Postoperative complications due to methicillin-resistant Staphylococcus aureus (MRSA) in an elderly patient: management and control of MRSA.

An elderly lady was admitted to hospital for elective resection of an adenocarcinoma of the colon. Following an anastomotic leak she developed intra-abdominal sepsis and underwent abdominal drainage of pus. During recovery from her second operation, she developed pneumonia and a bacteraemia due to methicillin-resistant Staphylococcus aureus (MRSA). She was treated with vancomycin and co-trimoxazole and survived without further sequelae. Details of the development and treatment of this case are discussed. Procedures for the control and eradication of MRSA infections in hospitals are reviewed.


Community-acquired pneumonia.

The aetiology of community-acquired pneumonia is reviewed, and the identification of the most likely pathogens, based on clinical presentation, is discussed. By far the major pathogen in community-acquired pneumonia is Streptococcus pneumoniae; the relative frequency of other pathogens, and particularly the atypical pneumonias caused by Mycoplasma and Legionella spp., will depend on local epidemiological factors. The diagnostic tests to confirm diagnosis and subsequent treatment of these infections are reviewed.


Activity of amoxycillin-clavulanic acid against Legionella pneumophila in vitro and in an experimental respiratory infection model.

Amoxycillin and clavulanic acid show good activity against Legionella pneumophila in vitro, and synergy has been observed between the two agents. However, in tissue culture studies, amoxycillin was inactive against intracellular legionellae, whereas clavulanic acid and amoxycillin plus clavulanic acid were as effective as erythromycin in preventing bacterial growth. These latter findings were reflected in the results of therapy of a L. pneumophila pneumonia in the neutropenic rat. Amoxycillin was ineffective in reducing bacterial counts in the lungs of infected animals, but clavulanic acid and amoxycillin-clavulanic acid produced bactericidal effects similar to those of erythromycin. The data illustrate the bactericidal activity of amoxycillin-clavulanic acid and clavulanic acid against intracellular L. pneumophila in contrast to the lack of activity of amoxycillin.


Comparative clinical and microbiological study of amoxycillin-clavulanic acid and ciprofloxacin in acute purulent exacerbations of chronic bronchitis.

In a retrospective study, the clinical and microbiological efficacy of amoxycillin-clavulanic acid and ciprofloxacin were evaluated in outpatients observed within the previous year who were affected by acute purulent exacerbations of chronic bronchitis. Of the 95 patients included in the trial, 50 received amoxycillin 875 mg-clavulanic acid 125 mg 8-hourly for 10 days and 45 received ciprofloxacin 500 mg 12-hourly before meals for 10 days. Of the amoxycillin-clavulanic acid-treated patients, 90% showed clear clinical improvement and in 10% treatment failed. In the ciprofloxacin group, 75.5% of patients showed improvement and in 24.5% treatment failed. All pathogens isolated prior to therapy were susceptible to the antibiotic used for therapy. At the end of treatment, in the amoxycillin-clavulanic acid-treated group, 84% of strains were eradicated and 8% persisted; others were superinfections. In the ciprofloxacin group, 57.7% of strains were eradicated, 26.6% persisted and 15.5% were superinfections. No clinically significant side effects were observed in either group. Overall, amoxycillin-clavulanic acid demonstrated superior clinical and microbiological efficacy to ciprofloxacin, although this might be attributable to the higher proportion of aerobic Gram-negative pathogens in the ciprofloxacin group.


The management of acute, serous and chronic otitis media: the role of anaerobic bacteria.

Otitis media (OM) is a common childhood disease and one which can cause significant morbidity. A knowledge of the pathogens responsible for OM enables the most appropriate treatment regimen to be selected and thus minimizes further complications which may require hospital admission and surgery. The microbiology of acute, serous and chronic OM is reviewed, with particular regard to the role of anaerobic bacteria. Anaerobes, mainly Gram-positive cocci, have been recovered from 25% of the ear aspirates of patients with acute otitis media. In a study of serous OM, anaerobic bacteria were recovered in 12% of the culture-positive aspirates. The predominant anaerobes were Gram-positive cocci and pigmented Prevotella. Several studies have reported the recovery of anaerobes from about 50% of patients with chronic OM and those with cholesteatoma. The predominant anaerobes were Gram-positive cocci, pigmented Prevotella, Porphyromonas sp., Bacteroides spp. and Fusobacterium spp. Many of these organisms produce beta-lactamase which might have contributed to the failure of the patients to respond to penicillins. The appropriate antimicrobial therapy for acute, serous and chronic otitis media is discussed.


In-vitro bactericidal activity of four oral antibiotics against pathogens responsible for acute otitis media in children.

This study was designed to test the in-vitro activity of four oral antibiotics against the four microorganisms most frequently isolated in acute otitis media: beta-lactamase-positive Haemophilus influenzae (N = 10), beta-lactamase-positive Moraxella catarrhalis (N = 10), penicillin-sensitive Streptococcus pneumoniae (N = 11) and methicillin-sensitive Staphylococcus aureus (N = 10), by the bactericidal curve method. Bactericidal kinetics were determined for concentrations of antibiotic equivalent to those found in the middle ear after treatment: amoxycillin-clavulanic acid (2.5 mg l-1/0.6 mg l-1 and 2.5 mg l-1/1.2 mg l-1), cefaclor (1 mg l-1), erythromycin (0.5 mg l-1) and erythromycin/sulfisoxazole (0.2/3 mg l-1). The inoculum was of 10(6) colony-forming units (cfu) ml-1. The bacterial counts were performed after 5 h and 24 h using a spiral inoculator system. The results showed that amoxycillin-clavulanic acid had rapid bactericidal activity (< 24 h) on the tested organisms at each of the doses used (reduction < or = 3 log10 cfu ml-1) which was not observed with the other antibiotics at either 5 or 24 h. Erythromycin alone or combined with sulfisoxazole had a bacteriostatic effect on Moraxella catarrhalis and Streptococcus pneumoniae but not on Haemophilus influenzae or Staphylococcus aureus. Cefaclor had no bactericidal action under these conditions.


A meta-analysis of the use of amoxycillin-clavulanic acid in surgical prophylaxis.

The efficacy of amoxycillin-clavulanic acid as antibiotic prophylaxis in surgery has been assessed in numerous clinical studies, chiefly in abdominal and gynaecological surgery. A meta-analysis of 21 trials covering 2685 patients given amoxycillin-clavulanic acid and 2220 patients given comparator regimens is presented. Monotherapy with amoxycillin-clavulanic acid was as effective as the comparators, including combination regimens utilizing gentamicin or metronidazole, in preventing wound infections (median wound infection rates were 6% and 10% respectively). The antibacterial activity of amoxycillin-clavulanic acid covers the broad range of aerobic Gram-negative and anaerobic organisms that have a major role in postoperative infections. In addition, amoxycillin-clavulanic acid may have benefits in terms of convenience, tolerance and cost.


Irradiation of Langmuir-Blodgett multilayer preparations of phospholipids and a fatty acid. 1: Effect of UV radiation.

Langmuir-Blodgett (LB) preparations containing stacked monolayers of phospholipids or stearic acid were irradiated with UV light and the electric conductance perpendicular to the planes of the monolayers was measured. There was no observable change of conductance when LB preparations of stearic acid were irradiated. For LB preparations of phospholipids, a rise of conductance, dependent on dose rate, was observed, reaching an equilibrium level after a few hours. After irradiation the conductance fell with a temperature-dependent time constant, and eventually reached a final level a little above the initial value. A three-state model is proposed for the LB phospholipid preparations. This suggests that the absorption of one photon raises a molecule from the ground to an excited state; and the absorption of a second photon carries it into a damaged but repairable or metastable state.


Irradiation of Langmuir-Blodgett multilayer preparations of phospholipids and a fatty acid. 2: Effect of X-radiation.

X-irradiation of Langmuir-Blodgett (LB) preparations of stearic acid with doses up to a few thousand Gy produced no change of measured electrical conductance in the direction perpendicular to the stacked monolayers. However, irradiation of LB preparations of phospholipids resulted in increased conductance. The effect depended on dose, but not on dose rate and, unlike the corresponding effect of UV-radiation, did not reverse at room temperature. For doses up to about 2 kGy the increased conductance fell away over some tens of minutes if the temperature was raised above 45 degrees C. For doses between 2 and 60 kGy the conductance increased linearly, but less rapidly than the initial rise and the increase was only partly reversible by heating. The rate of increase of conductance rose again for doses above about 60 kGy and for these doses the increase could not be reversed on heating. It is suggested that X-irradiation left molecules in a damaged but reversible state similar to that found after UV irradiation; and that subsequent excitation and ionization damaged the molecules irreversibly.


Metal ions protect DNA against strand breakage induced by fast neutrons.

Single and double strand breaks (SSB and DSB) are induced by fast neutrons in plasmid (pBR322) DNA in 1 mM potassium phosphate buffer (pH 7.25). Increasing the concentration of monovalent (Na+, Cs+, Li+), divalent (Mg2+, Ca2+) and trivalent (Al3+, Co3+ (NH3)6) metal cations strongly decreases the yield of DSB. The extent of the observed protection depends on the valence of the cation. The production of SSB is only slightly decreased, except for Al3+ and Co3+ (NH3)6, whose effects are particularly large (complete protection at 1 and 0.1 mM respectively). Circular dichroism spectra show that Al3+ induces an important structural change of DNA at the ion concentration where the protection becomes total. This change is probably a condensation (collapse), as in the well-known case of Co3+ (NH3)6. Our results suggest two mechanisms of protection by metal ions: (i) the induction of structural changes of DNA, that render less accessible the critical sites of attack by OH. radicals; and (ii) the stabilization of the double helical regions between two close-set nicks on opposite strands, that hinders the effective double strand breakage of DNA.


Extracellular DNA level in the blood of irradiated rats.

There is high-molecular DNA in the blood of unirradiated rats which moves as a single fraction during electrophoresis in 0.5% agarose. At short times (2-5 h) after gamma-irradiation at doses from 1 to 100 Gy a low-molecular species of DNA appears (about 180 nucleotide pairs), the amount of which is directly proportional to exposure dose at 5 h after exposure. It has been established by Southern hybridization that the low-molecular DNA has few nucleotide sequences common with those of the high-molecular DNA, but it shows homologously to genomic sequences.


Radiation-induced chromosome aberrations analysed by fluorescence in situ hybridization with a triple combination of composite whole chromosome-specific DNA probes.

