No abstract

To determine whether genetic factors could be involved in the pathogenesis of rheumatic heart disease, we performed HLA-A and HLA-B typing in 120 black patients with severe chronic rheumatic heart disease requiring cardiac surgery, and HLA-DR and HLA-DQ typing in 103 and 97 of these patients, respectively. The HLA typing was done by a standard microlymphocytotoxicity method. Patients were 12 to 60 years old (mean 27.6 ± 14.5). No differences in HLA-A, HLA-B, and HLA-DQ frequencies between patients and controls were noted. HLA-DR 1 antigen was present in 12.6% of patients compared with 2.7% of normal control subjects (corrected p<.045; relative risk = 5.2) and the HLA-DRw6 antigen was present in 31.1% of patients compared with 15% of control subjects (corrected p<.045; relative risk = 2.6). These findings suggest that genetically determined immune-response factors may play a role in the pathogenesis of severe chronic rheumatic heart disease.

Cell cycle checkpoints contribute to survival after exposure to ionizing radiation (IR) by arresting the cell cycle and permitting repair. As such, yeast and mammalian cells lacking checkpoints are more sensitive to killing by IR. We reported previously that Drosophila larvae mutant for grp (encoding a homolog of Chk1) survive IR as well as wild type despite being deficient in cell cycle checkpoints. This discrepancy could be due to differences either among species or between unicellular and multicellular systems. Here, we provide evidence that Grapes is needed for survival of Drosophila S2 cells after exposure to similar doses of IR, suggesting that multicellular organisms may utilize checkpoint-independent mechanisms to survive irradiation. The dispensability of checkpoints in multicellular organisms could be due to replacement of damaged cells by regeneration through increased nutritional uptake and compensatory proliferation. In support of this idea, we find that inhibition of nutritional uptake (by starvation or onset of pupariation) or inhibition of growth factor signaling and downstream targets (by mutations in cdk4, chico, or dmyc) reduced the radiation survival of larvae. Further, some of these treatments are more detrimental for grp mutants, suggesting that the need for compensatory proliferation is greater for checkpoint mutants. The difference in survival of grp and wild-type larvae allowed us to screen for small molecules that act as genotype-specific radiation sensitizers in a multicellular context. A pilot screen of a small molecule library from the National Cancer Institute yielded known and approved radio-sensitizing anticancer drugs. Since radiation is a common treatment option for human cancers, we propose that Drosophila may be used as an in vivo screening tool for genotype-specific drugs that enhance the effect of radiation therapy.

A new thebaine derivative, buprenorphine, 0.6 mg, was compared with morphine 15 mg in a double-blind trial, in patients recovering from elective Caesarean section. Within 1 h of administration analgesia was obtained with both drugs and was sustained for 7-8 h with buprenorphine, and 3-4 h with morphine. Buprenorphine caused a greater decrease in diastolic arterial pressure than did morphine, but arterial systolic pressure and heart rate were not influenced by either drug. No serious side-effects were encountered in this study.

The responses of urine and urinary solute outputs and flows to single doses of 80 mg furosemide, 25 mg hydrochlorothiazide, and 100 or 200 mg flosequinan were investigated in healthy subjects using a double-blind, randomized, crossover design. Treatment days were separated by 7 days. Volumes of urine passed between 0 and 3, 3 and 6, 6 and 9, 9 and 12, and 12 and 24 h after drug administration were determined and urinary concentrations of chloride, sodium, potassium, calcium, magnesium, phosphate, zinc, urate, urea and creatinine were measured. Venous blood was taken before and 6 and 24 h after dosing and the serum was analysed for the same solutes as urine. Excretions of urine and urinary solutes accumulated at the end of each collection period after each formulation were fitted by the UY function, whose derivative provided corresponding flows as functions of time. Instantaneous renal clearances of solutes 6 and 24 h after dosing were evaluated from the flows. This approach showed that 80 mg furosemide and 25 mg hydrochlorothiazide were equipotent 24-h natriuretics. Rapid urinary responses which then rebounded compared with the control responses were produced by 80 mg furosemide, whereas changes after 25 mg hydrochlorothiazide were smooth. Neither 100 or 200 mg flosequinan showed any important effect on urinary excretion.