Molecular evidence of presenilin 1 mutation in familial early onset dementia

Early onset familial Alzheimer disease (FAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. We reported previously a variant form of FAD, due to deletion of exon 9 of PSEN1, with spastic paralysis and rigidity. We describe a novel PSEN1 mutation in a family of Japanese origin with six affected individuals of both genders in two generations. The disease is characterized by presenile dementia, which is preceded by spastic paraparesis and apraxia. This mutation, which is predicted to cause a missense substitution of serine for glycine, occurred at codon 266 in exon 8 of PSEN1. The mutation was not found in 200 controls and 200 sporadic AD patients. On this basis alone, it seems this mutation is pathogenic. Our findings provide a new clue to the etiology of the familial early onset dementia.     

Baicalin induces apoptosis via mitochondrial pathway as prooxidant

Baicalin is a flavonoid and a major component of a herbal medicine, Sho-saiko-to, which is commonly used for treatment of chronic hepatitis in Japan and China. Flavonoids including baicalin have been reported to not only function as anti-oxidants but also cause cytotoxic effect. We investigated the mechanism of baicalin-induced cytotoxicity in leukemia-derived T cell line, Jurkat cells. When cells were cultured with 50-200 microg/ml baicalin for 6h, caspase-3 was activated and then cells fell into apoptosis. Induction of apoptosis by baicalin was accompanied with the marginal generation of intracellular reactive oxygen species (ROS), the increase of the cytosolic fractions of cytochrome c, and the disruption of mitochondrial transmembrane potential (DeltaPsi(m)) prior to the activation of caspase-3. The pre-culture with 5 mM of buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, facilitated baicalin-induced disruption of DeltaPsi(m) and induction of apoptosis. The pre-culture with N-benzyloxycarbonyl-valyl-alanyl-aspartyl fluoromethylketone (Z-VAD-fmk), a pan-caspase inhibitor, partially suppressed the induction of apoptosis. On the other hand, baicalin showed little toxic effect on peripheral blood mononuclear cells (PBMCs) from healthy volunteers. These results indicate that baicalin acts as a prooxidant and induces caspase-3 activation and apoptosis via mitochondrial pathway.     

Possible role of preproghrelin gene polymorphisms in susceptibility to bulimia nervosa.

Previous investigations have suggested that ghrelin, an endogenous orexigenic peptide, is involved in the pathology of eating disorders. We conducted a study to determine whether any preproghrelin gene polymorphisms are associated with eating disorders. Three hundred thirty-six eating disorder patients, including 131 anorexia nervosa (AN)-restricting types (AN-R), 97 AN-binge eating/purging types (AN-BP) and 108 bulimia nervosa (BN)-purging types (BN-P), and 300 healthy control subjects participated in the study. Genotyping was performed to determine the polymorphisms present, and with this information, linkage disequilibrium (LD) between the markers was analyzed and the distributions of the genotypes, the allele frequencies, and the haplotype frequencies were compared between the groups. The Leu72Met (408 C > A) (rs696217) polymorphism in exon 2 and the 3056 T > C (rs2075356) polymorphism in intron 2 were in LD (D' = 0.902, r2 = 0.454). Both polymorphisms were significantly associated with BN-P (allele-wise: P = 0.0410, odds ratio (OR) = 1.48; P = 0.0035, OR = 1.63, for Leu72Met and 3056 T > C, respectively). In addition, we observed a significant increase in the frequency of the haplotype Met72-3056C in BN-P patients (P = 0.0059, OR = 1.71). Our findings suggest that the Leu72Met (408 C > A) and the 3056 T > C polymorphisms of the preproghrelin gene are associated with susceptibility to BN-P.     

Localization and expression of the aquaporin-1 water channel in mesangial cells in the human glomerulus

The expression and localization of the aquaporin-1 (AQP1) water channel were examined in the glomeruli of the human kidney. A ribonuclease protection assay showed the expression of AQP1 mRNA in human glomeruli but not in rat glomeruli. Western blot analysis revealed 28 kDa and 35 kDa bands corresponding to unglycosylated and glycosylated AQP1 proteins in human glomeruli. Immunoreactive AQP1 was demonstrated almost exclusively in the mesangium in the human glomeruli by immunohistochemistry. The endothelium of glomerular capillaries was only partly immunostained while podocytes and Bowman's capsule epithelia were not immunolabeled. Immunoelectron microscopy localized the immunoreactive AQP1 on the plasma membrane of mesangial cells in human glomeruli. The immouno-gold labeling was dense on the projections of mesangial cells protruding to the glomerular capillary lumen or to endothelial cells, but was sparse on other parts of the mesangial cell surface. No immunoreactivity for AQP1 was demonstrated in rat glomeruli. This study showed the distinct localization of AQP1 in the mesangial cells of human glomeruli, suggesting its role in water movement through these cells.     

