Effects of combined sensory and muscular training on balance in Japanese older adults

BACKGROUND: Adequate levels of physical balance and muscular strength are necessary to live independently in old age. The effects of an exercise training program targeting the sensory and muscle systems on balance and strength in a group of older adults were determined in this study. METHODS: Static balance (one-leg balance with eyes closed), dynamic balance (limits of stability [endpoint excursion [EPE], maximum excursion [MXE]]), and strength (chair stand) were assessed before and after the intervention. Volunteers were divided randomly into a training group (TR, n = 15, 76 +/- 4 years) and a control group (CN, n = 14, 76 +/- 7 years). TR performed 12-week (2 days/week, 60 min/day) supervised training while standing on the floor (first 4 weeks) and progressing to standing on foam pads of different compliances. Exercises included movements that challenged the sensory and muscle systems. RESULTS: After 12 weeks of training, the TR demonstrated significant improvements in static balance (82%); EPE backward (72%), right (32%), and left (33%); MXE backward (74%), right (31%), and left (18%); and lower body muscle strength (20%) with no significant changes in CN. CONCLUSION: These results indicate that this training program is very effective in improving balance and lower body strength in older adults.     

Antiaggregatory activity in human platelets of potent antagonists of the P2Y 1 receptor

Activation of the P2Y(1) nucleotide receptor in platelets by ADP causes changes in shape and aggregation, mediated by activation of phospholipase C (PLC). Recently, MRS2500(2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate) was introduced as a highly potent and selective antagonist for this receptor. We have studied the actions of MRS2500 in human platelets and compared these effects with the effects of two acyclic nucleotide analogues, a bisphosphate MRS2298 and a bisphosphonate derivative MRS2496, which act as P2Y(1) receptor antagonists, although less potently than MRS2500. Improved synthetic methods for MRS2500 and MRS2496 were devised. The bisphosphonate is predicted to be more stable in general in biological systems than phosphate antagonists due to the non-hydrolyzable CP bond. MRS2500 inhibited the ADP-induced aggregation of human platelets with an IC(50) value of 0.95 nM. MRS2298 and MRS2496 also both inhibited the ADP-induced aggregation of human platelets with IC(50) values of 62.8 nM and 1.5 microM, respectively. A similar order of potency was observed for the three antagonists in binding to the recombinant human P2Y(1) receptor and in inhibition of ADP-induced shape change and ADP-induced rise in intracellular Ca(2+). No substantial antagonism of the pathway linked to the inhibition of cyclic AMP was observed for the nucleotide derivatives, indicating no interaction of these three P2Y(1) receptor antagonists with the proaggregatory P2Y(12) receptor, which is also activated by ADP. Thus, all three of the bisphosphate derivatives are highly selective antagonists of the platelet P2Y(1) receptor, and MRS2500 is the most potent such antagonist yet reported.     

Study on the toxic effects induced by different arsenicals in primary cultured rat astroglia

Arsenic toxicity is a global health problem affecting millions of people. The objectives of this study were to determine if the toxic effects on primary cultured rat astroglia would be induced by different arsenicals. Based on alamarBlue assay and the single cell gel electrophoresis (SCGE, comet assay), the cell viability and DNA damage in the cells exposed to different arsenicals were evaluated. Treatment of astroglia with methylated arsenicals, that is, pentavalent monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), resulted in no obvious changes in cell viability and DNA damage at micromolar concentrations. However, treatment of astroglia with inorganic arsenicals, that is, arsenite and arsenate, caused decreased cell viability and increased DNA damage at micromolar levels, and showing a dose-related decrease in mean alamarBlue reduced rate and a dose-related increase in mean comet length. Our study is therefore highly suggestive for a link between inorganic exposure and cellular toxicity or DNA damage. Based on the results of this study, the toxic effects induced by arsenite were stronger than those induced by arsenate.     

Polymorphism of Prodynorphin promoter is associated with schizophrenia in Chinese population

AIM: To investigate the correlation between single nucleotide polymorphisms (SNPs) of functional candidate gene Prodynorphin (PDYN) and schizophrenia. METHODS: SNPs in the promoter and exon regions of PDYN were screened and genotyped for association study in a cohort of Chinese Han schizophrenia cases and controls. RESULTS: Two SNPs PDYN-1576C>T and PDYN-946C>G were identified in the promoter region but PDYN-946C>G showed significant differences of allele distribution (x2=6.15, P=0.013) and genotype distribution (x2=6.87, P=0.032) between schizophrenic and control subjects. CONCLUSION: PDYN-946C>G polymorphism demonstrated an association with population susceptibility to schizophrenia (P<0.05).     

