Jagged1 (JAG1) mutations in patients with tetralogy of fallot or pulmonic stenosis

Mutations in the Notch pathway ligand Jagged1 (JAG1) cause Alagille syndrome (AGS), as well as cardiac defects in seemingly nonsyndromic individuals. To estimate the frequency of JAG1 mutations in cases with right‐sided cardiac defects not otherwise diagnosed with AGS, we screened 94 cases with tetralogy of Fallot (TOF) and 50 with pulmonic stenosis/peripheral pulmonary stenosis (PS/PPS) or pulmonary valve atresia with intact ventricular septum (PA) for mutations. Sequence changes were identified in three TOF and three PS/PPS/PA patients, that were not present in 100 controls. We identified one frameshift and two missense mutations in the TOF cases, and one frameshift and two missense mutations in cases with PS/PPS/PA. The four missense mutations were assayed for their effect on protein localization, posttranslational modification, and ability to activate Notch signaling. The missense mutants displayed heterogeneous behavior in these assays, some with complete haploinsufficiency, suggesting that there are additional modifiers leading to organ specific features. We identified functionally significant mutations in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients. Patients with right‐sided cardiac defects should be carefully screened for features of AGS or a family history of cardiac defects that might suggest the presence of a JAG1 mutation. Hum Mutat 31:594–601, 2010. © 2010 Wiley‐Liss, Inc.     

When autophagy meets viruses: a double-edged sword with functions in defense and offense

Autophagy is a ubiquitous catabolic process that ensures organism’s well-being by sequestering a wide array of undesired intracellular constituents into double-membrane vesicles termed autophagosomes for lysosomal degradation. Interest in autophagy research has recently gained momentum as it is increasingly being recognized to play fundamental roles in diverse aspects of human pathophysiology including virus infection and its subsequent complications. This review discusses recent advances in autophagy studies with respect to virus infection and pathogenesis. A growing body of evidence suggests that the autophagy pathway and/or autophagy genes play pleiotropic functions in the host’s intrinsic, innate, and adaptive immune response against viruses. However, some viruses have evolved to encode virulence factors that evade or counteract the execution of autophagy. Furthermore, certain viruses are equipped to enhance autophagy or exploit the autophagy machinery for their replication and pathogenesis. A comprehensive understanding of the roles of autophagy pathway and autophagy genes during viral infection may enable the discovery of novel antiviral drug targets.     

Isolation of the genome sequence strain Mycobacterium avium 104 from multiple patients over a 17-year period

The genome sequence strain 104 of the opportunistic pathogen Mycobacterium avium was isolated from an adult AIDS patient in Southern California in 1983. Isolates of non-paratuberculosis M. avium from 207 other patients in Southern California and elsewhere were examined for genotypic identity to strain 104. This process was facilitated by the use of a novel two-step approach. In the first step, all 208 strains in the sample were subjected to a high-throughput, large sequence polymorphism (LSP)-based genotyping test, in which DNA from each strain was tested by PCR for the presence or absence of 4 hypervariable genomic regions. Nineteen isolates exhibited an LSP type that resembled that of strain 104. This subset of 19 isolates was then subjected to high-resolution repetitive sequence-based PCR typing, which identified 10 isolates within the subset that were genotypically identical to strain 104. These isolates came from 10 different patients at 5 clinical sites in the western United States, and they were isolated over a 17-year time span. Therefore, the sequenced genome of M. avium strain 104 has been associated with disease in multiple patients in the western United States. Although M. avium is known for its genetic plasticity, these observations also show that strains of the pathogen can be genotypically stable over extended time periods.     

Interval timing and Parkinson’s disease: heterogeneity in temporal performance

Interval timing deficiencies in Parkinson’s disease (PD) patients have been a matter of debate. Here we test the possibility of PD heterogeneity as a source for this discrepancy. Temporal performance of PD patients and control subjects was assessed during two interval tapping tasks and during a categorization task of time intervals. These tasks involved temporal processing of intervals in the hundreds of milliseconds range; however, they also covered a wide range of behavioral contexts, differing in their perceptual, decision-making, memory, and execution requirements. The results showed the following significant findings. First, there were two clearly segregated subgroups of PD patients: one with high temporal variability in the three timing tasks, and another with a temporal variability that did not differ substantially from control subjects. In contrast, PD patients with high and low temporal variability showed similar perceptual, decision-making, memory, and execution performance in a set of control tasks. Second, a slope analysis, designed to dissociate time-dependent from time-independent sources of variation, revealed that the increase in variability in this group of PD patients was mainly due to an increment in the variability associated with the timing mechanism. Third, while the control subjects showed significant correlations in performance variability across tasks, PD patients, and particularly those with high temporal variability, did not show such task correlations. Finally, the results showed that dopaminergic treatment restored the correlation effect in PD patients, producing a highly significant correlation between the inter-task variability. Altogether, these results indicate that a subpopulation of PD patients shows a strong disruption in temporal processing in the hundreds of milliseconds range. These findings are discussed in terms of the role of dopamine as a tuning element for the synchronization of temporal processing across different behavioral contexts in PD patients.     

Seasonal variation in physical activity,sedentary behaviour and sleep in a sample of UK adults

Background: Physical activity (PA), sedentary behaviour (SB), sleep and diet have all been associated with increased risk for chronic disease. Seasonality is often overlooked as a determinant of these behaviours in adults. Currently, no study has simultaneously monitored these behaviours in UK adults to assess seasonal variation.

Aim: The present study investigated whether PA, SB, sleep and diet differed over season in UK adults.

Subjects and methods: Forty-six adults (72% female; age?=?41.7?±?14.4 years, BMI?=?24.9?±?4.4?kg/m²) completed four 7-day monitoring periods; one during each season of the year. The ActiGraph GT1M was used to monitor PA and SB. Daily sleep diaries monitored time spent in bed (TIB) and total sleep time (TST). The European Prospective Investigation of Cancer (EPIC) food frequency questionnaire (FFQ) assessed diet. Repeated measures ANOVAs were used to identify seasonal differences in behaviours.

Results: Light-intensity PA was significantly higher in summer and spring (p?p?p?>?0.05).

Conclusions: Findings support the concept that health promotion campaigns need to encourage year-round participation in light intensity PA, whilst limiting SB, particularly during the winter months.     

Effects of stimulus emotionality and sentence generation on memory for words in adults with unilateral brain damage

Does sentence generation and/or stimulus emotionality enhance verbal memory in patients with neurological impairment? This question was addressed by testing 40 patients with unilateral stroke (20 with left-brain and 20 with right-brain damage) and 20 healthy control participants for recall and recognition of 48 target words. During encoding, emotional and nonemotional words were either presented in sentences (read condition) or used to form sentences (generate condition). Both word emotionality and generative processing improved memory performance in all groups. The authors suggest that a similar influence (i.e., cognitive activation) underlies both of these memory-enhancing effects, although the putative origins of the 2 effects are quite different. Neuropsychological underpinnings and clinical implications of these phenomena are discussed.     

Geospatial patterns of access to self-care resources for obesity among endometrial cancer survivors in a high poverty urban community

Objective

To examine endometrial cancer survivors' access to recommended obesity-related self-care resources.