbilical artery and the levels of maternal serum aminopeptidase activities in pre-eclampsia. Kininase I was positively correlated with the S/D ratios, whereas placental leucine aminopeptidase (P-LAP) and aminopeptidase A were negatively correlated with the S/D ratios. It is known that the increased S/D ratios reflect the increased utero-placental blood flow resistance. Since our previous study showed that placental aminopeptidases degrade vasoactive peptides such as oxytocin, angiotensin and bradykinin, which the fetus actively produces, our present study suggests that the increased vascular resistance in feto-placental circulation in pre-eclampsia is partly controlled by changes in vaso-active peptides, via degradation by placental aminopeptidases.


Obsessive-compulsive disorder.

Obsessive-compulsive disorder is a well-defined clinical syndrome that has been difficult to treat with standard psychotherapies and medications. Data accumulated over the last decade have demonstrated that the disorder is relatively common and frequently coexists with phobia, depression, and alcohol abuse. The authors review current studies of the spectrum of obsessive-compulsive disorder and related disorders that respond to the new serotonergic antidepressants and behavioral therapy. Differential diagnosis, epidemiology and comorbidity, etiology, evaluation, and psychologic and pharmacologic treatments are discussed. Most patients with obsessive-compulsive disorder require long-term treatment with drugs, but behavioral therapy has also been used successfully. Serotonin reuptake inhibitors used in the treatment of depression have been found effective; clomipramine has produced the best results in large-scale tests. The fact that serotonin reuptake inhibitors are effective as both antidepressants and antiobsessional agents suggests common biological factors in disorders that respond to these drugs.


Clinical review of clozapine treatment in a state hospital.

Medical records of the first 37 patients to begin clozapine treatment at a state hospital in Oregon were reviewed for six months before clozapine treatment and six months after. Patients had a long history of schizophrenia and had responded poorly to antipsychotic medication. Clozapine treatment was generally well tolerated, although the rate of seizures (8 percent) was slightly higher than expected. Psychotic symptoms decreased as measured by the Brief Psychiatric Rating Scale, as did symptoms of tardive dyskinesia as measured by the Abnormal Involuntary Movement Scale. Thirty-four patients remained hospitalized after six months of treatment. However, indicators of social function (hospital privilege level, community passes, violent episodes, and episodes of seclusion and restraint) all showed that patients improved markedly after receiving clozapine.


Factors predicting referral to inpatient or outpatient treatment from psychiatric emergency services.

Dispositional decisions in ten psychiatric emergency rooms in New York State were examined using logistic regression. Variables influencing recommendations for inpatient or outpatient psychiatric treatment were fairly consistent across the hospitals. All terms used in the regression model were interactions formed from five variables: dangerous behavior as a reason for referral, severity of the mental disorder, the hospital where the patient presented, current signs of psychosis, and a diagnosis of major mental illness. A sixth variable, assaultive behavior in the emergency room, also influenced disposition decisions but could not be considered in the model because all patients with that characteristic were referred for inpatient treatment. A model of disposition decisions based on interactions of variables may be especially powerful because it captures the dynamic combination of factors clinicians encounter.


A survey of university-prison collaboration and computerized tracking systems in prisons.

It is conservatively estimated that 8 percent of inmates in U.S. prisons have significant psychiatric impairment. Correctional mental health systems are often unable to provide adequate treatment to such inmates because of staff recruitment problems. Collaboration between universities and departments of corrections can help solve recruitment problems, and needs assessment studies and computerized tracking systems can help obtain needed resources. A national survey collected data on collaborations between universities and corrections departments and on needs assessment and computerized tracking systems in prisons. Results indicated that such collaborations exist in more than half of state prison systems. Of 42 states responding, only ten states reported having systemwide computerized tracking systems, but others are in the process of developing such systems. Two-thirds of the correctional mental health systems did not have an ongoing needs assessment program.


A review of indications for routine EEG in clinical psychiatry.

With increasing recognition of the role of organic factors in the etiology of psychiatric disorders, greater use of neurodiagnostic tests is expected. Clinical electroencephalography (EEG) is a noninvasive, low-cost neurodiagnostic technique widely available in psychiatric hospitals. Based on a review of the literature, the author outlines clinical applications of routine (non-computerized) EEG related to evaluation of organic etiologies and symptoms of dementia, delirium, and lithium toxicity; evaluation before electroconvulsive therapy; and routine screening of patients. Screening EEGs are not recommended in settings in which complete neurological examinations are routinely performed.


