Mutalomycin, a new polyether antibiotic taxonomy, fermentation, isolation and characterization

Mutalomycin is a new metal-complexing polyether antibiotic produced by a strain of Streptomyces mutabilis NRRL 8088. The metabolite, a monocarboxylic acid, was isolated as the sodium salt C41H69NaO12. The structure of this polyether was established by X-ray analysis of its potassium salt C41H69KO12. Mutalomycin contains six heterocyclic rings and is structurally related to nigericin. The metabolite is active against gram-positive bacteria and Eimeria tenella (chicken coccidiosis).     

Experimentally induced supersensitivity of neocortical neurons to microiontophoretically administered serotonin

Central serotonergic fiber systems of the rat were selectively lesioned by intraventricular injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At various times thereafter, the sensitivity of rostral cortical neurons to microiontophoretically administered serotonin (5-HT) was compared in groups of lesioned and sham-operated animals pretreated with the 5-HT uptake inhibitor CGP 6085. Twenty-four hours after the injection of 5,7-DHT, at which time the cortical 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were both reduced by 40%, there was no significant difference in the sensitivity of cortical neurons to 5-HT. However, 3 days after such treatment, when the cortical 5-HT and 5-HIAA levels were reduced by 52% and 53% respectively, pronounced supersensitivity to 5-HT was noted. The depressant action of 5-HT on neuronal firing was potentiated with regard to both maximal firing depression and duration of the firing inhibition. A similar potentiation of the 5-HT responses was observed 7 days after lesioning. Supersensitivity thus appears to develop between 1 and 3 days after the injection of 5,7-DHT. Seven days after lesioning, the sensitivity of rostral cortical neurons to gamma-aminobutyric acid was unchanged compared to that observed in sham-operated animals.     

Time course of serial cystatin C levels in comparison with serum creatinine after application of radiocontrast media

BACKGROUND: The delayed increase of creatinine after radiocontrast application is a potential reason for overlooking radiocontrast nephrotoxicity. Cystatin C may be more useful to rapidly assess a decrease in glomerular filtration rate (GFR). We compared cystatin C and creatinine to examine their kinetics after application of radiocontrast media. PATIENTS AND METHODS: Forty-one patients (60.8 +/- 8.8 years, 68% males) with normal to subnormal GFR scheduled for coronary angiography (27% with angioplasty), were studied for serum cystatin C and creatinine levels before, 5 h, 24 h and 48 h after angiography. Furthermore, alpha1-microglobulin was checked for evidence of tubular damage. RESULTS: At 5 hours after angiography, there was no significant change compared to baseline in either serum creatinine nor cystatin C. In comparison with the value immediately before coronary angiography, the increase of cystatin C achieved a maximum at 24 h after the application of the contrast agent (+7.2%). Within 48 h, cystatin C decreased to the level before angiography. Serum creatinine increased at 24 h (+7.7%) and continued to increase at 48 h (+11.3%). CONCLUSION: Cystatin C increases earlier after radiocontrast application compared with creatinine. Therefore, cystatin C needs to be investigated as a potential early marker for nephrotoxicity, especially in the upcoming setting of short-time hospitalizations for coronary angiographies and interventions. Thus, further studies in patients with renal failure undergoing radiocontrast application are warranted to assess the usefulness of cystatin C in respect of an earlier detection of radiocontrast nephrotoxicity.     

