A randomized, placebo-controlled trial to assess the safety and acceptability of use of carraguard vaginal gel by heterosexual couples in Thailand

OBJECTIVES: To determine the safety and acceptability of use of Carraguard, a carrageenan-derived candidate microbicide gel, during sexual intercourse in women and men. STUDY DESIGN: We conducted a 6-month randomized, placebo-controlled trial among sexually active, couples at relatively lower risk for HIV infection in northern Thailand. METHODS: Women inserted 1 applicator of study gel vaginally every time the couple had sex. Safety was assessed by symptom report and genital examination of both partners and by changes in vaginal flora. Acceptability was assessed by participant interview. RESULTS: Overall, 55 couples were randomized, 28 to Carraguard use and 27 to the methyl-cellulose placebo gel group. Retention and study gel use were similarly high in both study groups; use of gel without condoms was reported in more than 95% of vaginal sex acts. The 2 study groups were similar in the proportions of women and men with symptoms or with genital findings without epithelial disruption, of men with findings with epithelial disruption, and of women with abnormal genital flora, whereas more women in the placebo group had findings with epithelial disruption. Women and men in both groups reported that the gel and applicator were acceptable. CONCLUSIONS: Carraguard can safely be used an average of 2 to 3 times per week during sex and is acceptable to Thai women and men.     

Acute Rejection of a Kidney Transplant in a Patient With Common Variable Immunodeficiency: A Case Report

Common variable immunodeficiency is a primary immunodeficiency characterized by hypogammaglobulinemia and recurrent bacterial infections. We report a case of a 44-year-old male patient with end-stage renal disease and an established diagnosis of common variable immunodeficiency who underwent a living unrelated kidney transplant. He remained nearly infection free on maintenance immunoglobulin replacement. However, his posttransplant course was complicated by acute rejection that ultimately led to allograft loss. This case illustrates the challenge of transplantation in this patient population because of the delicate balance that must be achieved between maintaining adequate immunosuppression and minimizing the risk of infection.     

Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)–derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetes-mediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE–driven diabetes-mediated kidney injury.     

Local cryoglobulin deposition in primary central nervous system lymphoma

Primary central nervous system lymphomas (PCNSLs) represent malignant non-Hodgkin's B-cell lymphomas confined to the central nervous system. Recent years have brought a dramatic increase in the frequency of PCNSL in the immunocompromised and immunocompetent populations. Cryoglobulins are cold-precipitable immunoglobulins associated with a number of infectious, autoimmune, and neoplastic disorders. Although it is known that patients with hematologic malignancies (eg, B-cell lymphomas, chronic lymphocytic leukemia, plasma cell dyscrasias) may have cryoglobulinemias and cryoglobulin deposition in several organs (eg, kidney, liver skin, blood vessels, peripheral nervous system), PCNSL associated with cryoglobulin deposition has not been previously described. This report demonstrates localized cryoglobulin deposition within the tumor bed in an immunocompetent patient with PCNSL.     

Microangiopathic injury and augmented PAI-1 in human diabetic nephropathy

BACKGROUND: Microvascular injury and mesangial dysfunction contribute to the pathogenesis of diabetic glomerulosclerosis. We investigated the extent of microvascular injury characterized by fragmented red blood cells (RBCs) in the mesangium of glomeruli in diabetic nephropathy, and its clinicopathologic significance. We also investigated the possible contributions of plasminogen activator inhibitor-1 (PAI-1), which has been implicated in thrombosis and sclerosis, and the novel steroid receptor superfamily member, peroxisome proliferator-activated receptorgamma (PPARgamma), implicated in monocyte-foamy macrophage transformation in atherosclerosis and improved insulin responsiveness in diabetes. METHODS: Sixty-four diabetic nephropathy (DN) cases in our renal biopsy files at VUMC, diagnosed between 1997 and 1999, were reviewed. Patients were classified based on the presence or absence of fragmented RBCs in the mesangium (M+, M-). PAI-1 and PPARgamma immunostaining was performed with double staining for the macrophage marker CD68. RESULTS: M+ lesions were present in 21.9% of cases, and in positive cases, involved on average 10.2 +/- 2.1% of glomeruli. M+ patients were 40- to 78-years-old (mean +/- SD, 60.4 +/- 9.8), the female/male ratio was 2.5, and the white/black ratio was 6. In M-, the patients' ages ranged from 29 to 81 years (57.6 +/- 13.3, P = NS vs. M+), the female/male ratio was 0.5 (P < 0.05 vs. M+), and the white/black ratio was 2.3 (P = 0.1 vs. M+). Mean 24-hour urine protein in M+ was 9.9 +/- 13.6 g/24 h, versus 4.0 +/- 2.8 g/24 h in M- (P < 0.05). The fragmented RBCs in M+ cases localized exclusively within Kimmelstiel-Wilson nodules. PAI-1 and PPARgamma immunostaining was increased in areas of sclerosis in arteries and glomeruli, with expression of both in glomerular mesangial, parietal and visceral epithelial cells. Infiltrating macrophages in glomeruli were PPARgamma negative, contrasting positivity in macrophages in control cases of carotid artery plaque and in renal interstitial macrophages. The Kimmelstiel-Wilson nodules in M+ patients showed increased PAI-1 staining. CONCLUSIONS: Mesangial RBC fragments are indicative of microvascular injury and mesangiolysis in DN and are associated with worse proteinuria, and possible worse prognosis. Possible pathogenic mechanisms involve the fibrinolytic/proteolytic system and locally activated PAI-1.     