A single-case-study method for treating resistiveness in patients with Alzheimer's disease.

A single-case-study approach was used to identify the best medication for treating resistiveness to care in patients with moderately advanced dementia. The double-blind research design incorporated three medications, placebo washout periods, multiple baselines, frequent ratings by nurses of patients' resistiveness, and visual and statistical analysis of results to find the optimal drug, one that provided a stable response at a low dose. Six patients completed the trials. Thiothixene was more effective than oxazepam and diphenhydramine. Important features of the design were its avoidance of polypharmacy and high doses and its use of frequent ratings (each nursing shift) of patients' resistiveness. Although the single-case-study method is labor intensive, it can be beneficial when adapted for clinical use.


Primary health care in the CMHC: a role for the nurse practitioner.

Although persons with chronic mental illness have a high incidence of physical health problems, they are often ill equipped to seek care within complex health care systems and tend to depend on community mental health centers as their only source of regular health care. The authors describe a role for the nurse practitioner in assessing the medical needs of chronic mentally ill outpatients at a community mental health center and in devising strategies to meet those needs. The nurse practitioner's activities include direct physical health screening and treatment, referral for specialized medical services, consultation, research, and staff and patient education.


New path. Today's executive career path: new realities, responsibilities for hospitals.

There may have been a time when hospital CEOs could promote executive advancement simply by hiring the most talented individuals who walked through their doors. But the world has changed, and a variety of factors, including fewer opportunities for advancement and greater work-force diversity, are compelling CEOs and boards to think carefully and strategically about the issue.


Survey: equipment budgets up; use in outpatient areas growing.

Most hospitals increased their capital equipment budgets this year, finds a new survey sponsored by Hospitals and the Linc Group Inc. Rather than adding new services, hospitals are replacing equipment. But they remain cautious about adding new services, experts note.


CEOs confuse roles of physician trustees.

A majority of hospital CEOs believe physician trustees on their boards tend to represent their medical staffs. But experts warn that CEOs must make certain that their physician trustees represent the community as a whole.


A hospital's teamwork and CQI advance shared vision, interdependence among top managers. Interview by Paula Eubanks.

As quality improvement programs are initiated in growing numbers of hospitals, senior executives in those hospitals find themselves addressing a range of issues: team building, leadership and interpersonal interaction. CEO Jim Biltz and nurse executive Linda Mild of 760-bed HCA Wesley Medical Center, Wichita, KS, tell Hospitals Staff Editor Paula Eubanks how their participative management style and the hospital's continuous quality improvement (CQI) initiative have fostered new levels of teamwork and shared vision among the institution's top managers.


AIDS and the politics of compassion.

The AIDS epidemic presents the health care community with an exceptionally complex set of challenges, says June E. Osborn, M.D., the chairwoman of the National Commission on AIDS. Care-giver burnout, clinical and cost issues, and above all the challenge the disease poses to health care provider--and societal--compassion, make this epidemic unusually difficult to tackle, she writes.


Macro-orchidism: light and electron microscopic study of four cases.

A hormonal and quantitative light microscopy study of one man with macro-orchidism associated with mental retardation and fragile X chromosome (case no. 1) and three men with idiopathic macro-orchidism (cases no. 2 to 4) is reported. Hormonal study revealed slightly increased follicle-stimulating hormone serum levels in cases no. 1 to 3. The testes from cases no. 1 (orchidoepididymoectomy specimen) and 2 (testicular biopsy) presented interstitial edema and three different tubular patterns that were arranged in a mosaic-like manner. Type I tubules had an increased diameter (less than 220 microns), dilated lumen, and thin seminiferous epithelium usually consisting of Sertoli cells, spermatogonia, primary spermatocytes, and sometimes a few spermatids. Type II tubules had a normal diameter (180 to 220 microns) and germ cell development varied between complete spermatogenesis and Sertoli-cell-only tubules. Type III tubules had decreased diameter (less than 180 microns), atrophic seminiferous epithelium, and thickened tunica propria. The appearance of the nuclei of the Sertoli cells in the three types of tubules could be either mature or immature. Some of the mature Sertoli cells presented a granular cytoplasm. A few of these granular cells grouped together, forming nests that protruded into the tubular lumen. The testicular biopsies from cases no. 3 and 4 only presented type II tubules that contained both mature and immature Sertoli cells. Quantitative study revealed that the large testicular size was principally due to an increased tubular length in all four cases. Although the seminiferous tubule lesions and interstitial edema suggest an obstructive process, the testicular excretory ducts (studied in case no. 1) appeared normal or only slightly dilated. It is possible that the seminiferous tubule lesions (dilated lumen and germ cell depletion) might be secondary to the Sertoli cell lesions (granular cytoplasm and nuclear immature-like pattern.


