Double-strand break DNA repair genotype predictive of later mortality and cancer incidence in a cohort of non-smokers

We followed-up for mortality and cancer incidence 1088 healthy non-smokers from a population-based study, who were characterized for 22 variants in 16 genes involved in DNA repair pathways. Follow-up was 100% complete. The association between polymorphism and mortality or cancer incidence was analyzed using Cox Proportional Hazard regression models. Ninety-five subjects had died in a median follow-up time of 78 months (inter-quartile range 59-93 months). None of the genotypes was clearly associated with total mortality, except variants for two Double-Strand Break DNA repair genes, XRCC3 18067 C>T (rs#861539) and XRCC2 31479 G>A (rs#3218536). Adjusted hazard ratios were 2.25 (1.32-3.83) for the XRCC3 C/T genotype and 2.04 (1.00-4.13) for the T/T genotype (reference C/C), and 2.12 (1.14-3.97) for the XRCC2 G/A genotype (reference G/G). For total cancer mortality, the adjusted hazard ratios were 3.29 (1.23-7.82) for XRCC3 C/T, 2.84 (0.81-9.90) for XRCC3 T/T and 3.17 (1.21-8.30) for XRCC2 G/A. With combinations of three or more adverse alleles, the adjusted hazard ratio for all cause mortality was 17.29 (95% C.I. 8.13-36.74), and for all incident cancers the HR was 5.28 (95% C.I. 2.17-12.85). Observations from this prospective study suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly influence the risk of cancer and non-cancer disease, and can influence mortality.     

The extent of linkage disequilibrium in four populations with distinct demographic histories

The design and feasibility of whole-genome-association studies are critically dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empirical data exist. The authors have determined the extent of LD among 38 biallelic markers with minor allele frequencies >.1, since these are most comparable to the common disease-susceptibility polymorphisms that association studies aim to detect. The markers come from three chromosomal regions-1,335 kb on chromosome 13q12-13, 380 kb on chromosome 19q13.2, and 120 kb on chromosome 22q13.3-which have been extensively mapped. These markers were examined in approximately 1,600 individuals from four populations, all of European origin but with different demographic histories; Afrikaners, Ashkenazim, Finns, and East Anglian British. There are few differences, either in allele frequencies or in LD, among the populations studied. A similar inverse relationship was found between LD and distance in each genomic region and in each population. Mean D' is.68 for marker pairs <5 kb apart and is.24 for pairs separated by 10-20 kb, and the level of LD is not different from that seen in unlinked marker pairs separated by >500 kb. However, only 50% of marker pairs at distances <5 kb display sufficient LD (delta>.3) to be useful in association studies. Results of the present study, if representative of the whole genome, suggest that a whole-genome scan searching for common disease-susceptibility alleles would require markers spaced < or = 5 kb apart.     

trans-(-)-ε-Viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington Disease

Huntington disease (HD) is an inherited neurodegenerative disorder caused by an abnormal polyglutamine expansion in the protein Huntingtin (Htt). Currently, no cure is available for HD. The mechanisms by which mutant Htt causes neuronal dysfunction and degeneration remain to be fully elucidated. Nevertheless, mitochondrial dysfunction has been suggested as a key event mediating mutant Htt-induced neurotoxicity because neurons are energy-demanding and particularly susceptible to energy deficits and oxidative stress. SIRT3, a member of sirtuin family, is localized to mitochondria and has been implicated in energy metabolism. Notably, we found that cells expressing mutant Htt displayed reduced SIRT3 levels. trans-(-)-ε-Viniferin (viniferin), a natural product among our 22 collected naturally occurring and semisynthetic stilbenic compounds, significantly attenuated mutant Htt-induced depletion of SIRT3 and protected cells from mutant Htt. We demonstrate that viniferin decreases levels of reactive oxygen species and prevents loss of mitochondrial membrane potential in cells expressing mutant Htt. Expression of mutant Htt results in decreased deacetylase activity of SIRT3 and further leads to reduction in cellular NAD(+) levels and mitochondrial biogenesis in cells. Viniferin activates AMP-activated kinase and enhances mitochondrial biogenesis. Knockdown of SIRT3 significantly inhibited viniferin-mediated AMP-activated kinase activation and diminished the neuroprotective effects of viniferin, suggesting that SIRT3 mediates the neuroprotection of viniferin. In conclusion, we establish a novel role for mitochondrial SIRT3 in HD pathogenesis and discovered a natural product that has potent neuroprotection in HD models. Our results suggest that increasing mitochondrial SIRT3 might be considered as a new therapeutic approach to counteract HD, as well as other neurodegenerative diseases with similar mechanisms.     

