Clustering of dystonia in some pedigrees with autosomal dominant essential tremor suggests the existence of a distinct subtype of essential tremor

<p>Abstract</p> <p>Background</p> <p>There is an ongoing debate whether essential tremor (ET) represents a monosymptomatic disorder or other neurologic symptoms are compatible with the diagnosis of ET. Many patients with clinically definite ET develop dystonia. It remains unknown whether tremor associated with dystonia represent a subtype of ET. We hypothesized that ET with dystonia represents a distinct subtype of ET.</p> <p>Methods</p> <p>We studied patients diagnosed with familial ET and dystonia. We included only those patients whose first-degree relatives met diagnostic criteria for ET or dystonia with tremor. This cohort was ascertained for the presence of focal, segmental, multifocal, hemidystonia or generalized dystonia, and ET.</p> <p>Results</p> <p>We included 463 patients from 97 kindreds with autosomal dominant mode of inheritance (AD), defined by the vertical transmission of the disease. ET was the predominant phenotype in every ascertained family and each was phenotypically classified as AD ET. "Pure" ET was present in 365 individuals. Focal or segmental dystonia was present in 98 of the 463 patients; 87 of the 98 patients had ET associated with dystonia, one had dystonic tremor and ten had isolated dystonia. The age of onset and tremor severity did not differ between patients with "pure" ET and ET associated with dystonia. We did not observe a random distribution of dystonia in AD ET pedigrees and all patients with dystonia associated with ET were clustered in 28% of all included pedigrees (27/97, p < 0.001).</p> <p>Conclusions</p> <p>Our results suggest that familial ET associated with dystonia may represent a distinct subtype of ET.</p

The role of family in the intergenerational transmission of collective action

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThe present research demonstrates intergenerational influences on collective action participation, whereby parents’ past and current participation in collective action (descriptive family norms) shape their children’s participation in conventional and radical collective action via injunctive family norms (perception that parents value such participation). Two unique data sets were used: dyads of activist parents and their adult children (Study 1, N = 100 dyads) and student activists who participated in a yearlong, three-wave longitudinal study (Study 2, Ns wave 1 = 1,221, Wave 2 = 960, and Wave 3 = 917). Parents’ past and current participation directly and indirectly predicted children’s protest participation in Study 1, while Study 2 showed a similar pattern longitudinally: Perceptions of parents’ participation (descriptive family norm) and approval (injunctive family norm) predicted change in collective action participation over time. Together, results highlight family environment as a critical setting for the intergenerational transmission of protest

The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory process, in which the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-α is considered to play a role. In the present study the putative involvement of TNF-α gene polymorphisms in pathogenesis of COPD was studied by analysis of four TNF-α gene polymorphisms in a Caucasian COPD population. METHODS: TNF-α gene polymorphisms at positions -376G/A, -308G/A, -238G/A, and +489G/A were examined in 169 Dutch COPD patients, who had a mean forced expiratory volume in one second (FEV1) of 37 ± 13%, and compared with a Dutch population control group of 358 subjects. RESULTS: The data showed that the TNF-α +489G/A genotype frequency tended to be different in COPD patients as compared to population controls, which was due to an enhanced frequency of the GA genotype. In line herewith, carriership of the minor allele was associated with enhanced risk of development of COPD (odds ratio = 1.9, p = 0.009). The other TNF-α gene polymorphisms studied revealed no discrimination between patients and controls. No differences in the examined four TNF-α polymorphisms were found between subtypes of COPD, which were stratified for the presence of radiological emphysema. However, comparison of the COPD subtypes with controls showed a significant difference in the TNF-α +489G/A genotype in patients without radiological emphysema (χ(2)-test: p < 0.025 [Bonferroni adjusted]), while no differences between COPD patients with radiological emphysema and controls were observed. CONCLUSION: Based on the reported data, it is concluded that COPD, and especially a subgroup of COPD patients without radiological emphysema, is associated with TNF-α +489G/A gene polymorphism

Increasing illness severity in very low birth weight infants over a 9-year period

BACKGROUND: Recent reports have documented a leveling-off of survival rates in preterm infants through the 1990's. The objective of this study was to determine temporal changes in illness severity in very low birth weight (VLBW) infants in relationship to the outcomes of death and/or severe IVH. METHODS: Cohort study of 1414 VLBW infants cared for in a single level III neonatal intensive care unit in Delaware from 1993–2002. Infants were divided into consecutive 3-year cohorts. Illness severity was measured by two objective methods: the Score for Neonatal Acute Physiology (SNAP), based on data from the 1(st )day of life, and total thyroxine (T(4)), measured on the 5(th )day of life. Death before hospital discharge and severe intraventricular hemorrhage (IVH) were investigated in the study sample in relation to illness severity. The fetal death rate was also investigated. Statistical analyses included both univariate and multivariate analysis. RESULTS: Illness severity, as measured by SNAP and T(4, )increased steadily over the 9-year study period with an associated increase in severe IVH and the combined outcome of death and/or severe IVH. During the final 3 years of the study, the observed increase in illness severity accounted for 86% (95% CI 57–116%) of the variability in the increase in death and/or severe IVH. The fetal death rate dropped from 7.8/1000 (1993–1996) to 5.3/1000 (1999–2002, p = .01) over the course of the study. CONCLUSION: These data demonstrate a progressive increase in illness in VLBW infants over time, associated with an increase in death and/or severe IVH. We speculate that the observed decrease in fetal death, and the increase in neonatal illness, mortality and/or severe IVH over time represent a shift of severely compromised patients that now survive the fetal time period and are presented for care in the neonatal unit