DNA cytometry in postirradiation cervical-vaginal smears.

Benign radiation change (BRC) in cervical-vaginal smears may be difficult to distinguish from postirradiation dysplasia (PRD) or recurrent cervical carcinoma. The utility of DNA analysis in postirradiation smears was evaluated retrospectively in 71 patients. Representative Papanicolaou smears were restained with a Feulgen method and 100 to 250 cells were analyzed for DNA content using the CAS 200 image analysis system. Thirty-three control irradiated patients had negative smears with a minimum 3-year follow-up. Thirty controls (91%) had diploid histograms with a mean coefficient of variation of 8.2% and an average of 6.8% of cells in S and G2/M phase. Three control patients had atypical nondiagnostic histograms. Twenty-three patients had abnormal smears and subsequent local recurrence; 21 (91%) had abnormal histograms, with seven showing polyploidy and 14 showing aneuploidy. The remaining 15 patients had abnormal smears diagnosed as PRD but no evidence of recurrent carcinoma. Five were polyploid, six were aneuploid, one was diploid, and three were atypical but nondiagnostic. Interactive DNA cytometry is useful in differentiating BRC from PRD and recurrent cancer. Aneuploidy is rarely, if ever, seen in negative smears with BRC. However, BRC may be associated with broad diploid peaks and increased proliferating cells. An abnormal histogram can be seen with PRD and does not always correlate with recurrent disease.


A quantitative approach to the classification of hypospermatogenesis in testicular biopsies for infertility.

Absolute counts of germ cells were performed in 110 testicular biopsy specimens from 59 patients with either idiopathic infertility or varicocele and in a series of five autopsy specimens from age-matched controls. The tubular diameter, thickness of the tubular wall, and density of Leydig cells were measured. The following patterns were identified by germ-cell counts in the biopsy specimens: normal cell population, mild decrease in germ cells with normal ratio of cell types, advanced hypospermatogenesis with abnormal ratio of cell types, and Sertoli cell only. This sequence of progressive hypospermatogenesis was remarkably similar in both series. A separate category of maturation arrest was not recognized. Cell counts also correlated between right- and left-sided samples from the same patient in both series of biopsies. Reduction of tubular diameter, thickening of the tubular wall, and increase in Leydig cell density were often seen in severe stages of germ-cell impairment, although with an irregular distribution.


Phagocytic capacity of human muscle fibers.

Isolated dead muscle cell fragments (apoptotic bodies [ABs]) were investigated by electron microscopy in different stages of phagocytosis. Phagocytosis of ABs was carried out by neighboring muscle cells. The mechanism of internalization took place in both mature and immature muscle cells and consisted of the progressive engulfment of ABs within cytoplasmic vacuoles and craters. In addition, concentrated microfilaments formed a dense ring in the muscle cytoplasm adjacent to the engulfed ABs. The above combination of membrane evagination and phagocytic vacuole formation as well as the extensive microfilament organization at the site of AB engulfment were analogous to the cytoplasmic response seen in the tissue of mononuclear phagocytic cells.


Flow cytometric DNA analysis of vascular soft tissue tumors, including African endemic-type Kaposi's sarcoma.