Measurement error affects risk estimates for recruitment to the Hudson River stock of striped bass

We examined the consequences of ignoring the distinction between measurement error and natural variability in an assessment of risk to the Hudson River stock of striped bass posed by entrainment at the Bowline Point, Indian Point, and Roseton power plants. Risk was defined as the probability that recruitment of age-1+ striped bass would decline by 80% or more, relative to the equilibrium value, at least once during the time periods examined (1, 5, 10, and 15 years). Measurement error, estimated using two abundance indices from independent beach seine surveys conducted on the Hudson River, accounted for 50% of the variability in one index and 56% of the variability in the other. If a measurement error of 50% was ignored and all of the variability in abundance was attributed to natural causes, the risk that recruitment of age-1+ striped bass would decline by 80% or more after 15 years was 0.308 at the current level of entrainment mortality (11%). However, the risk decreased almost tenfold (0.032) if a measurement error of 50% was considered. The change in risk attributable to decreasing the entrainment mortality rate from 11 to 0% was very small (0.009) and similar in magnitude to the change in risk associated with an action proposed in Amendment #5 to the Interstate Fishery Management Plan for Atlantic striped bass (0.006)--an increase in the instantaneous fishing mortality rate from 0.33 to 0.4. The proposed increase in fishing mortality was not considered an adverse environmental impact, which suggests that potentially costly efforts to reduce entrainment mortality on the Hudson River stock of striped bass are not warranted.     

What’s to like about the prion-like hypothesis for the spreading of aggregated α-synuclein in Parkinson disease?

α-Synuclein is a key protein in Parkinson disease. Not only is it the major protein component of Lewy bodies, but it is implicated in several cellular processes that are disrupted in Parkinson disease. Misfolded α-synuclein has also been shown to spread from cell-to-cell and, in a prion-like fashion, trigger aggregation of α-synuclein in the recipient cell. In this mini-review we explore the evidence that misfolded α-synuclein underlies the spread of pathology in Parkinson disease and discuss why it should be considered a prion-like protein.     

Epithelial lining fluid solute concentrations in chronic obstructive lung disease patients and normal subjects.

The exhaled breath condensate (EBC) method represents a new, noninvasive way to detect inflammatory and metabolic markers in the fluid that covers the airways [epithelial lining fluid (ELF)]. However, respiratory droplets represent only a very small and variable fraction of the EBC, most (approximately 99.99%) of which is water vapor. Our objective was to show that ELF concentrations could be calculated from EBC values by using any of three dilutional indicators (urea, total cations, and conductivity) in nine normal and nine chronic obstructive lung disease (COPD) subjects. EBC concentrations of Na(+), K(+), Ca(2+), Mg(2+), total cations, urea, and conductivity varied over a 10-fold range among individuals, but concentrations of these constituents (except Ca(2+)) remained well correlated (r(2) = 0.44-0.83, P < 0.001). Dilution (D) of respiratory droplets in water vapor was calculated by dividing plasma concentrations of the dilutional indicators by EBC concentrations. Estimates of D were not significantly different among these indicators, and urea D averaged 10,800 +/- 2,100 (SE) in normal and 12,600 +/- 3,300 in COPD subjects. Although calculated Na(+) concentrations in the ELF were less than one-half those in plasma, and concentrations of K(+), Ca(2+), and Mg(2+) exceeded those in plasma, total cation concentrations in ELF were not significantly different from those in plasma, indicating that ELF is isotonic in both normal and COPD subjects. EBC amylase concentrations (measured with an ultrasensitive procedure) indicated that saliva represented <10% of the respiratory (ELF) droplets in all but three samples. Dilutional and salivary markers are essential for interpretation of EBC studies.     