Comparison of methods of steroid administration combined with tonsillectomy for IgA nephropathy patients

Background

IgA nephropathy (IgAN) is a chronic glomerular disease that causes end-stage renal disease in 20–40 % of patients within 20 years. The efficacy of tonsillectomy combined with steroid pulse (SP) administration (TSP) for clinical remission of IgAN has been reported. Particularly in Japan, TSP has been performed widely. However, the optimum method for steroid administration in TSP has not been established.

Methods

We retrospectively compared clinical remission in IgAN patients treated with tonsillectomy combined with two different steroid administration methods: (1) three courses of SP therapy and oral prednisolone administered on alternate days (group 3A; n = 25); and (2) one course of SP therapy and oral prednisolone administered on consecutive days (group 1C; n = 22).

Results

There was no significant difference in the clinical remission rates between the two groups at 12 (48.0 vs. 40.9 %, P = 0.77) and 24 months after starting treatment (68.0 vs. 72.7 %, P = 0.76) and at the final observation (76.0 vs. 81.8 %, P = 0.73). The mean period from starting treatment to remission of hematuria in group 3A was significantly shorter than that in group 1C (5.7 ± 4.4 vs. 9.9 ± 5.9 months, P = 0.03). Dyslipidemic patients treated for the first time with statin after the SP therapy were more present in group 3A at 24 months (P = 0.02).

Conclusions

In IgAN patients, treatment of group 3A may be effective for inducing rapid remission of hematuria. Further studies are needed to establish an appropriate protocol for TSP.

     

Insulin response to oral glucose load is associated with coronary artery disease in subjects with normal glucose tolerance

AIM: The critical role of hyperinsulinemia, independent of hyperglycemia, in the pathogenesis of atherosclerosis has not been fully determined. We investigated the association between secretion patterns of insulin after oral glucose load and the severity of coronary artery disease (CAD) in patients with normal glucose tolerance (NGT). METHODS: We enrolled 116 subjects with NGT from 243 patients who had undergone coronary angiography and a standard 75-g oral glucose tolerance test. The patients were divided into 0-vessel, single-vessel and multi-vessel disease groups on the basis of the severity of CAD. RESULTS: The 2-h insulin levels in the multi-vessel disease group (p=0.005) and the single-vessel disease group (p<0.05) were significantly higher than those in the 0-vessel disease group. Multivariate analysis revealed that the levels of 2-h insulin were an independent variable for the presence of CAD (p=0.02) after adjustment for gender and the presence of each criterion of metabolic syndrome using the definition of the International Diabetes Federation. CONCLUSION: A slight but significant increase in prolonged insulin secretion, which is associated with the early stage of insulin resistance, in subjects with NGT, may play an important role in the pathogenesis of atherosclerosis.     

Peroxiredoxin I protects gastric mucosa from oxidative injury induced by H. pylori infection

Background and Aim: Helicobacter pylori (H. pylori) infection enhances the production of reactive oxygen species and peroxynitrite, thereby resulting in oxidative tissue damage. In this study, we examined the role of peroxiredoxin I (Prx I), a stress‐induced antioxidant enzyme, in protecting gastric mucosa from H. pylori‐induced gastric mucosal injury. Methods: Wild type (Prx I^+/+) and Prx I‐deficient type (Prx I^–/–) mice were maintained for 2 to 12 months with or without infection of H. pylori, Sydney strain‐1. Gastric mucosal expression of Prx I was assessed by immunoblot analysis and immunohistochemistry. The degree of gastritis was evaluated by the updated Sydney system and by mucosal levels of inflammatory cytokines (MIP‐2, IL‐1β, and TNF‐α). Oxidative DNA injury and apoptosis were analyzed by mucosal level of 8‐hydroxy‐2′‐deoxyguanosine, and the number of apoptotic cells stained with a single‐stranded DNA antibody, respectively. Results: H. pylori infection upregulated gastric mucosal Prx I expression in the Prx I^+/+ but not the Prx I^–/– mice. H. pylori infection also induced more severe gastritis and a more prominent increase in MIP level, more marked oxidative DNA injury, and apoptosis in the Prx I^–/– than the Prx I^+/+ mice. In the absence of H. pylori infection, no changes were demonstrated in gastric mucosa in either the Prx I^+/+ or the Prx I^?/? mice. Conclusion: These data suggest that H. pylori infection upregulates gastric mucosal Prx I expression, and further, that Prx I plays an important role in gastric mucosal protection against oxidative injury induced by H. pylori infection.