Fluorescence in situ hybridization (FISH) with a combination of three composite whole chromosome-specific DNA probes for human chromosomes 1, 4 and 12 was used to analyse in vitro radiation-induced dicentrics and symmetrical translocations in peripheral lymphocytes. Translocations could be rapidly and efficiently detected by FISH. Their frequencies were 1.8-fold higher than the frequencies for dicentrics at a given dose. The dose-response curves for translocations and dicentrics were linear quadratic with a significant higher quadratic component for translocations. The application of FISH for scoring stable translocations for biological dosimetry of radiation exposures is discussed.


Lack of differential G2 chromosomal radiosensitivity between non-tumorigenic and tumorigenic human hybrid cells (HeLa x skin fibroblasts).

Previous studies have shown, that for log phase cultures, tumorigenic segregants of HeLa x skin fibroblast human hybrid cells are slightly more radiosensitive in terms of cell killing than their nontumorigenic parents (Redpath et al. 1985, Colman et al. 1988). Other studies have shown that these same tumorigenic segregants exhibit a markedly enhanced G2 chromosomal radiosensitivity (Sanford et al. 1986) thus offering a possible explanation for the cell killing data. The present study set out to examine the G2-phase radiosensitivity of these cells in terms of cell killing with the expectation that an enhanced sensitivity in the tumorigenic cells would be seen. No enhanced sensitivity was observed. The G2 chromosomal radiosensitivity was then examined and no differential was seen between the non-tumorigenic and tumorigenic cells. This lack of confirmation of previously reported studies may be due to some technical differences in the experimental protocols.


Inter-individual differences in radiation response shown by an in vitro micronucleus assay: effects of 3-aminobenzamide on X-ray treatment.

Among the methods of biological dosimetry of ionizing radiation, we propose the cytokinesis-block micronucleus assay for the measurement of the individual dose absorbed. The dose-response curve was determined for in vitro-irradiated lymphocytes from 25 individuals. The dose-response relationship, fitted by the linear-quadratic function, was F(MN) = 0.015 (+/- 0.0016) + 0.043 (+/- 0.0075).D + 0.083 (+/- 0.0045).D2. Our results are compared with those of other authors. 3-aminobenzamide (3AB) combined with X-rays were used to evaluate the micronucleus dose-response relationship in blood from 14 individuals. While it is known that 3AB inhibits poly(ADP-ribose) polymerase activity in vitro, we demonstrate that it also increases the X-ray-induced micronucleus yields. The resulting dose-response relationship varies from subject to subject. The possibility of using this approach to identify the individual radiosensitivity level is discussed.


An automated flow cytometric micronucleus assay for human lymphocytes.

A new flow cytometric method is presented for scoring micronuclei (MN) in human lymphocytes after in vitro gamma-irradiation. Fifty to fifty-five hours after PHA-stimulation, the frequency of micronuclei per nucleus and the fraction of cells in the second cell cycle were measured using flow cytometry. All data were automatically analysed using our DAS-software package. Eight individual linear-quadratic dose response curves derived from five donors revealed inter- and intra-individual variabilities of all curve parameters. Since also an age dependence was found for spontaneous MN-frequencies and for the linear curve parameter, a combined linear-quadratic age-dose-effect model was used to fit the data. The 90% prediction intervals show that a reliable individual dose estimation for donors aged between 23 and 54 years cannot be achieved for exposures below 1 Gy.


Effect of multiple irradiation with low doses of gamma-rays on morphological transformation and growth ability of human embryo cells in vitro.

We have measured expression of transformed phenotypes in human embryo (HE) cells repeatedly irradiated with a dose of 7.5 cGy per week throughout the life span of these cells in vitro. Irradiation was repeated until the cells had accumulated 195 cGy at which time the cells had reached the equivalent of their 26th passage and samples of cells at several passages were assayed for cell survival by colony formation, for mutation at hypoxanthine guanine phosphoribosyl transferase (HGPRT) locus and for transformation by focus formation. The lifespan (mean population doublings) of multiple irradiated cultures with a total dose of 97.5 cGy was slightly, but significantly, prolonged over that of controls. For example, if cells had accumulated 195 cGy, the maximum number of cell division of HE cells in vitro extended to 130-160% of non-irradiated control. Although transformed foci were not observed with cells until cells had accumulated 97.5 cGy, it increased with increasing accumulated dose. No cells, however, showed unlimited life span in vitro and also expressed tumorigenicity.


Effects of tobacco-smoke on radiation-induced pneumonitis in rats.

To investigate the effect of exposure to tobacco smoke (TS) on the development of irradiation-induced pneumonitis in rats, five groups of animals were investigated including controls (C), tobacco smoke exposed (S), irradiated (RNS) and irradiated and tobacco smoke exposed (RS). An additional group (RS/NS) was exposed to tobacco before irradiation but not afterwards. Rats were exposed to diluted mainstream cigarette smoke at a concentration of about 0.4 mg/l in a nose-only exposure system for 1/day, 5 days/week for 10 weeks. Exposure to TS started 3 weeks before irradiation in which the basal one-third of both lungs was exposed to a single dose of 28 Gy. In previous studies this dose had been shown to cause significant pneumonitis. All the animals were killed at 7 weeks after irradiation. Examination of the morphology of lung sections showed less pulmonary inflammation in the RS group than in the RNS group. This was also reflected in the results of bronchoalveolar lavage (BAL) which showed a decline in cell recovery and a marked decrease in the numbers of mast cells and neutrophils in the RS rats compared with the RNS animals. The concentration of hyaluronan in lavage fluid was increased in the RNS and RS/NS group while no increase was found in the RS group. A marked increase in BAL protein was also seen in the RNS and RS/NS groups as compared with the RS group but all were significantly higher than in unirradiated controls. This indicates that smoking suppresses the radiation-induced inflammation but to a lesser degree affects the radiation-induced increase in membrane permeability as reflected by increased protein levels in BAL. Moreover, the marked effects on the numbers of mast cells and neutrophils in the RS group may indicate that these cells play an important role in the mechanism by which tobacco smoke modulates the effects of irradiation. When exposure to tobacco smoke was terminated immediately after irradiation (RS/NS), the inflammatory response was unaffected.


The effect of whole-body gamma-irradiation on localized beta-irradiation-induced skin reactions in mice.

The combined effects of whole-body radiation and localized radiation trauma have received scant experimental attention. However, in the recent accidents at Chernobyl and Goiania skin damage from beta-contamination was combined with total-body radiation and in many cases the skin lesions which covered large surfaces of the body were severe and recovery was prolonged. This paper models the immunosuppressive effects of whole-body gamma-radiation in the sublethal to lethal range (1-11 Gy) on the skin reactions produced by 50 Gy of superficial beta-radiation. For gamma ray doses < 4 Gy no synergistic effects were detectable. For gamma-ray doses of 4, 6 and 8 Gy there was a 4-5-day prolongation in time-course of the skin reaction but no significant exacerbation of its severity. The overall time for the resolution of the skin reaction (45 days) was also unaffected by the relatively high whole-body doses. These rather surprising findings of minimal synergy between whole-body exposure and a localized severe beta burn to the skin are perhaps explained by the mismatch between the maximal immunosuppression at 2-10 days postirradiation and the timing of the skin damage at 10-25 days.


Cytotoxic and photodynamic effects of Photofrin on sensitive and multi-drug-resistant Friend leukaemia cells.

To study cross-resistance to Photofrin (PF) photosensitization, a Friend leukaemia cell line (ADM-RFLC) with a high level of multi-drug resistance (MDR) and the parental sensitive cell line (FLC) have been used. PF uptake measured by HPLC shows a similar intracellular drug accumulation in both cell lines. The ID50s for cell growth inhibition by PF are also similar after exposure in the dark in the two cell lines, while after illumination they are slightly lower in ADM-RFLC than in FLC cells. Moreover, verapamil, known to reverse the MDR phenotype induced by P-glycoprotein over-expression (the drug efflux mechanism), affects equally ADM-RFLC and FLC cells sensitivity to PF. In addition, photodynamic treatment with PF did not reverse the resistance to rhodamine 123 and aclarubicin, but partly reverses resistance of ADM-RFLC cells to antitubulin drugs such as vinblastine or vincristine. These latter results could have clinical application in the treatment of tumours expressing the MDR phenotype.


Role of membrane components in thermal injury of cells and development of thermotolerance.

Exposure of cells to hyperthermia induces a transient resistance to subsequent heat treatment. The specific mechanisms responsible for hyperthermic cell killing and thermotolerance development are not well understood. It seems that heat may induce at least two different states of thermotolerance, of which one is dependent on protein synthesis. The expression of thermotolerance may include multiple cytoplasmic and membrane components. A number of studies have indicated that membranes play an important role in governing the thermal injury of cells. It seems, therefore, that heat denatured plasma membrane proteins may be a potential target for thermal stress and a trigger for the induction of thermotolerance. The localization of heat shock proteins in the plasma membrane and the suggestion of thermal resistance in enucleate erythrocytes support this suggestion. However, a direct relationship between the plasma membrane and hyperthermic killing or development of thermotolerance has not been found.


The role of V-ATPase in neuronal and endocrine systems.

Synaptic vesicles have important roles in the neural transmission at nerve terminals: the storage and the controlled exocytosis of neurotransmitters. At least two different factors are responsible for the concentration process: the vacuolar-type H(+)-ATPase (V-ATPase), establishing an electrochemical gradient of protons, and specific transport systems for transmitters. We will discuss our recent progress on the energy-transducing systems in synaptic vesicles: (1) structural aspects of V-ATPase; (2) energy coupling of transport of transmitters; (3) reconstitution of transporters; (4) effects of neurotoxins and neuron blocking agents; (5) function of synaptic-vesicle-like microvesicles from endocrine tissues.


[Contribution of proliferating cell nuclear antigen to prognostic evaluation of carcinomas of the maxillary sinus].

Proliferating cell nuclear antigen (PCNA) is a nuclear protein, synthesized in the late G1 and S phases of the cell cycle. Therefore, it is considered to be closely related to cell proliferation. The contribution of PCNA to prognostic evaluation of the disease was investigated in 42 squamous cell carcinomas of the maxillary sinuses, retrospectively. Histological sections were prepared by formalin-fixation, paraffin-embedding and staining with monoclonal antibody to PCNA (DAKO, PC10) using the Avidin-biotin peroxidase complex method. The percentage of tumor cells with positive staining for PCNA ranged from 26.3 to 92.3% (average; 61.7%). In order to evaluate PCNA in terms of prognosis, five-year survival rates in the following two groups were compared. One included cases with a PCNA positive rate above the mean level and the other, those below the mean level. Five year survival rate was 30.4% in the group with a higher positive rate, but 42.1% in the group with the lower rate. However, the difference in survival rate between the two groups was not statistically significant. In addition, no correlations either between the rate of PCNA positivity and T-classification of tumors or between the degree of tumor cell differentiation and metastasis to neck lymph nodes were obtained. Further study is necessary to evaluate PCNA as a prognostic marker in human malignancy.