Vascular tumors of the soft tissue display a wide spectrum of histologic features and biologic behavior. Flow cytometric DNA analysis was performed on 40 vascular tumors, including nine African endemic-type Kaposi's sarcomas, nine angiosarcomas, seven hemangiopericytomas, six glomus tumors, and nine capillary hemangiomas. Six of the nine angiosarcoma cases (67%) and one of the seven hemangiopericytomas cases (14%) were aneuploid. All benign vascular tumors and Kaposi's sarcomas were diploid. Clinically, five of the six angiosarcoma patients with aneuploidy died within 2 to 28 months, while the remaining patient, who had the smallest tumor (2 x 1 cm), survived more than 4 years after the initial diagnosis was made. All three angiosarcoma patients with diploidy died within 10 to 14 months. One hemangiopericytoma patient with aneuploidy died within 1 month. No cases of benign tumor recurred. These results suggest that most vascular tumors, which generally follow a benign clinical course, were diploid and that the majority of those with a poor outcome were aneuploid. However, flow cytometrically assessed DNA ploidy has no prognostic value in angiosarcomas or hemangiopericytomas.


A thyroid biopsy with histologic features of both Riedel's thyroiditis and the fibrosing variant of Hashimoto's thyroiditis.

We describe a 36-year-old woman with clinical, laboratory, and histologic features of both Riedel's thyroiditis and the fibrosing variant of Hashimoto's thyroiditis. Features of the former included a hard, fixed thyroid mass and extensive involvement of perithyroidal tissues by dense fibrosis with lymphocytes, histiocytes, and plasma cells. Features supporting Hashimoto's thyroiditis included high serum titers of antimicrosomal and antithyroglobulin antibodies and the histologic findings within the thyroid gland itself: dense fibrous bands dividing the thyroid parenchyma into nodules composed of lymphoid follicles with germinal centers, plasma cells, and oxyphilic metaplasia of follicular epithelial cells. Although Riedel's thyroiditis and the fibrosing variant of Hashimoto's thyroiditis were once considered morphologic variants of the same disease, since the 1970s these diseases have been considered as distinct clinicopathologic entities. The coexistence of both diseases in a patient is rare and is probably coincidental in this instance.


Renal insufficiency secondary to 2,8-dihydroxyadenine urolithiasis.

A 48-year-old man with a history of recurrent urolithiasis and chronic renal failure underwent a nephrectomy for a renal mass. At surgery the mass proved to be a calculus impacted in a dilated calyx. Gross examination of the kidney revealed chalky white deposits in the deep medulla and papillary tips. Histologic examination revealed chronic interstitial nephritis with brown spicules within some tubular epithelial cells and larger deposits of brown crystals within tubular lumina, the interstitium of the medulla, and papillary tips. Polarization microscopy revealed individual crystals scattered throughout the renal parenchyma. Although the arrangement of the crystals was reminiscent of uric acid, and, in fact, a clinical diagnosis of gouty nephropathy was made, x-ray diffraction analysis demonstrated crystals of 2,8-dihydroxyadenine. Enzymatic studies confirmed the complete absence of adenine phosphoribosyltransferase activity in erythrocyte lysates.


Chronic thyroiditis: thyroid function and histologic correlations in 601 cases.

Six hundred one patients with histologically proven "chronic thyroiditis" were assessed for the correlation of thyroid function to histologic findings. The histology of chronic thyroiditis was classified into four groups (oxyphilic, mixed, focal, and hyperplastic), and the thyroid function of patients was divided into hyperthyroid, euthyroid, latent hypothyroid, and overt hypothyroid, based on the laboratory data of serum triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) levels, as well as thyrotropin-releasing hormone (TRH) tests. In the oxyphilic group (137 cases), 116 (85%) of the patients were classified as hypothyroid: 52 (38%) as latent hypothyroid and 64 (47%) as overt hypothyroid. In the mixed group (161 cases), the thyroid function of the patients varied. Thirty-seven (23%) of the patients were classified as hyperthyroid, 61 (39%) as euthyroid, 54 (33%) as latent hypothyroid, and nine (5%) as overt hypothyroid. In this group thyroid function was intimately related to the ratio of replacement by hyperplastic-changed follicles and oxyphilic-changed follicles. In the focal group (149 cases), 123 (83%) of the patients were classified as euthyroid, while 22 (14%) were classified as latent hypothyroid. The frequency of latent hypothyroid patients increased in parallel with the severity of cell infiltration. In the hyperplastic group (154 cases), 130 (85%) of the patients were classified as hyperthyroid. In this series 19 patients under 10 years of age were included, and no difference in the distribution of histologic varieties was observed between juvenile and adult patients. Thyroid needle biopsy is a useful and safe tool, not only for the histologic diagnosis of chronic thyroiditis, but also for the evaluation of thyroid function and the identification of causes for hyperthyroidism or hypothyroidism.