Perspectives on the Trypanosoma cruzi-host cell receptor interaction

Chagas disease is caused by the parasite Trypanosoma cruzi. The critical initial event is the interaction of the trypomastigote form of the parasite with host receptors. This review highlights recent observations concerning these interactions. Some of the key receptors considered are those for thromboxane, bradykinin, and for the nerve growth factor TrKA. Other important receptors such as galectin-3, thrombospondin, and laminin are also discussed. Investigation into the molecular biology and cell biology of host receptors for T. cruzi may provide novel therapeutic targets

Epidemiology and outcomes of community-onset methicillin-susceptible Staphylococcus aureus bacteraemia in a university hospital in Singapore

10.1186/1471-2334-8-14BMC infectious diseases81

Empirical vs Bayesian approach for estimating haplotypes from genotypes of unrelated individuals

BACKGROUND: The completion of the HapMap project has stimulated further development of haplotype-based methodologies for disease associations. A key aspect of such development is the statistical inference of individual diplotypes from unphased genotypes. Several methodologies for inferring haplotypes have been developed, but they have not been evaluated extensively to determine which method not only performs well, but also can be easily incorporated in downstream haplotype-based association analyses. In this paper, we attempt to do so. Our evaluation was carried out by comparing the two leading Bayesian methods, implemented in PHASE and HAPLOTYPER, and the two leading empirical methods, implemented in PL-EM and HPlus. We used these methods to analyze real data, namely the dense genotypes on X-chromosome of 30 European and 30 African trios provided by the International HapMap Project, and simulated genotype data. Our conclusions are based on these analyses. RESULTS: All programs performed very well on X-chromosome data, with an average similarity index of 0.99 and an average prediction rate of 0.99 for both European and African trios. On simulated data with approximation of coalescence, PHASE implementing the Bayesian method based on the coalescence approximation outperformed other programs on small sample sizes. When the sample size increased, other programs performed as well as PHASE. PL-EM and HPlus implementing empirical methods required much less running time than the programs implementing the Bayesian methods. They required only one hundredth or thousandth of the running time required by PHASE, particularly when analyzing large sample sizes and large umber of SNPs. CONCLUSION: For large sample sizes (hundreds or more), which most association studies require, the two empirical methods might be used since they infer the haplotypes as accurately as any Bayesian methods and can be incorporated easily into downstream haplotype-based analyses such as haplotype-association analyses

Alcohol significantly lowers the seizure threshold in mice when co-administered with bupropion hydrochloride

<p>Abstract</p> <p>Background</p> <p>Bupropion HCl is a widely used antidepressant that is known to cause seizures in a dose-dependent manner. Many patients taking antidepressants will consume alcohol, even when advised not to. Previous studies have not shown any interactions between bupropion HCl and alcohol. However, there have been no previous studies examining possible changes in seizure threshold induced by a combination of alcohol and bupropion HCl.</p> <p>Methods</p> <p>Experimentally naïve female Swiss albino mice (10 per group) received either single doses of bupropion HCl (ranging from 100 mg/kg to 120 mg/kg) or vehicle (0.9% NaCl) by intraperitoneal (IP) injection in a dose volume of 10 ml/kg, and single-dose ethanol alone (2.5 g/kg), or vehicle, 5 min prior to bupropion dosing. The presence or absence of seizures, the number of seizures, the onset, duration and the intensity of seizures were all recorded for 5 h following the administration of ethanol.</p> <p>Results</p> <p>The results show that administration of IP bupropion HCl alone induced seizures in mice in a dose-dependent manner, with the 120 mg/kg dose having the largest effect. The percentage of convulsing mice were 0%, 20%, 30% and 60% in the 0 (vehicle), 100, 110, and 120 mg/kg dose groups, respectively. Pretreatment with ethanol produced a larger bupropion HCl-induced convulsive effect at all the doses (70% each at 100, 110 and 120 mg/kg) and a 10% effect in the ethanol + vehicle only group. The convulsive dose of bupropion HCl required to induce seizures in 50% of mice (CD₅₀), was 116.72 mg/kg for bupropion HCl alone (CI: 107.95, 126.20) and 89.40 mg/kg for ethanol/bupropion HCl (CI: 64.92, 123.10).</p> <p>Conclusion</p> <p>These results show that in mice alcohol lowers the seizure threshold for bupropion-induced seizures. Clinical implications are firstly that there may be an increased risk of seizures in patients consuming alcohol, and secondly that formulations that can release bupropion more readily in alcohol may present additional risks to patients.</p