Update on the search for DNA markers linked to manic-depressive illness in the Old Order Amish.

In this report we describe our efforts to identify a gene involved in bipolar illness using a large, multigenerational Old Order Amish pedigree with many affected individuals. The original collection of cell lines from Amish pedigree 110 has been extended to include 169 individuals. We have used over 250 markers spaced at approximately 20 centiMorgans that detect restriction length fragment polymorphisms, but no LOD scores greater than 3 have been obtained from pairwise linkage analyses. We are expanding our collection of cell lines from both normal and affected family members and updating our diagnostic data as we continue our systematic screening of the genome for a gene involved in bipolar illness.


Mapping psychiatric disease genes: impact of new molecular strategies.

Genetic mapping of genes which predispose to psychiatric illness is discussed in relation to recent developments in molecular genetic technology. Among the psychiatric disorders, the mechanism by which genetic factors contribute to illness is poorly understood, and the classification of phenotype (ill-status) is extremely complicated. These uncertainties, together with other complicating factors, tend to undermine the effectiveness of genetic linkage analysis. Two very powerful new molecular strategies have the potential to improve the overall gene mapping effort. First, new applications of polymerase chain reaction (PCR) technology will allow laboratories to generate much more genetic data than has been previously possible. Some of the factors which confound psychiatric linkage analysis should be mitigated by the larger data sets that will be generated with this technology. Second, the cloning of large segments of human chromosomes into yeast artificial chromosomes (YACs) has given rise to strategies to clone and catalog the entire human genome. The goal of constructing overlapping YAC clones (contigs) end-to-end across each human chromosome now appears imminent. This development will have immense effect upon our ability to identify disease genes.


Nonhuman behavioral models in the genetics of disturbed behavior.

The development of the association method in which genetic markers match quantitative traits had led to quantitative trait loci (QTL) interval mapping. The association method has been extensively used in animal behavior genetics. Animal research allows more suitable linkage studies and detailed assessment of cellular and subcellular components of the central nervous system that may play a crucial role in the development susceptibility to behavioral disorders. Moreover, experimental designs in the laboratory setting allow genotype x environment interactions to be controlled, thus possibly providing more information on the role of nongenetic factors in gene expression. Experimental results are discussed which indicate that animal studies will provide a sort of test for hypotheses arising in clinical settings, allowing gene-product and product-behavior pathways to be examined at molecular levels when the gene accounts for a very small amount of genetic variance. In such a perspective, new molecular biology approaches and behavior genetics in nonhuman species could provide useful tools in the assessment of the genetic as well as nongenetic factors that lead to psychopathology.


The pediatric nurse practitioner and the physician assistant: how are we different?

Changing health care needs over the past 30 years have created new roles for professionals in advanced health care practice settings. As new roles continue to evolve, educational preparation and clinical experiences must be considered when determining the most appropriate health care provider for a particular specialization. Although similarities exist between the PA and PNP, the extent of pediatric didactic and clinical experiences is limited in most PA programs. Only one program is identified by the American Academy of PAs as a child health PA program. PNP education provides the nurse in an advanced practice role with an extensive background in normal growth and development, family counseling, health promotion, and management of common pediatric problems and chronic illnesses. The PNP is a registered nurse who is experienced in the care of children before pursuing an advanced degree as a PNP. In comparison, many PAs are not required to hold a professional degree before enrollment in a PA program. Although students entering PA programs may have experience in health-related fields before enrollment, few are specialized in the care of children. The PA program is designed to prepare the student to assist the physician with diagnosis and treatment in primary care with limited exposure to pediatrics. In comparison, the PNP spends the entire educational program of study gaining expertise in the care of children from infancy to adolescence. Because of advanced educational preparation, the PNP is in a unique position to contribute substantially to the total care of the child and family.


Sulfasalazine in early rheumatoid arthritis. The Australian Multicentre Clinical Trial Group.

One hundred and five patients with a diagnosis of early nonerosive rheumatoid arthritis (RA) were randomized to receive enteric coated sulfasalazine as Salazopyrin En-tabs or placebo for 6 months. Sixty-five patients completed this 6 month treatment period. Patients taking sulfasalazine were significantly better than those taking placebo in terms of Ritchie articular index, number of swollen and tender joints and erythrocyte sedimentation rate. The sulfasalazine group also demonstrated a significant fall in serum hyaluronic acid, IgM rheumatoid factor and C-reactive protein concentration. Side effects leading to withdrawal from treatment occurred in 14 of the sulfasalazine group and 4 of the placebo group. The most common side effects of patients taking sulfasalazine were rashes, liver function test abnormalities and gastrointestinal upsets. Our study demonstrates the efficacy of sulfasalazine in early RA.


[Polymorphism of T cell receptor genes and hyper-production of cytokines: their possible contribution to the pathogenesis of IgA nephropathy in ddY mouse].

The ddY mouse has been used as the spontaneous model animal of human IgA nephropathy (IgAN), because kidney lesion as well as immunological abnormalities resemble that of human IgAN. The intensity of mesangial IgA deposition in neonatally thymectomized ddY mice, in which T cell function was impaired, was less severe, indicating that cytokines from T cells determine the amount of mesangial IgA deposition. Therefore ddY mouse may possess a large amount of cytokines due to hyperactivity of T cells. To elucidate the reason for T cell hyperactivity in ddY mice, genetic polymorphism of T cell receptor genes was examined. Though restriction fragment length polymorphism (RFLP) of alpha and beta chain genes is the same as that of normal mice, the RFLP of the gamma chain is unique. Since T cells bearing gamma chain are observed frequently in the tonsil gland or intestinal intraepithelium, which are indispensable lymphoid tissues for IgA production, an uncommon DNA sequence of the gamma chain could contribute to the pathogenesis of IgAN.


[Proto-oncogene, proliferating cell nuclear antigen, perforin and growth factor gene expression in peripheral blood mononuclear cells from patients with IgA nephropathy].

IgA nephropathy, which is widely recognized as one of the most common primary glomerulonephritides, is characterized by the constant presence of IgA in the glomerular mesangium. We investigated proto-oncogenes, proliferating cell nuclear antigen (PCNA), perforin, platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF) mRNA expression in peripheral blood mononuclear cells (PBMC) obtained from patients with IgA nephropathy, patients with other types of glomerulonephritis and healthy age-matched controls. The majority of patients with IgA nephropathy showed elevated c-myc, c-fos, c-jun, c-raf, PCNA, perforin, PDGF-B chain, and IGF-I and -II mRNA expression in PBMC, while no these mRNA expression was detected in PBMC obtained from patients with other types of glomerulonephritis or normal controls. A positive correlation was noted between mRNA levels and urinary protein excretion. mRNA expression also correlated with the histopathological findings in the renal tissue of patients with IgA nephropathy. These studies suggest that abnormal regulation of proto-oncogenes, PCNA, perforin, PDGF and IGF gene expression in PBMC may be associated with the progression of IgA nephropathy and may be useful as an indicator of disease activity.


[The significance of C4 locus II deletion in IgA nephropathy and Henoch-Schonlein nephritis and it's correlation with other HLA genes].

IgA nephropathy and HSP nephritis share some similar immunological abnormalities, for example, high IgA serum concentration, existence of IgA-IC, alternative pathway activation, monocyte and B-cell activation and the same histological findings of renal biopsy. The genetic factors may play an important role in both diseases. The increased frequency of homozygous null C4 phenotypes was reported in Caucasians. But the regional variation of C4 null alleles were recognized distinctly, and the significance of C4 isotype deficiency remained unclear. We studied the relationship between IgA nephropathy and Class II and Class III HLA antigens in Japanese by not only C4 protein phenotypes but also gene analysis (TaqI, Nla IV and EcoO 109). The frequency of C4 protein isotype deficiency was the same with control groups, but significantly increased C4 gene deletion was observed in both diseases. Neither DR4 nor DQB4/8/9 related to C4 gene deletion, but the total C4 serum concentration was lower in gene deletion groups. We could not detect any deviation between C4A and C4B locus deletion by Nla IV and EcoO 109 analysis. Considering the changing process of C4A to C4B, there is a possibility that the mechanism of deletion process itself causes the elevated sensitivity to the diseases.


[Renin gene analysis of familial Bartter's syndrome].

Familial Bartter's syndrome is considered to be an autosomal recessive disease. Because an activation of the renin-angiotensin system is a characteristic feature of this disease, we evaluated a possible changes in renin gene. However, we could not detected any molecular abnormalities of renin gene, i.e. gene duplication, insertion/deletion polymorphism, nor peculiar frequencies of renin RFLPs. For further study, we must collect large numbers of affected families of this disease, and examine more various candidate genes including Cl(-)-transport proteins.


[Effect of famotidine on gastrin cell, somatostatin cell, and prostaglandin E2 concentration of stomach in experimental pyloric stenosis model].

We investigated the effect of 4-weeks famotidine administration (15 mg/kg/day) on gastrin cell (G-cell), somatostatin cell (D-cell) and prostaglandin E2 (PGE2) of gastric mucosa in pyloric stenosis rats. As a result, the increase of G-cell number and serum gastrin level in pyloric stenosis rats were potentiated by famotidine administration. However, the increase of D-cell number in pyloric stenosis was remarkably abolished by famotidine administration, and G/D cell ratio was increased accordingly. Moreover, famotidine administration decreased PGE2 concentration in fundic mucosa of the stomach without altering PGE2 concentration in pyloric mucosa. Our results suggested that famotidine administration in pyloric stenosis had a possibility to worsen the balance of endocrine cell kinetics in stomach, and PGE2 in fundic mucosa would play a roll on the proliferation of D-cell in pyloric stenosis.


Pharmacological characterization of contractile responses induced by alpha 1-agonists, norepinephrine and clonidine, by selective antagonists of their subtypes in rabbit thoracic aorta.