Magnetic source images determined by a lead-field analysis: the unique minimum-norm least-squares estimation.

The minimum norm least-squares approach based on lead field theory provides a unique inverse solution for a magnetic source image that is the best estimate in the least-squares sense. This has been applied to determine the source current distribution when the primary current is confined to a surface or set of surfaces. In model simulations of cortical activity of the human brain, the magnetic field pattern across the scalp is interpreted with prior knowledge of anatomy to yield a unique magnetic source image across a portion of cerebral cortex, without resort to an explicit source model.


Assessing the effect of uncertainty in intracavitary electrode position on endocardial potential estimates.

The aim of this simulation study is to determine the effect of uncertainty in intracavitary probe electrode position on the accuracy of estimated endocardial potentials. Intracavitary probe position uncertainty is simulated by randomly moving an idealized probe surface about the center of an idealized left ventricular endocardial surface. These random deviations represent possible probe locations that are incorporated as correlated noise. An optimum inverse transfer coefficient matrix, relating intracavitary potentials to endocardial potentials, is computed and subsequently used to calculate the best linear estimate of the true endocardial potentials. For uncorrelated endocardial potentials and probe position uncertainty within 1.5 mm of the coordinates of the exact probe electrode locations, a root-mean-square (rms) error of 34.0% is obtained. Increasing probe position uncertainties to 3.0 and 6.0 mm results in rms errors of 60.8 and 88.3%, respectively. For endocardial potentials that are 90% dipolar, the rms errors for probe position uncertainties of 1.5, 3.0, and 6.0 mm are 11.3, 19.6, and 28.5%, respectively. These simulation results imply that position uncertainty of a multielectrode, intracavitary probe can be a major source of error in estimating endocardial potentials from intracavitary potentials.


A minimum profile uniform current density electrode.

Present methods of determining the safe injected charge levels for disk-type electrodes are given in terms of an average charge density, although the charge density is higher near the periphery of the electrode. This paper describes an electrode that produces an injected charge density that is uniform over the surface of the electrode and thus permits maximum utilization of the surface. Charge density is the time integral of current density, and the alteration of the current density is obtained by adding curvature to the electrode and recessing it within a cylindrical insulating well. A novel numerical method is used to determine the recession and curvature, and this numerical method is also presented. The benefit of this technique is that it permits a reduction in the electrode size while maintaining the maximum safe injected charge level of a disk-type electrode. A minimum profile uniform current density electrode and the algorithms used in its design are presented in this paper. Finally, a flat electrode that is recessed by as little as 1/10 of its diameter is shown to have an injected current density on the electrode surface that is superior to that of a flat surface mounted electrode.


Neural stimulation with magnetic fields: analysis of induced electric fields.

Spatial distributions of the derivative of the electric field induced in a planar semi-infinite tissue model by various current-carrying coils and their utility in neural stimulation are evaluated. Analytical expressions are obtained for the electric field and its spatial derivatives produced by an infinitely short current element. Fields and their derivatives for an arbitrarily shaped coil are then obtained by numerical summation of contributions from all the elements forming the coil. The simplicity of the solution and a very short computation time make this method particularly attractive for gaining a physical insight into the spatial behavior of the stimulating parameter and for the optimization of coils. Such analysis is useful as the first step before undertaking a more complex numerical analysis of a model more closely representing the tissue geometry and heterogeneity.


Maximal dynamic range electrotactile stimulation waveforms.

A new method to measure the dynamic range of electrotactile (electrocutaneous) stimulation uses both steepest ascent (gradient) and one-variable-at-a-time methods to determine the waveform variables that maximize the subjective magnitude (intensity) of the electrotactile percept at the maximal current without discomfort for balanced-biphasic pulse bursts presented at a 15-Hz rate. The magnitude at the maximal current without discomfort is maximized by the following waveform (range tested in parentheses): number of pulses/burst = 6 (1-20), pulse repetition rate within a burst = 350 Hz (200-1500), and phase width = 150 microseconds (40-350). The interphase interval (separation between positive and negative phases in a biphasic pulse) does not affect dynamic range from 0-500 microseconds. The number of pulses/burst has a large effect on the perceived dynamic range when this is measured using a subjective-magnitude-based algorithm, whereas it has little effect on the traditional dynamic range measure, i.e., (maximal current without discomfort)/(sensation threshold current). The perceived stimulus magnitude at the maximal current without discomfort is approximately twice as strong with 6 pulses/burst as it is with 1 pulse/burst (a frequently-used waveform).