ATM polymorphisms as risk factors for prostate cancer development

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17-3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk.     

An impaired neocortical Ih is associated with enhanced excitability and absence epilepsy

Neuronal subthreshold excitability and firing behaviour are markedly influenced by the activation and deactivation of the somato-dendritic hyperpolarization-activated cation current (Ih). Here, we evaluated possible contributions of Ih to hyperexcitability in an animal model of absence seizures (WAG/Rij rats). We investigated pyramidal neurons of the somatosensory neocortex, the site of generation of spike-wave discharges. Ih-mediated functions in neurons from WAG/Rij rats, Wistar rats (sharing the same genetic background with WAG/Rij, but less epilepsy-prone) and ACI rats (an inbred strain, virtually free of seizures) were compared. We complemented whole-cell recordings from layer 2-3 pyramidal neurons with immunohistochemistry, Western blot and RT-PCR analysis of the h-channel subunits HCN1-4. The fast component of Ih activation in WAG/Rij neurons was significantly reduced (50% reduction in the h-current density) and four times slower than in neurons from nonepileptic Wistar or ACI rats. The results showing decreases in currents corresponded to a 34% reduction in HCN1 protein in the WAG/Rij compared to the Wistar neocortex, but HCN1 mRNA showed stable expression. The other three Ih subunit mRNAs and proteins (HCN2-4) were not affected. The alterations in Ih magnitude and kinetics of gating in WAG/Rij neurons may contribute to augmented excitatory postsynaptic potentials, the increase in their temporal summation and the facilitation of burst firing of these neurons because each of these effects could be mimicked by the selective Ih antagonist ZD 7288. We suggest that the deficit in Ih-mediated functions may contribute to the development and onset of spontaneously occurring hyperexcitability in a rat model of absence seizures.     

Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease

Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE-4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the –219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. Despite these findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influenced risk of AD independent of the APOE-4 allele. In addition to risk, we tested for association between the SNPs and age at onset of AD, but found no association in the case-control or family based analyses. In conclusion, SNPs +5361, or a SNP in strong linkage disequilibrium, may confer some additional risk for developing AD beyond the risk due to APOE-4; however, the effect independent of APOE-4 is likely to be small.     

Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy

The LGI4 gene is located in a region linked to benign familial infantile convulsions (BFIC) and idiopathic generalized epilepsy. Screening of the LGI4 coding region in BFIC and childhood absence epilepsy (CAE) revealed several frequent exonic polymorphisms. A genotypic association was found for the c.1914GCAT polymorphism in 42 CAE patients compared with 110 population controls (²=6.66, df=1, P=0.01), providing evidence for a so far undetected susceptibility allele for CAE in the LGI4 region.     

Basal ganglia--hippocampal interactions support the role of the hippocampal formation in sensorimotor integration

Experiments were carried out to evaluate whether neural activity in the basal ganglia is functionally related to the neural activity underlying mechanisms of theta band oscillation and synchrony in the hippocampal formation. Experiment 1 demonstrated that electrical stimulation administered to the substantia nigra, globus pallidus (GP) and caudate-putamen (CPu) in urethane anesthetized rats elicited theta field activity in the hippocampal formation. Subsequent microinfusion of the local anesthetic procaine hydrochloride into the medial septum reversibly abolished this effect. In Experiment 2, single cell discharge profiles established for 152 cells recorded in nuclei of the basal ganglia resulted in 101 (66%) being classified as theta-related and 51 (34%) classified as nonrelated. Theta-related cells were further subclassified as tonic theta-ON cells (n = 79) and tonic theta-OFF (n = 22). Tonic theta-ON and tonic theta-OFF cells displayed irregular or regular (tonic) discharge patterns. Rhythmic discharge patterns did not occur in any theta-related cells in the nuclei of the basal ganglia. However, analyses using Kaneoke and Vitek's [J. Neurosci. Methods 68, (1996) 211] algorithms revealed that 51/101 (50%) theta-related cells displayed periodicity in their discharge patterns whereas 27/51 (53%) of the nonrelated cells displayed periodicity in their discharge patterns. The periodicities in the majority of cells were in frequency ranges above that of theta band oscillation and synchrony. The results support the following conclusions: (1) the cellular activity of the basal ganglia, composed of nuclei traditionally associated with motor functions, is functionally connected with the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation; (2) the observed functional connectivity provides support for the role of the hippocampal formation in sensorimotor integration.