In the rabbit isolated thoracic aorta, WB 4101 and 5-methylurapidil dose-dependently shifted the concentration-response curves for norepinephrine to the right. Schild plots showed that the inhibition of responses for WB 4101 and 5-methylurapidil was biphasic, implying that norepinephrine acted through two receptor populations. Clonidine produced a concentration-dependent contraction in the isolated rabbit thoracic aorta. WB 4101 and 5-methylurapidil antagonized the contractions for clonidine, and the Schild plot to both antagonists against clonidine yielded a monophasic slope. Schild plots of the results obtained from the inhibition by WB 4101 and 5-methylurapidil for norepinephrine in strips pretreated with chloroethylclonidine yielded a straight line with a slope of unity. Specific binding of [3H]prazosin in the aortic membrane preparations was saturable. The Hill coefficient obtained from the inhibition curves for clonidine was significantly different from unity. Clonidine interacted with two binding sites labelled by [3H]prazosin, but the low affinity site was completely eliminated by pretreatment with 10 microM chloroethylclonidine. These results suggest that the subtype activated by norepinephrine is different from that activated by clonidine, and that norepinephrine-induced contraction through both alpha 1A- and alpha 1B-subtypes and clonidine through only the alpha 1A-subtype in the rabbit thoracic aorta.


Dynorphin-(1-13): antinociceptive action and its effects on morphine analgesia and acute tolerance.

Antinociceptive actions and effects of intracerebroventricular (i.c.v.) dynorphin-(1-13) (DYN) on morphine (MOR) analgesia and acute tolerance were studied in male Sprague-Dawley rats. Antinociceptive effect against hind paw pressure was produced by 30 micrograms of DYN, but not by 0.5-10 micrograms. Acetic acid writhing was inhibited dose-dependently by DYN at the doses of 2-30 micrograms, and the order of potency of the anti-writhing effect was beta-endorphin > MOR > DYN >> Met-enkephalin. The anti-writhing effect of DYN that was partially antagonized by naloxone at 10 mg/kg, s.c. in MOR tolerant rats was the same as that in MOR naive rats. The anti-writhing effect of i.c.v.-MOR was increased synergistically by DYN. Continuous s.c. (6 mg/kg/hr) and i.c.v. (7.5 micrograms/rat/hr) infusion of MOR produced antinociception against hind paw pressure, which reached maximum (MAX) and attenuated thereafter during MOR infusion for 6 hr. The attenuation of antinociception was also produced during MOR infusion combined with multiple i.c.v.-injection of DYN. The MAX and area under the antinociceptive curve during MOR infusion was not affected by multiple injection of DYN, i.e., no effect of i.c.v.-DYN on the development of acute MOR tolerance induced by s.c.- and i.c.v.-infusion was observed. In conclusion, the anti-writhing effect of i.c.v.-DYN might not be mediated via mu-receptors, although DYN increased the anti-writhing effect of i.c.v.-MOR synergistically and the development of acute tolerance to MOR (i.c.v., s.c.) was not affected by i.c.v.-DYN.


Effects of guanosine 5'-triphosphate on the specificity of irreversible alpha 1-antagonisms by phenoxybenzamine in rabbit thoracic aorta.

Phenylephrine displacement curves for the specific binding of [3H]prazosin in the membrane fraction prepared from rabbit thoracic aorta showed high- and low-affinity sites with slope factors significantly less than unity. The irreversible alpha 1B-antagonist phenoxybenzamine shifted the binding sites to single high affinity sites with a slope factor close to unity in the presence of the metabolically stable GTP analog GTP gamma-S. These results indicate that phenoxybenzamine may have affected selectively the low affinity site to phenylephrine in the presence of GTP gamma-S.


Utilization of extracellular lipids by HT29/219 cancer cells in culture.

Uptake and incorporation of long-chain fatty acids were studied in a human colorectal cancer cell line (HT29/219) grown in culture medium supplemented with either fetal calf serum (FCS) or horse serum (HS). The cells were grown for 120 h with no change of medium; the two major cellular lipid classes, the phospholipids and the triacylglycerols, were analyzed at regular time-points. We observed significant changes in the concentration of most fatty acids throughout culture, and differences in their composition when different sera were used to supplement the medium. Minimal levels of free fatty acids were found in the cells, indicating a very small "free fatty acid pool". A major difference between the cells grown in media supplemented with different sera was the changes observed in concentrations of cellular polyunsaturated fatty acids during growth. In cells grown with FCS (in which 20:4n-6 is present), the levels of this acid in the phospholipid and triacylglycerol fractions declined rapidly during cell growth, suggesting further metabolism. In cells grown in medium supplemented with HS, 18:2n-6 was the major polyunsaturated acid present. There was clear evidence that this acid accumulated in the cellular triacylglycerol and phospholipid fractions. Furthermore, its concentration did not decline during growth in culture, suggesting minimal conversion to other polyunsaturated n-6 acids. Our results suggest that fatty acids from additional sources in the medium, for example triacylglycerols and phospholipids associated with the lipoproteins, are taken up by the cells. There is also indication of cellular fatty acid synthesis, particularly of monounsaturated and saturated acids during the culture period.(ABSTRACT TRUNCATED AT 250 WORDS)


Dominant familial syndromes with endocrine hyperfunction: an additional syndrome?

At least 8 separate dominant syndromes have been described which have hyperfunctioning endocrine tumors as an important component. Scattered reports in the literature suggest that there may be an additional syndrome, in which extra-adrenal paragangliomas (often multiple), pituitary adenomas, and parathyroid hyperplasia coexist. Of 3 such cases described to date, 2 have included information about the family history, which in each case suggested dominant inheritance. This would presumably be a less common syndrome than the others recognized previously, so that full evaluation of endocrine findings and family history in future cases will be important for developing our understanding of the syndrome.


Essentiality of dietary omega 3 fatty acids for premature infants: plasma and red blood cell fatty acid composition.

Pre-term infants, that are not breast-fed, are deprived of vital intrauterine fat accretion during late pregnancy and must rely on formula to obtain fatty acids essential for normal development, particularly of the visual system. Preterm infants (30 wk postconception) receiving human milk were compared to infants given one of the following formulae: Formula A was a commercial preterm formula with predominantly 18:2 omega 6 (24.2%) and low (0.5%) 18:3 omega 3; Formula B was based on soy oil and contained similar 18:2 omega 6 levels (20%) and high 18:3 omega 3 (2.7%); Formula C was also a soy oil-based formula (20% 18:2, 1.4% 18:3) but was supplemented with marine oil to provide omega 3 long-chain polyunsaturated fatty acids (LCP) at a level (docosahexaenoic acid, DHA, 0.35%) equivalent to human milk. At entry (10 days of age), the fatty acid composition of plasma and red blood cell (RBC) membrane lipids of the formula groups were identical. By 36 wk postconception, the DHA content in lipids of group A was significantly reduced compared to that in the human milk and marine oil formula groups. Omega-3 LCP results were further amplified by 57 wk with compensatory increases in 22:5 omega 6 in both plasma and RBC lipids. Provision of 2.7% alpha-linolenic acid in formula group B was sufficient to maintain 22:6 omega 3 levels equivalent to those in human milk-fed infants at 36 wk but not at 57 wk. Effects on the production of thiobarbituric acid reactive substances and fragility of RBC attributable to the marine oil supplementation were negligible. The results support the essentiality of omega 3 fatty acids for preterm infants to obtain fatty acid profiles comparable to infants receiving human milk. Formula for preterm infants should be supplemented with omega 3 fatty acids including LCP.


Neuroleptic malignant syndrome in Malaysia: a university hospital experience.

The neuroleptic malignant syndrome (NMS) is a potentially fatal complication of antipsychotic therapy. A retrospective study of nine patients seen over six years at the University Hospital, Kuala Lumpur (UHKL), is described. The estimated annualised incidence was 1.2 per 1000 in-patients with psychosis. No ethnic difference was detected. Clinical features were similar to experiences elsewhere, with wide variability seen in the severity of illness. The neuroleptic drugs implicated were haloperidol, trifluoperazine, chlorpromazine, fluphenazine and clopenthixol. Treatment consisted of withdrawal of offending drugs and supportive measures. Specific therapy was given to five patients. There was one death. At follow-up no deterioration was detected. A different neuroleptic drug was successfully re-introduced in four patients. In view of the wide usage of major tranquillizers, a high degree of clinical awareness of this serious complication is necessary for early diagnosis to reduce morbidity and mortality.


A microscopical assay using a densitometric application of image analysis to quantify neurotransmitter dynamics.

We have attempted to demonstrate the technical requirements and performance of a microscopical assay using a densitometric application of image analysis to measure immunohistochemical stain intensity. Not surprisingly, the techniques required were more demanding than those used for the quantification of field and object parameters in the nervous system. The following areas of methodology have been shown to be important: (1) use of buffers free of metallic ions for tissue processing, (2) selection and titration of first and second layer antibodies, (3) reduction and control of fading of fluorescence, (4) selection of microscopical and imaging equipment to give accurate, sensitive and uniform representations of low-light biological images, and (5) use of appropriate image analysis algorithms in order to generate binary images that match the spatial and intensity distributions of immunostaining. Incorporation of these techniques into our assay system gave sensitive measurements of the time-scale of uptake of 5-hydroxy-tryptamine (5-HT) into sympathetic nerve terminals. The microscopical assay appears to have advantages over alternative approaches used for studies of neurotransmitter dynamics, particularly in small, heterogeneous tissue samples.


Complement mRNA in the mammalian brain: responses to Alzheimer's disease and experimental brain lesioning.

This study describes evidence in the adult human and rat brain for mRNAs that encode two complement (C) proteins, C1qB and C4. C proteins are important effectors of humoral immunity and inflammation in peripheral tissues but have not been considered as normally present in brain. Previous immunocytochemical studies showed that C proteins are associated with plaques, tangles, and dystrophic neurites in Alzheimer's disease (AD), but their source is unknown. Combined immunocytochemistry and in situ hybridization techniques show C4 mRNA in pyramidal neurons and C1qB mRNA in microglia. Primary rat neuron cultures also show C1qB mRNA. In the cortex from AD brains, there were two- to threefold increases of C1qB mRNA and C4 mRNA, and increased C1qB mRNA prevalence was in part associated with microglia. As a model for AD, we examined entorhinal cortex perforant path transection in the rat brain, which caused rapid increases of C1qB mRNA in the ipsilateral, but not contralateral, hippocampus and entorhinal cortex. The role of brain-derived acute and chronic C induction during AD and experimental lesions can now be considered in relation to functions of C proteins that pertain to cell degeneration and/or cell preservation and synaptic plasticity.


