Determinants of Plasma Renin Activity: Role of a Human Renin Gene Variant as a Genetic Factor

The plasma renin activity (PRA) is affected by a number of environmental factors. However, significant heritability has been shown for the activity. A hypothesis that a candidate regulatory single-nucleotide polymorphism, C-5312T, of human renin gene should have a significant effect on PRA was elucidated and updating of independent determinants of PRA was attempted.Cross sectional study.Outpatient study.We enrolled consecutive 810 subjects who had consulted our hospitals for lifestyle-related diseases.Genotypes were assayed with genomic DNA for C-5312T. Among the genetic variants, the difference of PRA was evaluated. Monovariate linear regression analysis was performed to test the correlation between PRA and clinical variables. Finally, stepwise multiple regression analysis was performed to evaluate the independent determinants.On comparing 2 genotype groups, CC/CT and T allele homozygote, the geometric means of PRA were 0.778 and 0.941 ng/ml/h, respectively (F = 5.992, P = 0.015). Monovariate linear regression analysis revealed that a number of variables have a significant correlation with the activity, including urinary salt excretion. A stepwise multivariate regression analysis revealed that renin C-5312T variant (TT) is one of the independent determinants of PRA.Thus, for the first time, a human renin gene variant was associated with a significant increase in PRA as a genetic factor and the independent determinants for the activity were updated including genetic factor.     

beta-adrenergic receptor-mediated presynaptic facilitation of inhibitory GABAergic transmission at cerebellar interneuron-Purkinje cell synapses

Norepinephrine (NE) has been shown to elicit long-term facilitation of GABAergic transmission to rat cerebellar Purkinje cells (PCs) through beta-adrenergic receptor activation. To further examine the locus and adrenoceptor subtypes involved in the NE-induced facilitation of GABAergic transmission, we recorded inhibitory postsynaptic currents (IPSCs) evoked by focal stimulation with paired-pulse (PP) stimuli from PCs in rat cerebellar slices by whole cell recordings and analyzed the PP ratio of the IPSC amplitude. NE increased the IPSC amplitude with a decease in the variance of the PP ratio, which was mimicked by presynaptic manipulation of the transmission caused by increasing the extracellular Ca(2+) concentration, confirming that the presynaptic adrenergic receptors are responsible for the facilitation. Pharmacological tests showed that the beta(2)-adrenoceptor antagonist, ICI118,551, but not the beta(1)-adrenoceptor antagonist, CGP20712A, blocked the NE-induced IPSC facilitation, suggesting that the beta(2)-adrenoceptors on cerebellar interneurons, basket cells (BCs), mediate the noradrenergic facilitation of GABAergic transmission. Double recordings were performed from BCs and PCs to further characterize the regulation of the GABAergic synapses. First, on-cell recordings from BCs showed that the beta-agonist isoproterenol (ISP) increased the frequencies of the spontaneous spikes in BCs and the spike-triggered IPSCs in PCs recorded with the whole cell mode. The amplitude of the spike-triggered IPSCs decreased or increased depending on the individual GABAergic synapses examined. Forskolin invariably increased both the amplitude and the frequency of the spike-triggered IPSCs. Double whole cell recordings from BC-PC pairs showed that ISP mainly caused an increase in the amplitude of the IPSCs evoked in the PCs by an action current in the BCs produced in response to voltage steps from -60 to -10 mV. Our data suggest that the noradrenergic facilitation of GABAergic transmission in the rat cerebellar cortex is mediated, at least in part, by depolarization and action potential discharges in the BCs through activation of the beta(2)-adrenoceptors in BCs coupled to intracellular cyclic AMP formation.     