Modelling parasite aggregation: disentangling statistical and ecological approaches

The overdispersion in macroparasite infection intensity among host populations is commonly simulated using a constant negative binomial aggregation parameter. We describe an alternative to utilising the negative binomial approach and demonstrate important disparities in intervention efficacy projections that can come about from opting for pattern-fitting models that are not process-explicit. We present model output in the context of the epidemiology and control of soil-transmitted helminths due to the significant public health burden imposed by these parasites, but our methods are applicable to other infections with demonstrable aggregation in parasite numbers among hosts.     

Dynamic creep and pre-conditioning of the Achilles tendon in-vivo

Warm-up exercises are often advocated prior to strenuous exercise, but the warm-up duration and effect on muscle–tendon behavior are not well defined. The gastrocnemius–Achilles tendon complexes of 18 subjects were studied to quantify the dynamic creep response of the Achilles tendon in-vivo and the warm-up dose required for the Achilles tendon to achieve steady-state behavior. A custom testing chamber was used to determine each subject's maximum voluntary contraction (MVC) during an isometric ankle plantar flexion effort. The subject's right knee and ankle were immobilized for one hour. Subjects then performed over seven minutes of cyclic isometric ankle plantar flexion efforts equal to 25–35% of their MVC at a frequency of 0.75 Hz. Ankle plantar flexion effort and images from dual ultrasound probes located over the gastrocnemius muscle–Achilles tendon and the calcaneus–Achilles tendon junction were acquired for eight seconds at the start of each sequential minute of the activity. Ultrasound images were analyzed to quantify the average relative Achilles tendon strain at 25% MVC force (ε_25%MVC) for each minute. The ε_25%MVC increased from 0.3% at the start of activity to 3.3% after seven minutes, giving a total dynamic creep of ~3.0%. The ε_25%MVC increased by more than 0.56% per minute for the first five minutes and increased by less than 0.13% per minute thereafter. Therefore, following a period of inactivity, a low intensity warm-up lasting at least six minutes or producing 270 loading cycles is required for an Achilles tendon to reach a relatively steady-state behavior.     

Effects of a 4-week youth baseball conditioning program on throwing velocity

Effects of a 4-week youth baseball conditioning program on throwing velocity. This study examined the effects of a 4-week youth baseball conditioning program on maximum throwing velocity. Thirty-four youth baseball players (11-15 years of age) were randomly and equally divided into control and training groups. The training group performed 3 sessions (each 75 minutes) weekly for 4 weeks, which comprised a sport specific warm-up, resistance training with elastic tubing, a throwing program, and stretching. Throwing velocity was assessed initially and at the end of the 4-week conditioning program for both control and training groups. The level of significance used was p < 0.05. After the 4-week conditioning program, throwing velocity increased significantly (from 25.1 ± 2.8 to 26.1 ± 2.8 m·s) in the training group but did not significantly increase in the control group (from 24.2 ± 3.6 to 24.0 ± 3.9 m·s). These results demonstrate that the short-term 4-week baseball conditioning program was effective in increasing throwing velocity in youth baseball players. Increased throwing velocity may be helpful for pitchers (less time for hitters to swing) and position players (decreased time for a runner to advance to the next base).     

Direct comparison of kinematic data collected using an electromagnetic tracking system versus a digital optical system

The purpose of this study was to quantify the dynamic accuracy of kinematics measured by a digital optical motion analysis system in a gait analysis laboratory (capture volume approximately 20m(3)) compared to a standard range direct-current electromagnetic (EM) tracking device (capture volume approximately 1m(3)). This is a subset of a larger effort to establish an appropriate marker set for the optical system to quantify upperlimb kinematics simultaneously with gait, in comparison to previous studies of isolated upperlimb movements that have employed EM tracking devices. Rigid clusters of spherical reflective markers and EM sensors were attached to a mechanical articulator that mimicked three-dimensional joint rotations, similar to the elbow. As the articulator was moved through known ranges of motion (i.e. gold standard), kinematic data were collected simultaneously using both tracking systems. Both systems were tended to underestimate the range of motion; however, the application of post hoc smoothing and least-squares correction algorithms reduced these effects. When smoothing and correction algorithms were used, the magnitude of the mean difference between the gold standard and either the EM or optical system did not exceed 2 degrees for any of the compound motions performed. This level of agreement suggests that the measurements obtained from either system are clinically comparable, provided appropriate smoothing and correction algorithms are employed.