Release of amino acid neurotransmitters in different cortical areas of conscious adult and aged rats.

The aim of the present study was to investigate whether or not the levels of amino acid neurotransmitters change during the normal process of aging in the cerebral cortex. In vivo push-pull perfusions were performed in four different areas of the cortex of young (3-4 months) and aged (24-26 months) rats: medial prefrontal cortex, sulcal prefrontal cortex, parieto-temporal cortex and occipital cortex. Extracellular levels of Asp, Glu, Ser, Gln, and Gly were analyzed by HPLC-fluorimetric detection. Aspartate, glutamate, and serine showed no differences between young and aged animals in any of the four cortical areas studied. However, in the aged rats, the levels of glutamine, a precursor of acidic amino acid neurotransmitters, were significantly increased in medial prefrontal cortex, sulcal prefrontal cortex, and parieto-temporal cortex. No changes in glutamine were detected in occipital cortex. These results suggest that the extracellular levels of Asp and Glu in the cerebral cortex do not change during the normal process of aging possibly due to functional compensations made by intact neurons and/or astrocytes. In addition, the increase of glutamine in some areas of the cerebral cortex could be indicative of glial (astrocytes) proliferation as a result of neuronal degeneration during the normal process of aging.


Immunohistochemical colocalization of tyrosine hydroxylase and estradiol receptors in the sheep arcuate nucleus.

In sheep, the arcuate nucleus contains numerous tyrosine hydroxylase (TH) and estradiol receptor (rE2) immunoreactive (IR) perikarya and it has been shown previously in this species that catecholaminergic neurons can mediate the gonadal steroid action on the reproductive function. In the present study, double immunohistochemical labelling with antibodies against TH and rE2 have been used to demonstrate the presence of rE2 in TH-IR neurons in the arcuate nucleus where the distribution of TH-IR and rE2-IR neurons overlap each other. Only less than 10% of all the rE2-IR perikarya presented TH immunoreactivity. It was therefore hypothesized that either such a low number of double labelled neurons can support the effects of estradiol in this area or that the effect of this steroid was indirect. In the latter case it might be first mediated by beta-endorphin neurons which have been previously described in this nucleus.


Toward modeling age-related changes of attentional abilities in rats: simple and choice reaction time tasks and vigilance.

Fischer-344 rats aged 4, 12, or 18 months were trained in a simple or choice reaction time task (SRTT; CRTT). Animals were required to detect a brief (50 ms), rarely, and unpredictably occurring signal that was presented either at the central panel light (SRTT) or above one of the two levers (CRTT). Animals reported detection by pressing either lever (SRTT) or the cued lever (CRTT) within 3 s. False alarm rates were obtained from a nonsignal 3-s bin. In comparison to younger animals, 18-month-old animals showed a reduced signal detectability, and this effect did not interact with practice. These results suggest that age affected vigilance and practice did not attenuate this effect. The benzodiazepine receptor agonist chlordiazepoxide (at subsedative doses; 1, 3, and 5 mg/kg) and the beta-carboline ZK 93 426 (1, 3, and 5 mg/kg) failed to affect signal detectability. Scopolamine HBr and MBr impaired detectability and responsivity to a similar extent. However, scopolamine MBr, unlike the tertiary compound, failed to affect response accuracy in the CRTT. It is speculated that the failure of chlordiazepoxide to affect performance was related to low processing demands of both tasks. Although these behavioral models show good face validity, they do not allow determination of the major components of attentional processes (perceptual sensitivity, response criterion, processing capacity). Animal behavioral paradigms that allow determination of such components are required for the investigation of the neuronal basis of age-related changes in attentional abilities.


Regulation of the glutamine content of astrocytes by cAMP and hydrocortisone: effect of pH.

It was reported recently that the glutamine content of astrocytes incubated with glutamate and ammonium is steeply dependent on the pH of the solution. The present study shows that pretreatment of astrocytes with dibutyryl cAMP or with hydrocortisone, conditions that induce glutamine synthetase activity, increased glutamine content 2.4-fold and 5.3-fold, respectively. Nevertheless, a shift of pH from 7.4 to 7.8 increased glutamine content further by 2.7-fold and 3.0-fold, respectively. The net rates of uptake of glutamate and export of glutamine varied narrowly compared to these very large changes in glutamine content.


Astrocyte glutamate uptake during chemical hypoxia in vitro.

Glutamate uptake was measured in primary rat cortical astrocyte cultures exposed to sodium azide, 2,4-dinitrophenol, or antimycin A to assess the ability of astrocytes to function under hypoxic conditions. Uptake was maintained at 54-63% of control values despite maximal inhibition of oxidative ATP production. In contrast, the glycolytic inhibitor sodium fluoride (20 mM) reduced glutamate uptake by more than 95% when glucose was the only available substrate. These data suggest that glutamate uptake is largely maintained during hypoxia provided glucose remains available. Astrocyte glutamate uptake may aid neuronal survival during conditions such as incomplete ischemia where oxygen but not glucose is depleted.


Semiquantitative analysis of immunoreactivities of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the locus coeruleus of desipramine-treated mice.

The influence of antidepressant drugs on catecholaminergic neuron groups of the mouse brain was studied immunohistochemically, using a microphotometric semiquantitative method. The immunoreactive level of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) in the locus coeruleus (LC) was significantly decreased after 2 weeks of antidepressant administration. Our results suggest that long-term exposure to an antidepressant drug, desipramine, significantly affects intracellular catecholamine-synthesizing enzymes. These results may suggest some significant roles of the catecholaminergic neuronal groups to the action of the tricyclic antidepressant drugs.


Riluzole inhibits the release of glutamate in the caudate nucleus of the cat in vivo.

When applied locally to the caudate nucleus of the halothane-anaesthetized cat, riluzole (10(-5) M) markedly reduced (-57%) the spontaneous release of glutamate. This effect seems to be specific, since the efflux of the other amino acids, including aspartate was not affected. Indicating further its selective inhibitory effect on the spontaneous release of glutamate, the prolonged (90 min) application of riluzole (10(-5) M) enhanced the size of the potassium-releasable pool of glutamate, but not that of aspartate. This effect of riluzole was not noticed with classical anti-glutamatergic drugs, tested in the same conditions.


Intrathecal somatostatin in the guinea pig: effects on spinal cord blood flow, histopathology and motor function.

In the present investigation, the vasoconstrictive, motor and neurodegenerative effects of intrathecal somatostatin (SST) were assessed in guinea pigs implanted with lumbar intrathecal catheters. Five consecutive dose increments of SST (5, 10, 15, 30 and 60 micrograms) to a total of 120 micrograms during the period of 16 +/- 3 min, resulted in a moderate (< 20%), gradual decrease of the spinal blood flow monitored with the laser-doppler method. A subsequent injection of clonidine (50 micrograms) or norepinephrine (10 micrograms) resulted in a more pronounced decrease of spinal blood flow (35% and 79%, respectively). Three consecutive, daily intrathecal injections of 30 or 60 micrograms SST did not cause any loss of weight support or paralysis of the hind limbs. There were no histopathological changes in the white or gray matter of the thoracic and lumbar sections of the spinal cords. It is concluded that SST, in the doses studied, is not neurodegenerative in guinea pigs. These findings are in contrast to those previously seen in rats. The implication of this study may be the necessity to use several alternate animal species in order to evaluate the antinociceptive and neurodegenerative properties of the peptides administered by the intrathecal route and the choice of dose to be compared across species.


Juvenile granulosa cell tumor of an intraabdominal testis.

Juvenile granulosa cell tumor of the testis is a distinct form of sex cord-stromal tumor of neonates and infants [1]. This tumor comprises a significant percentage of testicular tumors in baby boys. We present a patient who had preoperative imaging studies.


[Current aspects of the pathology, diagnosis and therapy of C-cell carcinoma. A symposium held in Bonn, July 1991].

An essential element in the histological differentiation of medullary thyroid cancer (MTC) from other thyroid tumors is the use of immunohistochemical methods. The detection of calcitonin in the tumor cells is decisive. Factors which impair the prognosis of MTC are age (> 40 y), male sex, elevated DNA-content and mitotic activity of the tumor cells, immunoreactivity against dopa decarboxylase, histaminase and Leu-M1-antigen. Family screening is based mainly on calcitonin-stimulation tests (using pentagastrin or calcium) as a genetic marker for routine screening is not available yet. Scintigraphic methods using 99mTc-(V)-DMSA, 201Tl-chloride or 99mTc-anti-CEA antibodies become more important, especially in the detection of recurrent disease. Selective venous blood sampling is another sensitive method for localizing recurrent disease. Surgical treatment plays the dominant role in the management of MTC. Complete thyroidectomy in conjunction with systematic lymphadenectomy is now the primary treatment of choice.


Continuous spinal analgesia by means of micropumps[correction of micropumpus]: a report of 163 chronic pain patients.

Chronic pain in patients suffering from advanced cancer as well as unbearable chronic pain states depending on non-malignant pathology have always represented a test bench to verify results of advanced therapeutical programs as to more traditional approaches. The Authors present their experience resulting from longterm spinal infusion with peridural catheters connected to portable micropumps for the continuous administration of analgesic solutions. The availability of portable micropumps, a better understanding of spinal opioid receptors and advances in pharmacokinetics of opiate analgesics led in these years to a tremendous improvement of pain control possibilities and of the quality of life of patients.


Comparative variation of morphological and molecular evolution through geologic time: 28S ribosomal RNA versus morphology in echinoids.

The comparatively good fossil record of post-Palaeozoic echinoids allows rates of morphological change to be estimated over the past 260 million years and compared with rates of molecular evolution. Parsimony analysis of morphological data, based predominantly on skeletal characteristics, and parsimony, distance and maximum likelihood analyses of molecular data, from the first 380 bases from the 5' end of the 28S rRNA molecule, for 10 species of echinoid produce congruent phylogenies. The molecular sequence chosen is demonstrably far from saturation and sister groups have divergence times ranging from about 15 to 260 Ma. Parsimony analysis allows the great majority of molecular and morphological apomorphies to be placed in one of 18 independent geological time intervals, providing a direct measure of rates of evolution for periods in the geological past. Because most molecular fixed point mutations in our sequences cannot be polarized unambiguously by outgroup comparison (making the outgroup states effectively random), distance and parsimony analyses both tend spuriously to root the echinoid tree on the longest internal branch. A topology identical to that derived from morphological data is, however, obtained using Maximum Likelihood and also parsimony analysis where outgroup rooting is restricted to more conserved regions. This is taken as the correct topology for assessing rates of evolution. Overall, both morphological and molecular changes show a moderately strong correlation with time elapsed, but a weaker correlation with one another. Statistically significant differences in evolutionary rate are found between some, but not all, pair-wise comparisons of sister lineages for both molecular and morphological data. The molecular clock rate for echinaceans is three times faster than that for cidaroids and irregular echinoids. Spearman's rank correlation test, which requires only relative magnitude of changes to be known, suggests that morphological change has a slightly better correlation with time than does molecular change, averaged over all ten species. However, when just echinaceans are considered an extremely good correlation is found between the number of molecular changes and time elapsed, whereas morphological change remains poorly correlated. Thus, molecular rates approximate to a clocklike model within restricted echinoid clades, but vary significantly between clades. Averaging results over all echinoids produces a correlation that is no better than the correlation between morphological change and time elapsed.