Epidermal Growth Factor Receptor Inhibition Slows Progression of Diabetic Nephropathy in Association With a Decrease in Endoplasmic Reticulum Stress and an Increase in Autophagy

Previous studies by us and others have reported renal epidermal growth factor receptors (EGFRs) are activated in models of diabetic nephropathy. In the present study, we examined the effect of treatment with erlotinib, an inhibitor of EGFR tyrosine kinase activity, on the progression of diabetic nephropathy in a type 1 diabetic mouse model. Inhibition of renal EGFR activation by erlotinib was confirmed by decreased phosphorylation of EGFR and extracellular signal–related kinase 1/2. Increased albumin/creatinine ratio in diabetic mice was markedly attenuated by erlotinib treatment. Erlotinib-treated animals had less histological glomerular injury as well as decreased renal expression of connective tissue growth factor and collagens I and IV. Autophagy plays an important role in the pathophysiology of diabetes mellitus, and impaired autophagy may lead to increased endoplasmic reticulum (ER) stress and subsequent tissue injury. In diabetic mice, erlotinib-treated mice had evidence of increased renal autophagy, as indicated by altered expression and activity of ATG12, beclin, p62, and LC3A II, hallmarks of autophagy, and had decreased ER stress, as indicated by decreased expression of C/EBP homologous protein, binding immunoglobulin protein, and protein kinase RNA-like ER kinase. The mammalian target of rapamycin (mTOR) pathway, a key factor in the development of diabetic nephropathy and an inhibitor of autophagy, is inhibited by AMP-activated protein kinase (AMPK) activation. Erlotinib-treated mice had activated AMPK and inhibition of the mTOR pathway, as evidenced by decreased phosphorylation of raptor and mTOR and the downstream targets S6 kinase and eukaryotic initiation factor 4B. Erlotinib also led to AMPK-dependent phosphorylation of Ulk1, an initiator of mammalian autophagy. These studies demonstrate that inhibition of EGFR with erlotinib attenuates the development of diabetic nephropathy in type 1 diabetes, which is mediated at least in part by inhibition of mTOR and activation of AMPK, with increased autophagy and inhibition of ER stress.In the industrialized world, diabetes mellitus represents the leading cause of end-stage renal disease (ESRD). Diabetic nephropathy is one of the major microvascular complications of diabetes and a major source of morbidity and mortality. The renal lesions are similar in type 1 and 2 diabetes (1). Both the incidence and prevalence of ESRD secondary to diabetes continue to rise. In the United States, >30% of patients receiving either dialytic therapy or renal transplantation have ESRD as a result of diabetic nephropathy, and >40% of the incident cases of ESRD are attributable to diabetes. Given the global epidemic of obesity in developed countries, an increasing incidence of diabetic nephropathy is being widely reported.The underlying mechanisms predisposing to development and progression of diabetic nephropathy are an area of active investigation. Inadequate control of blood glucose and blood pressure undoubtedly contributes, and there is evidence for a genetic predisposition, although the modifier genes involved have yet to be conclusively identified. Studies in experimental animals have implicated a number of cytokines, hormones, and intracellular signaling pathways in either development or progression of diabetic nephropathy. Angiotensin II and transforming growth factor-β have been posited to play central roles in mediating the progressive glomerulopathy and tubulointerstitial fibrosis that characterize diabetic nephropathy. Blockade of angiotensin II production or signaling is the only specific intervention currently available for treatment of patients with diabetic nephropathy, and given that renin-angiotensin system inhibition can slow but usually not prevent progressive injury in diabetic nephropathy, it is imperative that additional, complementary therapeutic targets be identified. In previous studies, we reported that epidermal growth factor receptor (EGFR) phosphorylation increased in murine kidneys within 2 weeks of induction of diabetes by streptozotocin (STZ), which was inhibited by the EGFR tyrosine kinase inhibitor erlotinib. Erlotinib also inhibited renal extracellular signal–related kinase (ERK) activation and transforming growth factor-β expression and signaling in these animals (2). The current studies investigated whether prolonged EGFR signaling plays a role in mediating progressive glomerular and tubulointerstitial injury in diabetic nephropathy.     

Preoperative irinotecan/5-FU/leucovorin plus concurrent radiotherapy in rectal cancer

PURPOSE: To evaluate results of preoperative irinotecan/5-FU/leucovorin plus radiotherapy for locally-advanced rectal cancer. METHODS: Thirty-five patients with locally-advanced rectal cancer were treated with preoperative irradiation 46 Gy plus concurrent chemotherapy(irinotecan 10 mg/m(2)/d d1-d5, d22-d26, 5-FU 350 mg/m(2)/d d1-d5, d22-d26, and leucovorin 20 mg/m(2) d1-d5, d22-d26), followed by radical surgery. RESULTS: There were no treatment-related deaths. Acute toxicity was mainly in neutropenia and diarrhea, with both grade 4 neutropenia and grade 3 diarrhea observed in 4 patients(11%). Radical resectability was performed in 29 patients(83%)with sphincter preservation surgery in 7 patients. Six patients did not undergo the planned surgery due to patient refusal and disease progression. A complete pathological response was observed in 14%(4/29). Pathological T-downstaging was observed in 55%(16/29). CONCLUSIONS: These results suggest that preoperative radiochemotherapy with irinotecan/5-FU/leucovorin is safe and effective in tumor downstaging and allows sphincter-saving resection to be performed in locally-advanced rectal cancer.     

September 2003: a 79-year-old female with right frontal lobe mass

The September2003 COM. A 79-year-old woman with prior history of breast cancer and meningioma presented with headache, memory changes and sleep disturbance for four months. CT and MRI revealed a large cystic mass in the right frontal lobe with heterogeneity and an enhancing border. She had a craniotomy and resection of tumor. The tumor was histologically consistent with gliosarcoma. Gliosarcomas exhibit clinical features and genetic profiles similar to primary (de novo) glioblastoma. Gliosarcomas have the same as prognosis as glioblastoma multiforme.