Huntington disease: natural history, biomarkers and prospects for therapeutics

Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials

The question of declining sperm density revisited: an analysis of 101 studies published 1934-1996.

In 1992 Carlsen et al. reported a significant global decline in sperm density between 1938 and 1990 [Evidence for Decreasing Quality of Semen during Last 50 Years. Br Med J 305:609-613 (1992)]. We subsequently published a reanalysis of the studies included by Carlsen et al. [Swan et al. Have Sperm Densities Declined? A Reanalysis of Global Trend Data. Environ Health Perspect 105:1228-1232 (1997)]. In that analysis we found significant declines in sperm density in the United States and Europe/Australia after controlling for abstinence time, age, percent of men with proven fertility, and specimen collection method. The declines in sperm density in the United States (approximately 1.5%/year) and Europe/Australia (approximately 3%/year) were somewhat greater than the average decline reported by Carlsen et al. (approximately 1%/year). However, we found no decline in sperm density in non-Western countries, for which data were very limited. In the current study, we used similar methods to analyze an expanded set of studies. We added 47 English language studies published in 1934-1996 to those we had analyzed previously. The average decline in sperm count was virtually unchanged from that reported previously by Carlsen et al. (slope = -0.94 vs. -0.93). The slopes in the three geographic groupings were also similar to those we reported earlier. In North America, the slope was somewhat less than the slope we had found for the United States (slope = -0.80; 95% confidence interval (CI), -1.37--0.24). Similarly, the decline in Europe (slope = -2.35; CI, -3.66--1.05) was somewhat less than reported previously. As before, studies from other countries showed no trend (slope = -0.21; CI, -2.30-1.88). These results are consistent with those of Carlsen et al. and our previous results, suggesting that the reported trends are not dependent on the particular studies included by Carlsen et al. and that the observed trends previously reported for 1938-1990 are also seen in data from 1934-1996

The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8+ T cell recognition of endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 c1-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV c2-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8+ T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed

Measure of Activity Performance in the Hand (MAP-Hand) questionnaire

Background: Developed in the Norway, the Measure of Activity Performance of the Hand (MAP-Hand) assesses 18 activities performed using the hands. It was developed for people with rheumatoid arthritis (RA) using patient generated items, which are scored on a 0-3 scale and summarised into a total score range (0 to 54). This study reports the development and psychometric testing of the British English MAP-Hand in a UK population of people with RA. Methods: Recruitment took place in the National Health Service (NHS) through 17 Rheumatology outpatient clinics. Phase 1 (cross-cultural adaptation) involved: forward translation to British English; synthesis; expert panel review and cognitive debriefing interviews with people with RA. Phase 2 (psychometric testing) involved postal completion of the MAP-Hand, Health Assessment Questionnaire (HAQ), Upper Limb HAQ (ULHAQ), Short-Form 36 (SF-36v2) and Disabilities of the Arm Shoulder Hand (DASH) to measure internal consistency (Cronbach’s alpha); concurrent validity (Spearman’s correlations) and Minimal Detectable Difference (MDC95). The MAP-Hand was repeated three-weeks later to assess test-retest reliability (linear weighted kappa and Intra-Class Correlations (ICC (2,1)). Unidimensionality (internal construct validity) was assessed using (i) Confirmatory Factor Analysis (CFA) (ii) Mokken scaling and (iii) Rasch model. The RUMM2030 software was used, applying the Rasch partial credit model. Results: In Phase 1, 31 participants considered all items relevant. In Phase 2, 340 people completed Test-1 and 273 (80%) completed Test-2 questionnaires. Internal consistency was excellent (α=0.96). Test-retest reliability was good (ICC (2,1) = 0.96 (95% CI 0.94, 0.97)). The MAP-Hand correlated strongly with HAQ20 (rs=.88), ULHAQ (rs=.91), SF-36v2 Physical Functioning (PF) Score (rs=-.80) and DASH (rs=.93), indicating strong concurrent validity. CFA failed to support unidimensionality (Chi-Square 236.0 (df 120; p <0.001)). However, Mokken scaling suggested a probabilistic ordering. There was differential item functioning (DIF) for gender. Four testlets were formed, resulting in much improved fit and unidimensionality. Following this, testlets were further merged in pairs where opposite bias existed. This resulted in perfect fit to the model. Conclusions: The British English version of the MAP-Hand has good validity and reliability in people with RA and can be used in both research and clinical practice. Keywords: PROMS; Patient Reported Outcome Measures; hand activity performance; hand function; hand pain; psychometric testing; Rasch analysis; validity; reliabilit

Electrostatic charging of jumping droplets

With the broad interest in and development of superhydrophobic surfaces for self-cleaning, condensation heat transfer enhancement and anti-icing applications, more detailed insights on droplet interactions on these surfaces have emerged. Specifically, when two droplets coalesce, they can spontaneously jump away from a superhydrophobic surface due to the release of excess surface energy. Here we show that jumping droplets gain a net positive charge that causes them to repel each other mid-flight. We used electric fields to quantify the charge on the droplets and identified the mechanism for the charge accumulation, which is associated with the formation of the electric double layer at the droplet–surface interface. The observation of droplet charge accumulation provides insight into jumping droplet physics as well as processes involving charged liquid droplets. Furthermore, this work is a starting point for more advanced approaches for enhancing jumping droplet surface performance by using external electric fields to control droplet jumping.United States. Dept. of Energy. Office of Basic Energy Sciences (Solid-State Solar-Thermal Energy Conversion Center Award DE-FG02-09ER46577)United States. Office of Naval ResearchNational Science Foundation (U.S.) (Major Research Instrumentation Grant for Rapid Response Research (MRI- RAPID))National Science Foundation (U.S.) (Award ECS-0335765)National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant 1122374