To breed or not to breed: an analysis of the social and density-dependent constraints on the fecundity of female badgers (Meles meles).

Data from post-mortem examinations, population density estimates and long term capture-mark-recapture studies have been combined to look at the pattern of reproductive behaviour and the social factors leading to reproductive failure in badgers in Britain. The results are used to evaluate whether the hypothesis that the defence of oestrous females (as opposed to defence of food resources) best explains territorial behaviour and the social organization of badgers. Badgers in Britain have two peaks of reproductive activity, one immediately post partum and one in the summer/autumn. These coincide with two peaks of ovulation, and in the late winter/spring there is a steep rise in the number of sows carrying blastocysts, to reach an asymptote in June for yearling sows and April in older sows. Measured by their contribution to overall productivity, winter/spring matings were much more important than summer/autumn matings, contributing 65% of total autumn blastocysts in yearling sows and 71% of autumn blastocysts in older sows. The relative importance of the two mating periods is reflected in the seasonal pattern of bite wounding in adult male badgers; minor bite wounding in January-March was 2.3 times as frequent as in August-October, and moderate-extensive bite wounding was 3.1 times more frequent. In the populations studied, pre- and post-natal losses were high, with reproductive failure occurring at all stages of the breeding cycle, so that less than 30% of potential productivity was achieved. Indeed 22% of sows failed to develop blastocysts; these had a lower body mass, less body fat, larger adrenal glands, poorer health and higher bite wound scores than sows with blastocysts. Only 44% of adult sows implanted their blastocysts and proceeded to the end of pregnancy. However, it was less easy to identify features characteristic of sows that did or did not go on to implant their blastocysts. Finally, 35% of sows that produced cubs ceased lactation early, and this loss of entire litters was thought to be due to infanticide by dominant sows. The presence of annexe setts correlates with increased productivity in younger sows, and this is thought to be because annexe setts enable younger sows and their cubs to avoid the aggression of older, more dominant sows. Living in large social groups has no net reproductive gain for adult males or females, and there was a decline in productivity (per adult) with increasing group size.(ABSTRACT TRUNCATED AT 400 WORDS)


[The role of E. coli adhesiveness in the pathogenesis and clinical course of urinary tract infections].

An infection with E. coli is the most frequent cause of the urinary infections in childhood. Virulence depends on several factors out of which a principal role is played by the adhesion of bacteria to the urinary tract epithelium. Such a property have E. coli strains with adherence mannose-positive fimbriae of type P with antigens recognizing and binding glycolipid receptors on epithelial cells in the urinary tract. Children with such infections owe their "sensitivity+" (10% of the population) to genetically determined large number o receptors binding E. coli strains. Incidence and clinical course of the urinary tract infections have been analysed in the group of 184 children. Moreover, sequelae of the urinary tract infections with E. coli have been analysed in dependence on E. coli strain characteristics, i.e. presence or absence of adherent fimbriae from cases of cystitis and significant asymptomatic bacteriuria. Considering pathogenesis of the urinary tract infections as the result of interactions between bacteria and host, antigenic properties of adherent fimbriae might be used for preparation of a vaccine preventing such infections.


Zidovudine therapy in combination with intravenous immunoglobulin in HIV infected children.

There is little published data on concomitant use of zidovudine and intravenous immunoglobulin (IV IgG). In this paper we review our experience of four HIV-1 infected children treated with zidovudine for periods of 19-33 months (mean 26.5 months) subsequent to starting IV IgG for period of 18-20 months (mean 19 months). In these children the only clear benefit we found was in one child who had developed HIV encephalopathy which resolved after starting zidovudine. The respective roles of zidovudine and intravenous immunoglobulin in HIV-1 infected children need to be clarified in larger comparative trials.


The use of granulocyte-macrophage colony-stimulating factor in bone marrow transplantation.

GM-CSF represents an important advance in bone marrow transplantation. The drug can be given safely and does not appear to increase the risk of graft-versus-host disease or tumor relapse. This is a rare example of a new technology reducing the cost of health care. By shortening the duration of hospitalization, GM-CSF can significantly reduce the cost of a bone marrow transplant (Table 2). However, there are few data to support the conclusion that the reduction in the duration of neutropenia is associated with a superior survival. This attests to the excellent supportive care that has been developed for patients undergoing bone marrow transplantation. At present, GM-CSF has become a standard therapy in autologous bone marrow transplantation. However, the future will undoubtedly see the development of combinations of hematopoietic growth factors and/or new growth factors that will further improve our ability to perform bone marrow transplantation.


Genetic variation in pathogenic bacteria.

In contrast to textbook ideas of pure cultures and defined strains, genetic variation is a fact of life in the microbial world. It not only allows pathogens to establish themselves in their chosen host, but also allows them to resist that host's subsequent attempts to evict them. Here we review some of the mechanisms that bring about this variation, and some of the functional consequences that result from it.


Population analysis of single neurons in cat somatosensory cortex.

Single neurons in the somatosensory cortex are divisible into a population with receptive fields and a population without receptive fields. These two populations display different laminar distributions, and their respective functions are unknown. We compared other physiological characteristics of these two neuronal populations in an attempt to understand why some neurons lack a receptive field. Only 23% of 465 neurons isolated in the somatosensory cortex of halothane-anesthetized cats displayed a cutaneous receptive field. The iontophoretic administration of glutamate uncovered input from the periphery in another 34% of the sample, leaving 43% of the neurons without evidence of peripheral input under these experimental conditions. Neurons with a receptive field were spontaneously active much more often than neurons lacking peripheral inputs, and their rates of discharge were higher. No differences were found between neurons having a receptive field uncovered with glutamate and those unaffected by glutamate. In all classes of neurons, those cells with spontaneous activity were excited by smaller amounts of glutamate than were silent neurons, but sensitivity to glutamate was not correlated with the presence or absence of a receptive field. We infer that some classes of somatosensory cortical neurons receive strong thalamocortical inputs, whereas others have only relatively weak or no thalamocortical connections. In other experiments we have shown also that those neurons lacking a receptive field and/or spontaneous activity were more likely to be plastic than those with stronger inputs (see Warren and Dykes, 1993a,b), suggesting that neurons having weaker afferent inputs can be more readily modified under certain circumstances.


Secretion of urokinase and tissue-plasminogen activator by epidermal cells in the presence of psoriatic fibroblast-conditioned medium.

The present study examined secretion of urokinase and tissue-plasminogen activator by epidermal cells in the presence of psoriatic or uninvolved skin fibroblast-conditioned medium. Using zymographic analyses, a 54kD lysis band and a small 110kD band derived from urokinase could be detected in the harvest fluid from keratinocytes treated with both psoriatic and uninvolved fibroblast-conditioned medium, as well as very weak lysis bands of 63kD and 120kD derived from tissue-plasminogen activator in the harvest fluid treated with psoriatic fibroblast-conditioned medium, but not with uninvolved fibroblast-conditioned medium.


Gene typing of Chlamydia trachomatis by polymerase chain reaction and restriction endonuclease digestion.

A portion of the major outer membrane protein (MOMP) gene from 15 Chlamydia trachomatis serovars was amplified by polymerase chain reaction (PCR) and the product was analyzed by restriction fragment length polymorphism (RFLP). A set of primers was used to amplify an 871 base pair gene fragment encompassing the 4 hypervariable regions of MOMP. AluI digestion of the product gave distinctive patterns for the 15 serovars as demonstrated on silver-stained polyacrylamide gels. A triple digest with EcoRI, HinfI, and HpaII allowed improved discrimination between closely related serovars (C, H, I, J, L3). PCR and RFLP were used to type 50 wild-type clinical isolates and results were compared to results of the solid-phase enzyme immunoassay typing method. These isolates represented the most prevalent genital serovars (D, E, F, K, I and J) in the local sexually transmitted diseases clinic population. For specimens containing 1 serovar, the results of the two methods were similar for 42 samples and discordant for 1 sample. In addition, two samples showed evidence of mixed infection with two serovars as identified by both methods. Five additional specimens contained two serovars, as shown by one or both methods. In all five such specimens, the two typing methods agreed on at least one of the two serovars. For both single and multiple serovar specimens, there was concordance between the two typing methods for 16/17 E serovars, 8/9 D serovars, 8/8 F serovars, 7/7 I serovars, 7/7 J serovars, 5/8 K serovars, and 0/2 G serovars.(ABSTRACT TRUNCATED AT 250 WORDS)


The hairless mouse model for assaying the atrophogenicity of topical corticosteroids.

The daily application of corticosteroids for 18 days to the dorsal skin of hairless mice resulted in loss of volume of all the cutaneous compartments. The epidermis thinned, sebaceous glands regressed, dermal thickness was reduced, horn-filled cysts shrunk, subcutaneous fat disappeared, and regression of the muscular layer occurred. The magnitude of these changes correlated strongly with the accepted potency ranking of these agents by clinical efficacy. Thus, atrophogenicity predicts anti-inflammatory activity. This model furnishes a simple screening method for assaying corticosteroid activity and for optimizing proprietary formulations.


[Bilateral abdominal testicles in the adult. Microsurgical and laparoscopic therapy].

B. L. a 27 year old bilaterally cryptorchid patient underwent right testicular autotransplantation in the presence of a quite normal testis. After one year the patency of microsurgical anastomosis was confirmed by means of Doppler flowmetry and scrotal echography demonstrated the presence in the scrotum of a testis provided will normal echogenicity. Left laparoscopic orchiectomy was planned. A small semilunar skin incision was made just below the rim of the umbilicus. Veress needle was introduced: as soon as the needle pierced the parietal peritoneum, its spring mechanism was released allowing the sharp needle point to retract leaving only the blunt tip protruding. Carbon dioxide gas was insufflated through the side part of the Veress needle until adequate abdominal distension was achieved. After having removed the Veress needle, the laparoscope on its sharp-pointed trocar was introduced into the peritoneal cavity and left testis was easily localized. Four trocars were introduced up to proceed to laparoscopic orchiectomy. The patient was discharged two days after. In our opinion in the presence of a bilateral cryptorchism in the adult, is better to plan a monolateral autotransplantation. After having verified the long-term result of microsurgery we can decide if a contralateral orchiectomy has to be planned.


