Glomerular targeting of acidic fibroblast growth factor-1 in renal transplanted rats

BACKGROUND: Acidic fibroblast growth factor (FGF-1) functions as a potent hormonal inducer of wound repair mechanisms in vivo. In addition, the involvement of FGF-1 in a number of pathophysiological conditions, including chronic human renal allograft rejection, has been described. Consequently, there is an increasing need to monitor FGF-1 pharmacokinetics and distribution for both therapeutic and diagnostic opportunities. We now describe in vivo imaging and targeting of FGF-1 in renal transplanted rats. METHODS: Sham-operated, syngeneic renal transplanted, and allogeneic renal transplanted rats were imaged using an Anger gamma camera. Renal function was evaluated first by dynamic 99mTc-MAG3 imaging, and subsequently, 99mTc-labeled FGF-1 (99mTc-FGF-1) was imaged after i.v. injection. Microautoradiography of harvested kidneys determined the compartmental localization of 99mTc-FGF-1. RESULTS: 99mTc-MAG3 renal scans were grossly abnormal in the allogeneic renal transplanted rats. In this group, a significant reduction in 99mTc-FGF-1 renal binding was measured by imaging analyses, as compared with renal binding in the sham-operated and syngeneic renal transplanted groups, which were not significantly different. Both groups of renal transplanted rats showed a redistribution of FGF-1 to the glomerular compartment. CONCLUSIONS: 99mTc-FGF-1 serves as a new radiotracer to measure in vivo targeting of the growth factor. Reduced renal binding of 99mTc-FGF-1 in the allogeneic transplanted kidney was consistent with decreased blood flow. Unique glomerular targeting of 99mTc-FGF-1 in the transplanted kidney provides additional evidence supporting a role for this growth factor in the pathogenesis of chronic rejection.     

Gender-specific protective effect of hemoglobin on arsenic-induced skin lesions.

Chronic arsenic poisoning remains a public health crisis in Bangladesh. As arsenic has been shown to bind to human hemoglobin (Hb), hematologic mechanisms may play a role in the pathway through which arsenic exerts its toxicity. Two separate studies, a case-control and a cohort, were conducted to investigate the role of Hb in the development of arsenic-induced skin lesions. In the first, conditional logistic regression was used to investigate the effect of Hb on skin lesions among 900 case-control pairs from Pabna, Bangladesh, in which individuals were matched on gender, age, and location. In the second, mixed linear regression models were used to examine the association between toenail arsenic, urinary arsenic, and Hb within a cohort of 184 individuals from 50 families in the same region who did not have arsenic-induced skin lesions. Hb was significantly associated with skin lesions but this association was gender specific. In males, a 40% reduction in the odds of skin lesions occurred for every 1 g/dL increase in Hb (odds ratio, 0.60; 95% confidence interval, 0.49-0.73). No effect was observed for females (odds ratio, 1.16; 95% confidence interval, 0.92-1.46). In the cohort of 184 individuals, no associations between toenail arsenic or urinary arsenic species and Hb levels were observed. Low Hb levels may exacerbate the detrimental health effects of chronic arsenic poisoning. Whereas providing clean water remains the optimal solution to Bangladesh's problem of arsenic poisoning, improving nutrition and reducing iron-deficiency anemia may ameliorate negative health effects, such as skin lesions in individuals who have been exposed.     

Chemotherapy induced toxicities in therapeutic trials of Acute Lymphoblastic Leukaemia

It is common practice in therapeutic trials in Acute Lymphoblastic Leukaemia (ALL) to treat chemotherapy induced toxicities. In this study, 50 newly diagnosed ALL patients were enrolled and the median age was 14.5 years. 32 patients were male and 18 female. Prognostic factors were analysed. Remission induction, consolidation and maintenance therapy with conventional combination chemotherapy and CNS prophylaxis with intrathecal methotrexate and radiotherapy were instituted to all patients for long term event free survival. Results of induction therapy and overall outcomes of treatment were observed. Chemotherapy induced toxicities were also detected and treated accordingly. These toxicities were described in 4 groups depending on the frequency of their development in chemotherapy received patients. Haematological and gastrointestinal side effects and alopecia were expected i.e., developed in >75% of patients. Prednisolone and vincristine induced toxicities were common i.e., observed in >25% of patients. Hepatic complications and anthracycline induced tachycardia were occasional i.e., occurred in <25% and localized phlebitis and/ or soft tissue necrosis were rare and accidental i.e., developed in 5% of patients.     

Binding of bacterial endotoxin to murine spleen lymphocytes.

The early events in lipopolysaccharide (LPS)-induced B-cell activation were investigated by studying the binding of 14C-labeled LPS to murine lymphocytes in vitro. In these studies we utilized intrinsically labeled 14C-labeled LPS from Salmonella minnesota or the 14C-labeled glycolipid derived from the Re mutant of S. minnesota (R595). Bone marrow-derived (B) lymphocytes bound more LPS than did thymus-derived (T) lymphocytes. Binding of LPS to murine spleen lymphocytes from strain C3H/HeN was compared with the binding to spleen lymphocytes from strain C3H/HeJ, a strain resistant to certain biological activities of LPS including mitogenesis. Spleen cells from both strains bound LPS equally well, suggesting that unresponsiveness of C3H/HeJ mice to LPS is due to factors other than a defect in binding of LPS. LPS binding to cells appeared to be due to a nonspecific interaction between the lipid moiety of LPS and the lipid components of the cell membrane. Thus, the highly lipophilic, polysaccharide-deficient glycolipid from R595 bound at least 20 times better than did LPS. Furthermore, partial removal of cell surface proteins with trypsin or sialic acids with neuraminidase enhanced glycolipid binding, suggesting that binding is not through a protein- or sialic acid-containing receptor. The binding of glycolipid to lymphocytes was only partially specific since unlabeled glycolipid R595, lipid A, and LPS did not completely inhibit the uptake of 14C-labeled glycolipid R595. In addition, binding could be inhibited by a nonmitogenic phospholipid (phosphatidyl ethanolamine), which also is consistent with a nonspecific lipid-lipid interaction. Experiments were performed to determine the relationship of LPS binding to lymphocyte activation in the lymphocytes. The process of activation of lymphocytes by LPS was a slow one, since LPS was required to be present in culture for at least 24 h in order to obtain significant lymphocyte activation, suggesting that the amounts of LPS bound earlier are either quantitatively or qualitatively insufficient to irreversibly activate the cell.     

Autopsy diagnosis of endemic burkitt lymphoma as the primary etiology of acute renal failure in children

Two cases of Burkitt lymphoma are reported who presented atypically with acute renal failure and significant proteinuria as initial features of the lymphoma. The cases underscore the need for high index of suspicion for Burkitt lymphoma in any child with rapidly enlarging kidneys and acute renal failure of obscured origin in parts of the world where Burkitt lymphoma is endemic.     

The question of C- vs. O-silylation of ketenes: electrophilic triethylsilylation of diphenylketene

Electrophilic triethylsilylation of diphenylketene leads to exclusive C-silylation giving the diphenyl(triethylsilyl)acetyl cation in the solution phase even though density functional theory calculations at the B3LYP/6-311+G* level indicate that the O-silylation of diphenylketene is preferred over C-silylation by 5.4 kcal/mol in the gas phase. On the other hand, in the case of the parent ketene, similar density functional theory calculations show that C-silylation is preferred over O-silylation by 8.2 kcal/mol.