A movement pattern generator model using artificial neural networks.

Artificial neural networks (ANN's) allow a new approach to biological modeling. The main applications of ANN's have been geared towards the modeling of the association and learning mechanisms of the brain; only a few researchers have explored them for motor control. The fact that ANN's are based on biological systems indicates their potential application for a biological act such as locomotion. Towards this goal, we have developed a "movement pattern generator," using an ANN for generating periodic movement trajectories. This model is based on the concept of "central pattern generators." Jordan's sequential network, which is capable of learning sequences of patterns, was modified and used to generate several bipedal trajectories (or gaits), coded in task space, at different frequencies. The network model successfully learned all of the trajectories presented to it. The model has many attractive properties such as limit cycle behavior, generalization of trajectories and frequencies, phase maintenance, and fault tolerance. The movement pattern generator model is potentially applicable for improved understanding of animal locomotion and for use in legged robots and rehabilitation medicine.


Recognition of multiunit neural signals.

An essential step in studying nerve cell interaction during information processing is the extracellular microelectrode recording of the electrical activity of groups of adjacent cells. The recording usually contains the superposition of the spike trains produced by a number of neurons in the vicinity of the electrode. It is therefore necessary to correctly classify the signals generated by these different neurons. This paper considers this problem, and a new classification scheme is developed, which does not require human supervision. A learning stage is first applied on the beginning portion of the recording to estimate the typical spike shapes of the different neurons. As for the classification stage, a method is developed, which specifically considers the case when spikes overlap temporally. The method minimizes the probability of error, taking into account the statistical properties of the discharges of the neurons. The method is tested on a real recording as well as on synthetic data.


Time-frequency transforms: a new approach to first heart sound frequency dynamics.

This study employed a new analytical tool, the Binomial joint time-frequency transform, to test the hypothesis that first heart sound frequency rises during the isovolumic contraction period. Cardiac vibrations were recorded from eight open chest dogs using an ultralight accelerometer cemented directly to the epicardium of the anterior left ventricle. The frequency response of the recording system was flat +/- 3 dB from 0.1 to 400 Hz. Three characteristic time-frequency spectral patterns were evident in the animals investigated: 1) A frequency component that rose from approximately 40-140 Hz in a 30-50 ms interval immediately following the ECG R-wave. 2) A slowly varying or static frequency of 60-100 Hz beginning midway through the isovolumic contraction period. 3) Broad-band peaks occurring at the time of the Ia and Ib high frequency components. The presence of rapid frequency dynamics limits the usefulness of stationary analysis techniques for the first heart sound. The Binomial transform provided much better resolution than the spectrograph or spectrogram, the two most common non-stationary signal analysis techniques. By revealing the onset and dynamics of first heart sound frequencies, time-frequency transforms may allow mechanical assessment of individual cardiac structures.


Analysis of ECG from pole-zero models.

A complete solution to the fundamental problem of ECG analysis, viz., delineation of the signal into its component waves, is proposed from a system theoretic point of view. The discrete cosine transform of a bell shaped biphasic function is approximated mathematically by a system function with two poles and two zeros, i.e., of order (2, 2). Using this concept as the basis, a pole-zero model of suitable order is derived from the discrete cosine transform (DCT) of the given signal using Steiglitz-McBride method. This model is expanded into a unique set of partial fractions each of order (2, 2), and a biphasic function is recovered from each one of these fractions in the inverse process. Each of the P and T waves usually requires only one biphasic function, while the QRS complex needs two or at most three such fractions. A one-to-one relationship between the pole pattern in the z-plane and component wave pattern in the time signal is established. Results of analysis of continuous strips of ECG show that the delineated component waves are in excellent agreement with the original waves both qualitatively and quantitatively. The method is robust for the analysis of signals with artifacts of various kinds, independent of the sampling rate used, and is free from ad hoc back and forth search procedures.