Expression of loricrin in skin disorders.

Loricrin, the major component of the cornified envelope, is normally expressed in the granular layer of epidermis during the last steps of keratinocyte differentiation. Using an antiloricrin antiserum (A8-73), an increased expression of this envelope precursor was found in some disorders of hyperorthokeratosis (ichthyosiform erythroderma; lichen ruber), but not in others (keratodermia ichthyosis vulgaris). In disorders accompanied by parakeratosis, a sign of incomplete differentiation (psoriasis, prurigo nodularis) loricrin was not detected, whereas the tissue expressed filaggrin. Treatment of normal skin with retinoic acid, increasing epidermal thickness in some subjects, led to an increased expression of loricrin. Loricrin might be a useful indicator of the extent of terminal epidermal differentiation in skin disorders.


Adenosine deaminase activity in sera of patients with psoriasis, mycosis fungoides and adult T cell leukemia.

Adenosine deaminase activities in sera were measured in 18 psoriatic patients, 8 mycosis fungoides patients, and 9 patients with adult T cell leukemia. Adenosine deaminase activity in the sera of the psoriatic patients showed no significant increase. An elevated adenosine deaminase activity was observed in 7 of the 8 patients with mycosis fungoides and 8 of the 9 patients with adult T cell leukemia. After chemotherapy, adenosine deaminase activity in serum of acute adult T cell leukemia was reduced. Adenosine deaminase activity in the sera of 2 patients with smoldering adult T cell leukemia was more elevated, with exacerbation of the disease. It is difficult to grade the extension of the tumors in plaque stage mycosis fungoides and smoldering adult T cell leukemia. To know the progression of the disease is critical in determining its management. These results indicate that adenosine deaminase activity in serum is one of the reliable indicators for the grading of mycosis fungoides and adult T cell leukemia.


Localized proliferative effect of preadipocytes on cultured human epidermal keratinocytes.

The effect of preadipocytes (ST 13) on cultured normal human epidermal keratinocytes (NHEK) was investigated. The growth of NHEK was accelerated with co-cultured ST 13 cells. This stimulative effect must have been localized around viable ST 13 cells, because neither the medium nor the surface conditioned by ST 13 or the ST 13 cell fragments showed any promotion of NHEK growth, and NHEK showed a compact, paving-like arrangement only when they were attached directly to ST 13 cells. It became clear that these compactly arranged keratinocytes have an active proliferative ability, since their nuclei showed a marked uptake of 5-bromodeoxyuridine (BrdU) and they were positively stained with anticytokeratin 37, a monoclonal antibody against the basal epidermis. Under electron microscopy, ST 13 preadipocytes were closely connected with NHEK. These results, together with those of previous reports, suggest that the localized proliferative effect of ST 13 cells on NHEK is due to cell-to-cell contact.


Lifetime topical application of tretinoin to hairless mice.

The discovery that topical tretinoin can reverse some of the effects of photodamage may lead to its chronic application. Examination of long-term effects was of interest. Three groups of hairless mice (age 6-8 weeks) were treated dorsally with 1) tretinoin (0.025%), 2) cream vehicle, 3) sham treatment. Applications were 3 times weekly and continued for up to 2 years until all mice were sacrificed or had died. Biweekly examinations showed no sign of retinoid toxicity, with growth and longevity similar in all groups. Tretinoin-treated skin was smooth and pink, resembling that of younger mice. Controls had yellowed, irregularly thickened skin. Histologically, tretinoin-treated skin had a hyperplastic epidermis consisting of plump, cytologically normal cells. Control skin had 3-4 compressed cell layers. Foci of new normally staining collagen were present in the subepidermal dermis of tretinoin-treated skin; fibroblasts were large and abundant in these areas. These foci were absent in controls. Mice treated with tretinoin also appeared to have increased amounts of elastic fibers and glycosaminoglycans.


Elemental changes in guinea pig epidermis at repeated exposure to sodium lauryl sulfate.

Epidermal hyperplasia is the response of the epidermis to external harmful stimuli. The control and regulation of this hyperplasia is not completely understood. It has been proposed that changes in the cellular sodium/potassium ratio are of importance in the regulation of cell proliferation. To evaluate if such a change in the elemental content of epidermal cells can be one factor to consider at irritant contact dermatitis, we performed a quantitative assessment of sodium lauryl sulfate (SLS)-induced contact reactions in the guinea pig. SLS was applied 1, 2 or 3 times and biopsies were obtained at 24 and 84 h after the last application. It was found that repeated exposures to SLS induced a hyperplasia of epidermis at 24 h persisting at 84 h. At 24 h there were significant changes in the sodium and potassium content of the keratinocytes. At 84 h there was still an increased potassium level in the cells and the sodium/potassium ratio was significantly decreased in epidermis exposed three times to SLS. This implies that changes in cellular sodium/potassium ratios occur in epidermal hyperplasia following irritant stimuli.


A dose-response study of irritant reactions to sodium lauryl sulphate in patients with seborrhoeic dermatitis and atopic eczema.

The susceptibility of the skin of patients with seborrhoeic dermatitis to surfactant irritation was investigated and compared to that of a group of normal subjects and patients with a history of atopic eczema. Responses to six concentrations of sodium lauryl sulphate (SLS), applied to forearm skin, were assessed clinically and measured by laser Doppler flowmetry. Analysis of dose-response curves showed statistically significant increased susceptibility to SLS-induced irritation in patients with seborrhoeic dermatitis and atopic eczema compared with normal subjects. Increased susceptibility to chemical irritation may be important in the pathogenesis of seborrhoeic dermatitis.


Cyclosporin A responsive chronic severe vesicular hand eczema.

A patient with an otherwise recalcitrant chronic vesicular hand eczema responded with a dramatical improvement within 2 weeks of cyclosporin A (CsA) therapy 5.0 mg/kg daily. The patient was still free of eczema in spite of reducing the CsA dose to 2.5 mg/kg daily. CsA therapy was finally stopped due to a moderate increase in blood pressure, resulting in rapid recurrence of the hand eczema. The case report clearly demonstrates that oral CsA should be considered in patients with severe hand eczema that cannot be controlled on conventional immunosuppressive treatments.


Folinic acid rescue used routinely in psoriatic patients with known methotrexate "sensitivity".

Many combinations of methotrexate and folic or folinic acid have been used to limit the side effects of methotrexate therapy in psoriasis or psoriatic arthropathy. Methotrexate inhibits the enzyme dihydrofolate reductase and prevents the formation of DNA and RNA. Folinic acid, the 5-formyl derivative of tetrahydrofolic acid, is the active form of folic acid. We have confirmed in 5 patients that continuous administration of folinic acid with weekly oral methotrexate prevents improvement of psoriasis. When folinic acid was ceased on the day of methotrexate in these patients their psoriasis improved. Five other patients with previous sensitivity to methotrexate, forcing cessation of therapy, were given weekly oral methotrexate and folinic acid every day except the day of methotrexate. Marked improvement of psoriasis or arthropathy occurred in each case without side effects. This method precisely limits the exposure to methotrexate, allowing a therapeutic effect without complication even in those patients who exhibit methotrexate sensitivity.


Intertriginous drug eruption.

Presented are two patients who developed an unusual, and as yet unreported eruption due to amoxycillin. They exhibited an eruption confined to the intertriginous areas, which mimicked intertrigo. Although drug eruption can mimic a variety of idiopathic skin diseases, intertrigo is easily distinguished from drug eruption and has not been mentioned in the differential diagnosis of this reaction. It is suggested that drug reactions should be considered in the differential diagnosis of intertrigo, in particular of atypical and therapy-resistant cases. Early detection of these cases has practical importance since the elimination of the causative drug is essential for therapy success. Case 2 showed a response of the toxic epidermal neurolysis (TEN) type, which could have been very severe and dangerous had the diagnosis not been made in an early stage before the development of generalized TEN.


Juvenile generalized pustular psoriasis in a pair of monozygotic twins presenting strikingly similar clinical courses.

We describe an exceptionally rare case of juvenile generalized pustular psoriasis noted in monozygotic twins who, after developing the disease on the same day (the 48th day after birth) continued to show strikingly similar clinical features of generalized pustular psoriasis for 7 years. Not even therapeutic intervention by tonsillectomy performed at age 4 years on one of the twins, which was expected to have some beneficial effect, could decrease the number of attacks or pustulation compared with the counterpart.


Efficacy and skeletal side effects of two years' acitretin treatment.

In this prospective study, 51 patients suffering from psoriasis and ichthyosis were treated with acitretin for 2 years. The average dose was 0.5 mg/kg/day. We have evaluated the efficacy and side effects, focusing on skeletal side effects. X-ray examinations were done before treatment and after 1 and 2 years. Forty-five patients completed the study. Acitretin had a good clinical effect, with 75% improvement in 35 of the patients. Apart from the well-known side effects affecting the mucous membranes, one patient developed biopsy- proven toxic hepatitis. In 2 patients we observed unusual skeletal calcifications located in the forearms and in the hip. These were considered to be caused by the drug. In this study, which included patients up to 71 years, only radiographs of the pelvis and the forearms were of value as routine follow-up films.


One-minute dithranol therapy in psoriasis: a placebo-controlled paired comparative study.

In a double-blind left-right randomised comparison, 27 patients suffering from chronic plaque-type psoriasis vulgaris were treated for one minute with dithranol 2% ointment, Psoralon (Psoralon MT), on a selected psoriasis plaque on one half of the body and with a placebo ointment on a corresponding plaque on the other. The preparations were applied once daily for 8 weeks. Seventeen patients achieved clearing or considerable improvement with dithranol therapy, as compared with 6 patients with placebo (p = 0.002). Erythema, infiltration, scaling, pruritus and the overall result were assessed. Statistically significant differences in favour of dithranol treatment were seen for all five variables, except for pruritus. The average of these five variables, designated the mean score, was also analysed; dithranol was seen to yield significantly better results (p = 0.001). Staining of clothes and the bathroom was noted by 3 and 5 patients, respectively, but no medical side effects were seen.


