SCH 45752--an inhibitor of calmodulin-sensitive cyclic nucleotide phosphodiesterase activity

A highly potent inhibitor of calmodulin-sensitive phosphodiesterase (PDE) activity was isolated from the culture broth of an unidentified fungal isolate, SCF-125. A chemically defined medium was developed for production of this compound. The PDE inhibitor was isolated from the fermentation filtrate by adsorption on a macro-reticular resin and further purified by gel filtration chromatography and reverse-phase HPLC. The major PDE inhibitor was identified as cephalochromin, a bis-naphthopyrone, by spectral data analysis. The compound, SCH 45752, inhibited calmodulin-sensitive PDE activities with IC50 values of 40-47 nM. It inhibited the activities of calmodulin-independent PDE and various protein kinases with higher IC50 values (2-40 microM). SCH 45752 does not appear to be a calmodulin antagonist. Furthermore, SCH 45752 affects smooth muscle contraction at a concentration of 30 microM; it potentiated the relaxing effect of sodium nitroprusside on carotid artery media contracted by histamine. Thus SCH 45752 is one of the most potent inhibitors of calmodulin-sensitive PDE activity known, and it is capable of exerting a pharmacological effect in at least one intact tissue model.     

Evaluation of commercial presence-absence test kits for detection of total coliforms, Escherichia coli, and other indicator bacteria

Evaluations of several commercial presence-absence (P-A) test kits were performed over a 6-month period in 1990 by using the Ontario Ministry of the Environment (MOE) P-A test for comparison. The general principles of the multiple-tube fermentation technique formed the basis for conducting the product evaluations. Each week, a surface water sample was diluted and inoculated into 25 99-ml dilution blanks for each of three dilutions. The inoculated dilution blanks from each dilution series were randomly sorted into sets of five. Three of these sets were inoculated into the P-A test kits or vice versa, as required. The other two sets were passed through membrane filters, and one set of five membrane filters was placed onto m-Endo agar LES to give replicate total coliform counts and the other set was placed onto m-TEC agar to give replicate fecal coliform results. A statistical analysis of the results was performed by a modified logistic transform method, which provided an improved way to compare binary data obtained from the different test kits. The comparative test results showed that three of the four commercial products tested gave very good levels of recovery and that the fourth commercial product gave only fair levels of recovery when the data were compared with the data from MOE P-A tests and membrane filter tests. P-A bottles showing positive results after 18 h of incubation that were subcultured immediately in ECMUG tubes frequently could be confirmed as containing total coliforms, fecal coliforms, or Escherichia coli after 6 h of incubation; thus, the total incubation time was only 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Apoptosis (the 1992 Frank Rose Memorial Lecture)

Lymphocyte subset abnormalities have been observed in a series of patients diagnosed with Wegener's granulomatosis (WG). Fifteen patients with WG were evaluated for lymphocyte subset abnormalities by two-color immunofluorescence flow cytometry. The WG group showed a decrease in CD4+ cells and an extraordinary increase in HLA-DR+ cells. The average percentages of HLA-DR+ cells of the normal group and WG group were 11.0 +/- 4.0 and 40.5 +/- 13.9% (CD3+HLA-DR+ = 20.3 + 9.4%). Within the CD8 family, CD8+57+, CD8+38+ and CD8+HLA-DR+ cells were markedly elevated. Our findings differ from other series which reported that the lymphocyte subsets in the peripheral blood of patients with WG were normal.     

Protective effects of a recombinant N-terminal fragment of bactericidal/permeability increasing protein on endotoxic shock in conscious rabbits

Endotoxin (lipopolysaccharide, LPS) can induce shock, multiple organ failure, and death. A recombinant N-terminal fragment of bactericidal/permeability increasing protein, rBPI23, binds with high affinity to gram-negative bacterial LPS and neutralizes its biological activity. We sought to determine the effect of rBPI23 on LPS-induced respiratory dysfunction and cardiovascular depression in conscious rabbits. Rabbits were injected with Escherichia coli O113 LPS (6 micrograms/kg) and treated with rBPI23 (2 mg/kg), vehicle, or control protein after recovery from surgery performed to implant catheters for hemodynamic assessments and intravenous injections. LPS challenge caused respiratory dysfunction including tachypnea, significant decreases in arterial O2 tension (PO2), arterial oxygen content, and an increase in alveolar-arterial O2 gradient (A-aDO2). LPS administration also resulted in profound and prolonged decreases in mean arterial blood pressure and cardiac index. Treatment with rBPI23 prevented LPS-induced respiratory dysfunction and significantly ameliorated the cardiovascular depression. 5 of 16 LPS-challenged animals died of respiratory failure and acidosis, whereas none died in the rBPI23 treated group (p = .11). The results demonstrate that rBPI23 protects animals against LPS-induced cardiopulmonary depression in endotoxic shock.     

Removable partial prostheses for the elderly

Elderly partially edentulous patients can have teeth replaced with removable or fixed prostheses supported by mucosa, teeth, or implants. Age per se does not influence which option is best. Instead, the relative health of the patient, dental tissues, and the patient's finances determine treatment. A three-level index of these factors, the PTF index, is proposed to assist in the decision-making for treatment. Removable partial prostheses (RPPs) can be indicated for all patients because RPPs offer esthetic, versatile, noninvasive, and reversible features. They are particularly indicated when remaining teeth are questionable. If teeth are lost, they can be more easily added to existing RPPs compared with fixed prostheses. Six changes to ideal designs are illustrated in this article for prostheses with a compromised dentition, to make continued prosthetic service simpler.     

Severe fetomaternal alloimmune thrombocytopenia presenting with fetal hydrocephalus

We report two patients where the finding of isolated fetal hydrocephalus led to the detection of severe fetal thrombocytopenia, using fetal blood sampling. Serological investigation led to the diagnosis of fetomaternal alloimmune thrombocytopenia (FMAIT) due to anti-HPA-1a. Both women had had previous unsuccessful pregnancies probably due to FMAIT; one had had four miscarriages at 17-18 weeks' gestation. The other had had one previous pregnancy complicated by severe fetal anaemia, and eventually hydrocephalus developed and the fetus died without the diagnosis of FMAIT being considered. Subsequent pregnancies in the two women were also affected by FMAIT, but prenatal treatment, predominantly with serial fetal platelet transfusions, resulted in a successful outcome in both cases. These observations suggest that FMAIT should be suspected if there is isolated fetal hydrocephalus, unexplained fetal anaemia, or recurrent miscarriages. The accurate diagnosis of FMAIT is important because recent advances in prenatal management can improve the outcome of subsequently affected pregnancies.