Genetic susceptibility to type 2 diabetic nephropathy in human and animal models

SUMMARY:   Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in Japan, Western Europe, and the United States. Mega studies such as Diabetes Control and Complication Trial (DCCT), Epidemiology of Diabetes Interventions and Complications (EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS) clarified that poor glycemic and blood pressure control are undoubtedly involved in the development of nephropathy. However, these factors are not sufficient to predict which diabetic patients will develop renal disease, because not all patients with poor glycemic and blood pressure control develop renal disease. Since ethnic variations and familial clustering of diabetic nephropathy have been observed, genetic factors might contribute to susceptibility to this disease. Several methods such as (genome wide) association studies, sib-pair analysis, and quantitative trait loci (QTLs) analysis are available to examine polygenic diseases. However, no mutations that could explain the majority of nephropathy cases have been identified so far. The development of most diabetic nephropathy might be explained by the polygenic effect (i.e. many minor gene-gene interactions might be very important in the development of nephropathy). Identification of candidate genes of nephropathy enables targeting of therapy in patients at risk and development of novel therapeutic agents.     

Intussusception in children of school age

BACKGROUND: There are only a few reports discussing the characteristics of intussusception developing in school-age children. The characteristics of these cases are discussed, with reference to previous literature. METHODS: The present study included eight cases of intussusception in school-age children among 143 intussusception patients treated on an inpatient basis at Nihon University Itabashi Hospital, during the 11 year period from 1993 to 2003. The remaining 135 patients were assigned to the infant group as controls. The clinical characteristics of intussusception in school-age children were compared with those of the condition developing in infants. RESULTS: The eight children of school age with intussusception ranged in age from 8 to 15 years (mean, 11.6 years), and consisted of five boys and three girls. The major symptom was abdominal pain, occurring in 100% (8/8). Bloody stools and vomiting were reported in two patients each (25%) from this group. The triad of abdominal pain, bloody stools and vomiting was recognized in only one child (12.5%) of this group. Two children (25.0%) had a palpable abdominal mass, and one child (12.5%) complained of diarrhea. None of the school-age children with intussusception had any antecedent infection; five, two and one patients had the ileo-colic type, ileo-ileo-colic type and ileo-ileal type of intussusception, respectively. Four underwent enema reduction and four underwent surgical reduction. One of the eight children (12.5%) had underlying organic abnormality; in the remaining children the condition was labeled idiopathic. One child developed recurrences. CONCLUSIONS: In school-age children intussusception is generally believed to be commonly secondary to underlying organic abnormality, but in the present study only one of eight school-age children had underlying organic abnormality; in the remaining children, the condition was labeled idiopathic. The major symptom in school-age intussusception was abdominal pain. Therefore this may need to be differentiated from appendicitis in children of school age. It is considered that abdominal ultrasonography (USG) is a simple and useful method for making the diagnosis of intussusception, and that diagnostic USG should be conducted in all school-age children presenting with acute abdominal pain.     

Effects of Isoquinolinesulphonamide Compounds on Multidrug-resistant P388 Cells

Abstract— The effects of eight isoquinolinesulphonamide compounds on resistance to vinblastine in adriamycin-resistant mouse leukaemia cells (P388/ADR) which overexpress the relative molecular weight (M_r) 140 kDa P-glycoprotein in the plasma membrane were investigated. N-[2-(Methylamino)ethyl]-5-isoquinolinesulphonamide (H-8) and N-(2-aminoethyl)-5-isoquinolinesulphonamide (H-9) did not reverse vinblastine resistance. N-[2-[N-[3-(4-Chlorophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulphonamide (H-86) and N-[2-[N-[3-(4-chlorophenyl)-1-methyl-2-propenyl]amino]ethyl]-5-isoquinolinesulphonamide (H-87) caused accumulation of intracellular vinblastine and inhibition of vinblastine efflux from the cells and reversed the resistance. Addition of an aminoethyl group to the nitrogen atom of the sulphonamide group (W-66) or a formyl group at the terminal amino group (H-85) of H-86 reduced those activities. Conversion of the chlorophenyl group of H-87 to pyridinyl (H-31) or furanyl (H-34) markedly decreased activities against the drug resistance. The activity against vinblastine accumulation closely correlated with the apparent partition coefficient of compounds. These compounds dose-dependently inhibited photoaffinity labelling of a photosensitive analogue of vinblastine, N-(p-azido-(3-[¹²⁵I])salicyl)-N′-β-aminoethylvindesine ([¹²⁵I]NASV), and there was a good correlation between inhibition of [¹²⁵I]NASV-photolabelling and hydrophobicity. Although these isoquinolinesulphonamides inhibited protein kinase A with different magnitudes, this activity did not correlate with the effect on the drug resistance. These results indicate that isoquinolinesulphonamide compounds with a hydrophobic group interact with antitumour drugs on P-glycoprotein and reverse multidrug resistance without involvement of their activity on protein kinase A.