Aberrant cutaneous weal and flare responses in chronic urticaria.

This study examined cutaneous mast cell behaviour in 14 patients with chronic urticaria but no dermographism and 11 healthy controls, by measuring cutaneous weal and flare reactions evoked in response to intradermal challenge injections of 0.1 ml isotonic saline, histamine (20 micrograms), codeine phosphate (10 micrograms) and compound 48/80 (10 micrograms). Five minutes after each injection, the area of the resulting weal and flare was calculated by computer-aided planimetry. The process was repeated at 15, 30 and 45 min following the injection. In patients, saline flares were significantly larger than those of the volunteers at 15, 30 and 45 min (p < 0.05). However, histamine and codeine flare areas were significantly smaller in the patients when compared to the controls at 15, 30 and 45 min (p < 0.05). Compound 48/80 produced smaller reactions in the patients without reaching statistical significance.


Treatment with bifonazole shampoo for seborrhea and seborrheic dermatitis: a randomized, double-blind study.

Forty-four patients with seborrhea and seborrheic dermatitis of the scalp were treated with either bifonazole shampoo (22 patients) or the vehicle shampoo (22 patients) in a randomized, double-blind vehicle-controlled study. The patients were instructed to wash their scalps 3 times weekly for 6 weeks and were examined every 3 weeks. Responses were evaluated by clinicians using a clinical grading of scaling, erythema and overall improvement, and also by the patients, who assessed pruritus and overall improvement, using a scale of 0 to 3. The improvement following the bifonazole shampoo was found to be significantly greater than that achieved with the vehicle shampoo in regard to the clinical evaluation of scaling (p = 0.01) as well as patient evaluation of pruritus (p = 0.008) and overall improvement (p = 0.03). No major adverse side effects were recorded.


Allergic contact sensitization in an unselected Danish population. The Glostrup Allergy Study, Denmark.

The distribution of allergic contact sensitization was assessed in an unselected population, living in western Copenhagen, Denmark. Ready-to-apply patch tests comprising 23 haptens and mixtures of haptens were mailed to 793 adults, and 567 (71.5%) participated. The tests were read 2 days after application. A total of 111 positive reactions were found among 86 (15.2%) subjects. Sensitization was less frequent in men than in women (11.5% versus 18.8%). Twenty out of the 23 chemicals in the test elicited positive reactions. Positive reactions to nickel and thiomersal were found most frequently (6.7% and 3.4%, respectively). Concerning the other chemicals the frequencies were 1.1% or less. Nickel sensitivity was less frequent in men than in women (2.2% versus 11.1%). The frequencies of sensitization probably represent minimum figures. Regulation of exposure needs to be considered in order to prevent primary sensitization and disease recurrences in those already sensitized.


Intractable chronic furunculosis: prevention of recurrences with pentoxifylline.

A 60-year-old HIV-negative man with known noninsulin-dependent diabetes mellitus and glucose 6-phosphate-dehydrogenase deficiency anemia suffered from chronic recurrent furunculosis since the age of 30. In recent years, his condition had become increasingly severe and the recurrences increasingly frequent. Different measures including continuous therapy with large doses of systemic antibiotics for a period of 6 months failed to prevent the recurrences. Oral treatment with pentoxifylline 400 mg t.i.d. was prescribed, and 2 months later the patient experienced a dramatic and complete remission of his furunculosis. Six months later he was still totally free of lesions while continuing to take the same medication. Pentoxifylline may provide a new and effective approach to the previously difficult and often disappointing problem of the management of patients with chronic recurrent furunculosis.


Cholinergic modulation of GH secretion in acromegalic patients before and after pituitary surgery.

Cholinergic neurotransmission exerts a physiological control on GH secretion. Pirenzepine (Pz), an antagonist of muscarinic receptors, by enhancing hypothalamic somatostatin release, inhibits stimulated GH secretion in normal subjects but not in acromegalic patients. To address the hypothesis that a feedback effect of GH hypersecretion can be involved in this condition, GH responses to GHRH 1-29, 1 microgram/kg iv, with and without administration of Pz, 40 mg iv before tests, were investigated in eight acromegalic patients, before and 20-30 days after transsphenoidal adenomectomy. Pz diminished (p < 0.001) the incremental area under the curve (AUC) of GH responses to GHRH in seven normal controls. In contrast, GHRH responsiveness in untreated acromegalic patients was not affected by Pz. Postoperative basal GH levels decreased by 62.4 +/- 14.9% (p < 0.01). Pz inhibited GH responses to GHRH (p < 0.01). Furthermore, a direct relationship (r = 0.73, p < 0.01) between basal concentrations and the AUC of GH responses following Pz plus GHRH-test was found. The finding that muscarinic receptor activity recovered after the reduction of serum GH basal levels by pituitary surgery lends support to the proposed pathophysiological role of GH excess as a possible determinant factor in cholinergic-somatostatinergic dysfunction in acromegaly.


Growth hormone secretion in old female rats analyzed by the reverse hemolytic plaque assay.

Growth hormone (GH) release was studied in young (3-4-month-old) and old persistent diestrous (20-21-month-old) female rats using the reverse hemolytic plaque assay. A bimodal distribution of reverse hemolytic plaque area was observed in both young and old female rats. The mean and median of the plaque area of GH cells from old females were smaller than those from young female rats. The percentage of plaque-forming GH cells in old female rats was lower than in young female rats. The percentage of large plaque-forming GH cells (plaque area, more than 8 x 10(3) microns2) was lower in old female rats than in young female rats. GH-releasing hormone (GHRH) increased the mean and median of plaque areas in both young and old female rats. However, responsiveness to GHRH was reduced in old female rats. These results indicate that the amount of GH released from individual GH cells decreases with age in female rats, resulting in diminished GH secretion.


Effect of insulin-like growth factor I on the thyroid axis in patients with Laron-type dwarfism and healthy subjects.

We have evaluated the effect of exogenous administration of IGF-I on the thyroid axis in four separate studies: (1) iv bolus injection; (2) single sc injection; (3) seven days' sc treatment, and (4) four months' treatment. Thirteen patients with Laron-type dwarfism (LTD) participated in the investigations. In studies 1 and 2, 10 healthy subjects were also included. Before and during long-term treatment (study 4) six LTD patients underwent a TRH test. IGF-I was administered in a dose of 75 micrograms.kg-1 iv or 120-150 micrograms.kg-1 sc. Single injections of IGF-I caused significant decreases of serum TSH in LTD patients (iv: 1.7 +/- 0.2 to 1.1 +/- 0.1 mU/l; sc: from 2.1 +/- 0.4 to 1.1 +/- 0.2; p < 0.0005). In controls the decrease was for iv from 1.2 +/- 0.2 to 0.8 +/- 0.2 mU/l (p < 0.02) and for sc from 2.0 +/- 0.5 to 0.8 +/- 0.2 mU/l (p < 0.05). Long-term administration of IGF-I induces a transitory decrease of both serum TSH and fT4, followed by a spontaneous rise to pretreatment or even higher values. No changes in T3 were observed. TSH stimulation by TRH was significantly augmented after four months of IGF-I treatment (p < 0.005). The effects of IGF-I can be explained by an early stimulation of somatostatin release causing a decrease in TSH and followed by the development of compensatory mechanisms. All changes were within the normal ranges, not causing abnormal thyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)


[Autologous blood-derived stem cell transplantation in the treatment of proliferative disorders of the hematopoietic system (I)].

Peripheral blood can be an alternative source of hematopoietic stem cells which after autografting are capable of sustaining or completely recovering of lymphopoiesis without the necessity of bone marrow harvesting. Theoretical assumptions conditioning the clinical application of circulating stem cells autotransplantation have been described. The results of experimental studies performed in animals and humans have allowed for closer characterization of these cells. However, the physiological significance of their presence in the peripheral blood still remains unknown.


The role of purinergic neurotransmission in various cardiovascular reflexes.

In urethane-anaesthetized rats the effects of alpha-adrenoceptor antagonists and desensitization of P2-purinoceptors with alpha,beta-methylene ATP on the pressor reflex responses were investigated. Pressor responses were elicited by electrical stimulation of the central end of the sciatic nerve, by asphyxia and by occlusion of the common carotid artery. Responses to sciatic nerve stimulation and to asphyxia, but not those to carotid artery occlusion were entirely suppressed by dihydroergotamine and phentolamine. Under the action of dihydroergotamine the sinocarotid reflex decreased by over 70% in 40% of the experiments. In 60% of experiments the response was only slightly reduced or even augmented, but it was entirely inhibited by subsequent desensitization with alpha,beta-methylene ATP. The magnitude of response to sciatic nerve stimulation was almost unaffected by alpha,beta-methylene ATP, while the response to carotid occlusion was decreased by 40-50%. The recovery of purinoceptor sensitivity to alpha,beta-methylene ATP was accompanied by restoration of the sinocarotid reflex. It is suggested that purinergic neurotransmission plays a considerable role in the pressor sinocarotid reflex, while in the pressor response to stimulation of somatic afferents its role is negligible.


Modulation of G proteins and second messenger responsiveness by steroid hormones in GH3 rat pituitary tumour cells.

We have investigated the modulation of different G protein alpha- and beta-subunit levels in prolactin (PRL) and growth hormone producing rat pituitary adenoma cells (GH3 cells) in culture after prolonged exposure (6-48 h) to the steroid hormones 17 beta-oestradiol and dexamethasone. Gi-3 alpha- and G beta-subunits were the only G protein subunits which increased in response to 10(-6) M oestradiol (to approximately 150 and 200% of controls, respectively), while the other alpha-subunits investigated (Gs alpha, Gi-2 alpha and G(o) alpha) remained relatively unchanged. Thyroliberin (TRH)--and guanosine 5'-[beta gamma-imido]trisphosphate (Gpp(NH)p)-elicited adenylyl cyclase (AC) activities were reduced during 6-12 h of oestradiol treatment (by 60 and 20%, respectively), while the inhibitory effect of somatostatin (SRIF) increased by approximately 100%. Dexamethasone (10(-6) M) increased levels of the stimulatory G protein Gs alpha (to approximately 340%) and decreased levels of Gi-3 alpha (to 25%). After 48 h, the AC response to TRH was reduced by approximately 70%, whereas the effect of the other modulators remained close to controls. We conclude that G protein subunits in GH3 cells are subject to specific regulation by steroid hormones and that this may be important in the tuning of the responsiveness of PRL secretion to hormones in the in vivo situation.