A novel tyrosine hydroxylase variant in a group of Chinese patients with dopa-responsive dystonia.

Dopa-responsive dystonia (DRD) comprises a heterogeneous group of movement disorders. A limited number of studies of Chinese patients with DRD have been reported. In the present study, we investigated the clinical and genetic features of 12 Chinese DRD families. Point mutation analysis of the GTP-cyclohydrolase I (GCH1), tyrosine hydroxylase (TH) and sepiapterin reductase (SPR) genes was conducted by direct sequencing. In addition, multiplex ligation-dependent probe amplification targeting GCH1 and TH was performed in "mutation-free" patients. Three reported mutations (IVS2-2A>G, c.293C>T, c.550C>T) were detected in GCH1, whereas two compound heterozygous variants were identified in TH, one of which was novel (c.1083C>A). Furthermore, this novel variant was not detected in any of the 250 ethnicity-matched, healthy controls. No exon deletions or duplicate mutations in the two genes were found in patients with DRD. No mutation in SPR was found. In addition, one patient with the IVS2-2A>G mutation in GCH1 showed signs of Parkinsonism. In conclusion, we here identified a novel heterozygous variant in TH (c.1083C>A). It is important to perform routine screening of GCH1 and TH for patients with DRD. While for patients with Parkinsonism, GCH1 mutation analysis should be performed after screening of genes like PARKIN, PARK7 (DJ-1) and PINK1.

[The effect of smoking on resting energy expenditure in patients with early diabetic kidney disease].

OBJECTIVE: To study the effect of smoking on resting energy expenditure (REE) and the relationships among REE, smoking, inflammation and oxidative stress in patients with diabetic kidney disease. METHODS: A case control study of 31 smokers and 40 non-smokers with early stage of diabetic kidney disease (stage III) were performed to evaluate the chronic effect of smoking on REE. REE/fat free mass (FFM), biomarkers of oxidative stress malondialdehyde (MDA), superoxide dismutase (SOD) and inflammation high-sensitivity C-reactive protein (hs-CRP), adiponectin, TNFα were also measured in these subjects. Data were analyzed by Pearson correlation analysis. RESULTS: Compared with non-smokers, REE/FFM in smokers group was significantly increased by 15.96% (P = 0.001). Pearson analysis showed that smoking was significantly correlated with REE/FFM (t = 0.395, P = 0.001). There were significantly different between smokers and non-smokers in MDA, SOD and hs-CRP (P < 0.05). But no difference between two groups in adiponectin and TNFα (P > 0.05). No significant relationships between REE/FFM and MDA, SOD, hs-CRP, adiponectin, TNFα was found (P > 0.05). CONCLUSION: Chronic smoking can lead to increased REE, arouse oxidative stress and inflammatory in patients with early stage of diabetic kidney disease. However, there is no relationship between increased REE due to smoking and oxidative stress and inflammatory.

Intranasal Insulin Ameliorates Cerebral Hypometabolism, Neuronal Loss, and Astrogliosis in Streptozotocin-Induced Alzheimer's Rat Model.

Intracerebroventricular injection of streptozotocin (ICV-STZ) in rodents leads to cognitive impairments and several pathological changes like Alzheimer's disease (AD). However, there is hardly any research about the effect of ICV-STZ on regional cerebral glucose metabolism in rodents. Previous studies have demonstrated that intranasal insulin improves cognition in AD patients. However, the underlying mechanism remains elusive. Here, we treated the ICV-STZ rats with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks, then monitored 18F-fluorodeoxyglucose (18F-FDG) uptake using a high-resolution small-animal positron emission tomography (microPET) and studied the expression of neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) using immunohistochemical staining. We observed that 18F-FDG uptake decreased significantly at the prefrontal cortex, cingulate cortex, striatum, hippocampus, and entorhinal cortex in ICV-STZ rats as compared with the control rats. Intranasal insulin restores the cerebral glucose metabolism in prefrontal and cingulate cortex and attenuates astroglia activation and neuronal loss in the hippocampus of ICV-STZ rats. These findings provide the mechanistic basis for treating AD patients with intranasal insulin.

Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer's rat model.

Recent evidence reveals that aberrant brain insulin signaling plays an important role in the pathology of Alzheimer's disease (AD). Intranasal insulin administration has been reported to improve memory and attention in healthy participants and in AD patients. However, the underlying molecular mechanisms are poorly understood. Here, we treated intracerebroventricular streptozotocin-injected (ICV-STZ) rats, a commonly used animal model of sporadic AD, with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks and then studied their cognitive function with the Morris water maze test and biochemical changes via Western blotting. We observed cognitive deficits, tau hyperphosphorylation, and neuroinflammation in the brains of ICV-STZ rats. Intranasal insulin treatment for 6 weeks significantly improved cognitive function, attenuated the level of tau hyperphosphorylation, ameliorated microglial activation, and enhanced neurogenesis in ICV-STZ rats. Additionally, our results indicate that intranasal delivery of insulin probably attenuates tau hyperphosphorylation through the down-regulation of ERK1/2 and CaMKII in the brains of ICV-STZ rats. Our findings demonstrate a beneficial effect of intranasal insulin and provide the mechanistic basis for treating AD patients with intranasal insulin.

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice.

Brain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces ß-amyloid (Aß) production and plaque formation after 6 weeks of treatment in 4.5-month-old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c-Jun N-terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aß metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aß pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

Association of CD33 and MS4A cluster variants with Alzheimer's disease in East Asian populations.

CD33 and MS4A cluster variants have been identified to modulate the risk of Alzheimer's disease (AD) in several recent genome-wide association studies (GWAS) in Caucasians. In the present study, we first conducted a case-control study to investigate the CD33 single nucleotide polymorphisms (SNPs) rs3865444 and rs3826656 and the MS4A cluster SNPs rs610932 and rs670139 in a cohort from eastern China that comprised 126 late-onset Alzheimer's disease (LOAD) patients and 129 healthy controls. The results revealed that the frequency of rs3826656 major (G) allele carriers was higher among the LOAD patients than among the controls [P=0.005; odds ratio (OR), 1.760; 95% confidence interval (CI), 1.185-2.615]. In apolipoprotein E (APOE) ε4 allele carriers, the G allele of the SNP rs3865444 was found to be associated with an increased risk of LOAD (P=0.002; OR, 3.391; 95% CI, 1.512-7.605). Next, we re-evaluated the association between these variants and LOAD by conducting a meta-analysis using data from studies of East Asian populations, including the present case-control study, and confirmed that rs3826656 increased the risk of LOAD. In addition, we identified a significant association between rs610932 and LOAD (P=0.035; OR, 0.79; 95% CI, 0.63-0.98). Note that heterogeneity should be considered during the interpretation of these results; significant heterogeneity was identified among studies on rs3865444, even in a subgroup analysis based on stratification of studies by the country of origin. In summary, our results suggest that CD33 and MS4A cluster variants are associated with LOAD susceptibility in East Asian populations.