Tolerance induction in clinical transplantation

Introduction of modern immunosuppressive agents has led to great success of allotransplantation in humans, and survival rates for all solid organs have been dramatically improved. However, a constant proportion of organs is lost every year due to chronic allograft rejection and immunosuppressive drug toxicity. This has led to a situation where, despite the of donor organ shortage, about one third of the patients on the kidney transplant waiting list are listed for a retransplant. The induction of donor-specific tolerance has the potential of at least partially resolving this problem, since it might prevent chronic rejection and drug toxicity at the same time. For a variety of protocols, successful tolerance induction has been demonstrated in rodent models. However, translation of such protocols to large animal models and on clinical trials has turned out to be very difficult. This review briefly describes mechanisms and barriers to transplantation tolerance, and then focuses on pre-clinical and clinical studies in non-human primates and humans. We have divided the strategies into two groups, based on the principle mechanisms of tolerance induction: the first group are protocols not using hematopoietic stem cell transplantation (HCT) as part of there regimen. They rely mainly on intensive T cell depletion (either by total body irradiation, total lymphoid irradiation or treatment with T cell-depleting agents such as anti-thymocyte globulin, anti-CD52 antibody or CD3 immunotoxin), which have been combined with costimulatory blockade, signaling blockade or donor antigen infusion. The second group are HCT-based protocols combining HCT with T cell-depleting agents and cytoreductive treatment. So far, only two protocols (one with total lymphoid irradiation and anti-thymocyte globulin, but no HCT; one with HCT, cyclophosphamide, anti-thymocyte globulin and thymic irradiation) have been translated into successful human studies. We summarize and discuss the results of these trials and suggest goals for further studies for the development tolerance protocols applicable for a broad population of allograft recipients.     

Coagulation activation markers do not correlate with the clinical risk of thrombosis in pregnant women

OBJECTIVE: Because coagulation activation markers have been shown to indicate an increased risk of thrombosis, we tested whether thrombin-antithrombin III complexes and D-dimers correlated with the risk assessment in pregnant women on the basis of clinical data. STUDY DESIGN: We divided a group of 261 pregnant women (305 pregnancies) into low- and high-risk groups according to the personal and family histories of thrombosis and the presence of a hereditary or an acquired thrombophilia. Women with a thrombotic event in the current pregnancy formed a separate group. All pregnancies with or without heparin therapy were closely monitored with thrombin-antithrombin III and D-dimer values for the entire course of the pregnancy. Retrospectively, the data were then correlated with the different groups and subgroups. RESULTS: The course of the mean thrombin-antithrombin III values of all 305 pregnancies was close to or slightly above the upper cutoff line, whereas the D-dimer values were well within the normal range. Independent of heparin, there was no difference in the course of the thrombin-antithrombin III and D-dimer values between the low- and high-risk groups. Only women with ongoing thrombosis during pregnancy had significantly higher thrombin-antithrombin III and D-dimer values with or without heparin therapy. Among those individuals with elevated thrombin-antithrombin III or D-dimer values, there were no specific, recognizable patients who had elevated markers more often than others. CONCLUSIONS: Thrombin-antithrombin III and D-dimer values do not correlate with a risk stratification assessed by clinical criteria. There are many women at low clinical risk who have elevated markers, and there are many women at very high clinical risk who have normal markers. Thus thromboprophylaxis would often be used inadequately if the indication were based on coagulation markers.     

Source distribution of neuromagnetic slow-wave activity in schizophrenic patients--effects of activation

When slow waves in the EEG delta and theta frequency range appear in the waking state, they may indicate pathological conditions including psychopathology. The generators of focal slow waves can be mapped using magnetic source imaging. The resulting brain maps may possibly characterize dysfunctional brain areas.The present study examined the stability of the density and distribution of MEG slow waves during three conditions-rest, mental arithmetic and imagery-in 30 schizophrenic patients and 17 healthy controls. Schizophrenic patients displayed a higher density of delta and theta generators primarily in temporal and parietal areas. The group difference was not affected by the particular conditions. The focal concentration of delta and theta slow waves did not differ between patients with and without neuroleptic medication, whereas the prominence of theta dipoles in the temporal area correlated with neuroleptic dosage. The relative amount of temporal slow waves was correlated with the negative symptoms score (PANSS-N) suggesting that temporal dysfunction may be related to negative symptomatology.Results suggest that the distribution of slow-wave activity, measured in a standardized setting, might add diagnostic information about brain abnormalities in schizophrenia.