Lipids modulate the conformational dynamics of a secondary multidrug transporter

Direct interactions with lipids have emerged as key determinants of the folding, structure and function of membrane proteins, but an understanding of how lipids modulate protein dynamics is still lacking. Here, we systematically explored the effects of lipids on the conformational dynamics of the proton-powered multidrug transporter LmrP from Lactococcus lactis, using the pattern of distances between spin-label pairs previously shown to report on alternating access of the protein. We uncovered, at the molecular level, how the lipid headgroups shape the conformational-energy landscape of the transporter. The model emerging from our data suggests a direct interaction between lipid headgroups and a conserved motif of charged residues that control the conformational equilibrium through an interplay of electrostatic interactions within the protein. Together, our data lay the foundation for a comprehensive model of secondary multidrug transport in lipid bilayers

WHODAS 2.0 in prodromal Huntington disease : measures of functioning in neuropsychiatric disease

We thank the PREDICT-HD sites, the study participants, the National Research Roster for Huntington Disease Patients and Families, the Huntington’s Disease Society of America and the Huntington Study Group. This research was supported by the National Center for Advancing Translational Sciences, and the National Institutes of Health (NIH), through Grant 2 UL1 TR000442-06. This research is supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NS040068), CHDI Foundation, Inc (A3917), Cognitive and Functional Brain Changes in Preclinical Huntington’s Disease (HD) (5R01NS054893), 4D Shape Analysis for Modeling Spatiotemporal Change Trajectories in Huntington’s (1U01NS082086), Functional Connectivity in Pre-manifest Huntington’s Disease (1U01NS082083), and Basal Ganglia Shape Analysis and Circuitry in Huntington’s Disease (1U01NS082085).Peer reviewedPublisher PD

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

Geographic differences in semen quality of fertile U.S. males.

Although geographic variation in semen quality has been reported, this is the first study in the United States to compare semen quality among study centers using standardized methods and strict quality control. We evaluated semen specimens from partners of 512 pregnant women recruited through prenatal clinics in four U.S. cities during 1999-2001; 91% of men provided two specimens. Sperm concentration, semen volume, and motility were determined at the centers, and morphology was assessed at a central laboratory. Study protocols were identical across centers, and quality control was rigorously maintained. Sperm concentration was significantly lower in Columbia, Missouri, than in New York, New York; Minneapolis, Minnesota; and Los Angeles, California. Mean counts were 58.7, 102.9, 98.6, and 80.8 X 10(6)/mL (medians 53.5, 88.5, 81.8, and 64.8 X 10(6)/mL) in Missouri, New York, Minnesota, and California, respectively. The total number of motile sperm was also lower in Missouri than in other centers: 113, 196, 201, and 162 X 10(6) in Missouri, New York, Minnesota, and California, respectively. Semen volume and the percent morphologically normal sperm did not differ appreciably among centers. These between-center differences remained significant in multivariate models that controlled for abstinence time, semen analysis time, age, race, smoking, history of sexually transmitted disease, and recent fever (all p-values < 0.01). Confounding factors and differences in study methods are unlikely to account for the lower semen quality seen in this mid-Missouri population. These data suggest that sperm concentration and motility may be reduced in semirural and agricultural areas relative to more urban and less agriculturally exposed areas

Quality of Data Entry Using Single Entry, Double Entry and Automated Forms Processing–An Example Based on a Study of Patient-Reported Outcomes

Background: The clinical and scientific usage of patient-reported outcome measures is increasing in the health services. Often paper forms are used. Manual double entry of data is defined as the definitive gold standard for transferring data to an electronic format, but the process is laborious. Automated forms processing may be an alternative, but further validation is warranted. Methods: 200 patients were randomly selected from a cohort of 5777 patients who had previously answered two different questionnaires. The questionnaires were scanned using an automated forms processing technique, as well as processed by single and double manual data entry, using the EpiData Entry data entry program. The main outcome measure was the proportion of correctly entered numbers at question, form and study level. Results: Manual double-key data entry (error proportion per 1000 fields = 0.046 (95 % CI: 0.001–0.258)) performed better than single-key data entry (error proportion per 1000 fields = 0.370 (95 % CI: 0.160–0.729), (p = 0.020)). There was no statistical difference between Optical Mark Recognition (error proportion per 1000 fields = 0.046 (95 % CI: 0.001–0.258)) and double-key data entry (p = 1.000). With the Intelligent Character Recognition method, there was no statistical difference compared to single-key data entry (error proportion per 1000 fields = 6.734 (95 % CI: 0.817–24.113), (p = 0.656)), as well as double-key data entry (error proportion per 1000 fields = 3.367 (95 % CI: 0.085–18.616)), (p = 0.319))