PAI-1 can regulate TGF-beta expression by binding to uPAR and activating the extracellular-regulated signal kinase (ERK)/MAPK pathway. Therefore, PAI-1 contributes to diabetic nephropathy by regulating TGF-beta and renal ECM production and may be a therapeutic target in diabetic nephropathy.

Plasma human immunodeficiency virus (HIV) type 1 RNA levels, CD4 lymphocyte changes, and drug resistance were studied in HIV-infected patients with 200-500 CD4 lymphocytes/microL who received zidovudine and didanosine combination therapy for 2 years. Among 35 patients, 10 had sustained and 16 had transient > 10-fold reductions in HIV RNA: 9 did not have 10-fold HIV RNA reductions. Only patients with sustained HIV suppression maintained increased CD4 cell counts for 2 years (370 to 501 cells/microL; P = .006). Patients with transient HIV suppression were more likely to develop drug-resistant HIV strains (12/16 vs. 5/19, P = .01) and reverse transcriptase (RT) mutations (4.5 vs. 2.5/strain; P = .02) than were patients with sustained or no HIV suppression. Zidovudine resistance occurred with RT mutations at codons 41, 67, 70, 215, and 219. Multidrug resistance occurred with mutations at codons 62, 75, 77, 116, and 151. Mutations occurred at codons 60, 68, 118, 210, and 228 in > or = 4 patients each. Heterogeneity exists among individual virologic responses to zidovudine and didanosine combination therapy. HIV resistance mechanisms during combination therapy appear more complex than reported with monotherapy.

Background/Aims: The streptozotocin (STZ)-induced diabetic rat is a widely used animal model of human diabetic nephropathy. In this model, diabetic nephropathy progresses without significant elevation in blood pressure. Therefore, studies have examined the effect of hypertension in STZ spontaneously hypertensive rats (SHR). This study investigated angiotensin II (Ang II)-induced hypertension in diabetic nephropathy in the STZ-diabetic rat independent of deleterious genetic effects in SHR. Methods: Animals were divided as follows: nondiabetic controls (ND; n = 18); diabetic (STZ: 65 mg/kg; n = 16); Ang II-induced hypertensive ND (Ang II: 120 ng/kg/min; n = 9), and hypertensive diabetic rats (n = 18). Systolic blood pressure was measured by the tail-cuff method prior to STZ injection and then weekly. After 3 months, plasma creatinine, and 24-hour urine albumin and creatinine were measured and kidneys harvested for morphometry. Results: Ang II infusion increased systolic blood pressure in diabetic and ND rats. When combined with diabetes, Ang II increased albumin excretion rate (14-fold, p < 0.05), plasma creatinine (1.5-fold, p < 0.005) worsened creatinine clearance (37%, p < 0.002) and increased glomerular basement membrane width (1.2-fold, p < 0.0001). Conclusion: Ang II caused moderate hypertension and accelerated diabetic nephropathy and glomerular structural changes. The Ang II-infused STZ-diabetic rat is an excellent model to study the deleterious glomerular effects of hypertension on diabetes independent of genetic traits.

Among 75 consecutive human immunodeficiency virus type 1 (HIV-1)-infected patients with moderate and advanced immunosuppression, those harboring syncytium-inducing (SI) HIV-1 had a lower CD4 ؉-cell count (145 versus 278 cells per l, P < 0.001) and 10-fold-higher virus titers than patients with non-SI HIV-1 (398 versus 39 infectious units per 10 6 CD4 ؉ lymphocytes; P < 0.001). In patients with SI virus, the mean titer of SI virus, determined with a quantitative MT-2 cell assay, was 135 SI infectious units per 10 6 CD4 ؉ lymphocytes. Virus titer correlated inversely with CD4 ؉-cell count in patients with SI (r ‫؍‬ ؊0.67) but not non-SI (r ‫؍‬ ؊0.29) virus.