Latent adenoviral infection modifies the steroid response in allergic lung inflammation

BACKGROUND: Steroid-resistant asthma develops after adenoviral bronchiolitis. OBJECTIVE: We sought to determine the effect of steroids on allergic lung inflammation in the presence of latent adenoviral infection. METHODS: Guinea pigs with latent adenoviral (n = 12) or sham (n = 12) infections were sensitized and challenged with ovalbumin (OA) or sham sensitized and challenged with saline solution. The effect of steroids (20 mg/kg administered intraperitoneally) on OA-induced lung inflammation was examined by using quantitative histology as the outcome measure. RESULTS: Latent adenoviral infection increased CD8(+) cells in the airway wall and CD8(+) cells, macrophages, B cells, and CD4(+) cells in the lung parenchyma. Ovalbumin challenge, on the other hand, increased eosinophils, macrophages, B cells, and CD4(+) cells in both the airway wall and lung parenchyma independent of the effect of latent adenoviral infection. In the sham-infected groups steroid treatment caused the expected reduction in the eosinophilic infiltrate induced by OA challenge in the airways without affecting the other cells. In the presence of both latent adenoviral infection and OA challenge, steroid treatment had no effect on allergen-induced eosinophilia but reduced CD8(+) cells in the airways and CD8(+) cells, CD4(+) cells, and B cells in the parenchyma. CONCLUSION: Latent adenoviral infection and OA challenge result in different types of lung inflammation, and the presence of latent adenoviral infection causes OA-induced eosinophilic airway inflammation to become steroid resistant.     

Protective effects of idebenone and α-tocopherol on β-amyloid-(1–42)-induced learning and memory deficits in rats: implication of oxidative stress in β-amyloid-induced neurotoxicity in vivo

Amyloid β-peptide (Aβ), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of Aβ-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of Aβ-(1–42). In the Aβ-(1–42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with Aβ-(40–1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with Aβ-(1–42). Potent antioxidants idebenone and α-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in Aβ-(1–42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of Aβ infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of Aβ-(1–42)-infused rats did not differ from those in control animals, and neither idebenone nor α-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and α-tocopherol prevents learning and memory deficits caused by Aβ.     

Negative pressure wound therapy for a large skin ulcer following repair of huge myeloschisis with kyphosis in a newborn

Background

In surgery of repair for spina bifida, various skin plastic techniques are sometimes necessary due to large skin defect or subsequent ulcers in cases when approximation on the midline is difficult.

Case report

A baby was born with a large skin defect due to huge lumbar myeloschisis and kyphosis, which was repaired 2 days after birth using Limberg’s skin flap at the peak of kyphosis. Skin ischemia around the tip of the flap gradually enlarged and resulted in a large skin ulcer. We performed negative pressure wound therapy (NPWT) using a Vacuum Assisted Closure (V.A.C.®) therapy system for 4 weeks which shrank the ulcer remarkably. Subsequently, a pedicle skin flap without graft was performed to cover the rest of the ulcer, which adapted well without CSF leakage postoperatively.

Conclusion

A combination treatment of NPWT and skin plastic surgery was successfully performed for a very young infant with spina bifida. NPWT could be another useful option for the treatment of ulcer following spina bifida repair surgery, though surgeons should carefully confirm that there is no CSF leakage before and during the procedure.     

Anti-fibrillogenic and fibril-destabilizing activities of anti-Parkinsonian agents for alpha-synuclein fibrils in vitro

The aggregation of alpha-synuclein (alphaS) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Among the antioxidant strategies proposed, increasing evidence points to the possibility of achieving neuroprotection by dopamine agonists, as well as monoamine oxidase B inhibitors. We showed previously that the anti-Parkinsonian agents dose-dependently inhibited beta-amyloid fibrils (fAbeta)(1-40) and fAbeta(1-42) formation as well as destabilized preformed fAbetas. Using fluorescence spectroscopy with thioflavin S, electron microscopy, and atomic force microscopy, we examined the effects of anti-Parkinsonian agents, selegiline, dopamine, pergolide, bromocriptine, and trihexyphenidyl on the formation of alphaS fibrils (falphaS) and on preformed falphaS. All molecules except for trihexyphenidyl, dose-dependently inhibited the formation of falphaS. Moreover, these molecules dose-dependently destabilized preformed falphaS. The overall activity of the molecules examined was in the order of: selegiline = dopamine > pergolide > bromocriptine. These agents and other compounds related structurally could be key molecules for the development of therapeutics for LBD and MSA.     

Tethered cord syndrome: overview of diagnosis and treatment

This article covers the basis of tethered cord syndrome as a stretch-induced spinal cord disorder, including pathophysiology, signs and symptoms, imaging diagnosis, indication for surgical treatment, and surgical procedures. Anomalies that cause mechanical spinal cord tethering are listed, and the surgical untethering technique for each anomaly is described.