Glucose Peaks and the Risk of Dementia and 20-Year Cognitive Decline.
Hemoglobin A1c (HbA1c), a measure of average blood glucose level, is associated with the risk of dementia and cognitive impairment. However, the role of glycemic variability or glucose excursions in this association is unclear. We examined the association of glucose peaks in midlife, as determined by the measurement of 1,5-anhydroglucitol (1,5-AG) level, with the risk of dementia and 20-year cognitive decline. Nearly 13,000 participants from the Atherosclerosis Risk in Communities (ARIC) study were examined. Dementia was ascertained from surveillance, neuropsychological testing, telephone calls with participants or their proxies, or death certificate dementia codes. Cognitive function was assessed using three neuropsychological tests at three visits over 20 years and was summarized as z scores. We used Cox and linear mixed-effects models. 1,5-AG level was dichotomized at 10 μg/mL and examined within clinical categories of HbA1c. Over a median time of 21 years, dementia developed in 1,105 participants. Among persons with diabetes, each 5 μg/mL decrease in 1,5-AG increased the estimated risk of dementia by 16% (hazard ratio 1.16, P = 0.032). For cognitive decline among participants with diabetes and HbA1c <7% (53 mmol/mol), those with glucose peaks had a 0.19 greater z score decline over 20 years (P = 0.162) compared with those without peaks. Among participants with diabetes and HbA1c ≥7% (53 mmol/mol), those with glucose peaks had a 0.38 greater z score decline compared with persons without glucose peaks (P < 0.001). We found no significant associations in persons without diabetes. Among participants with diabetes, glucose peaks are a risk factor for cognitive decline and dementia. Targeting glucose peaks, in addition to average glycemia, may be an important avenue for prevention.


A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma.
Perifosine, a heterocyclic alkylphosphocholine signal transduction inhibitor, has activity against multiple cell types in vitro. This is a phase II study to determine activity and toxicity of perifosine in pancreatic adenocarcinoma. Previously untreated patients with locally advanced, unresectable, or metastatic pancreatic adenocarcinoma, performance status Eastern Cooperative Oncology Group 0 or 1, were enrolled. An oral loading dose of 900 mg was followed by 100 mg per day until progression or unacceptable toxicity. Response criteria in solid tumors (RECIST) methodology and a 2-stage design were used. Suspension could occur for inadequate response in the first cohort or for more than 25% grade 3 or greater toxicity. Ten patients were enrolled. Six received 1 month and 4 received 2 months of treatment. Four discontinued therapy as a result of progression and 2 because of clinical deterioration. Three died during treatment. One patient had stable disease but discontinued therapy as a result of unacceptable adverse events (95% confidence interval: 0.3-45%). There were no objective responses and all patients died of progressive disease. Median overall and progression-free survival was 1.85 months (95% confidence interval: 0.9-2.7) and 1.5 months (95% confidence interval: 0.9-1.9) respectively. The study was suspended and subsequently terminated as a result of unacceptable adverse events during the first stage. Perifosine does not appear to be worthy of further study in this group of patients.


Role of σ,π-Digold(I) Alkyne Complexes in Reactions of Enynes.
Gold(I) acetylide and σ,π-digold(I) alkyne complexes derived from one prototypical 1,6-enyne and from 7-ethynyl-1,3,5-cycloheptatriene have been prepared and structurally characterized. Their possible role in gold(I)-catalyzed cycloisomerizations has been studied by experiment and by DFT calculations. Gold(I) acetylides are totally unproductive complexes in the absence of Brønsted acids. Similarly, no cyclizations were observed by heating σ,π-digold(I) alkyne digold(I) at least up to 130 °C. Theoretical studies provide a rationale for the much lower reactivity of digold species in reactions of enynes.


Islamic fasting leads to an increased abundance of Akkermansia muciniphila and Bacteroides fragilis group: A preliminary study on intermittent fasting.
It has been largely accepted that dietary habits affect intestinal microbiota composition. In this pilot study, we hypothesized that time-restricted feeding, which can be regarded as a type of intermittent fasting, may have a distinct effect on intestinal microbiota. Ramadan fasting is an excellent model to understand how time-restricted feeding affect the microbiota. A total of nine subjects were included in this study during Ramadan, consisting of 17 h of fasting/day during a 29-day period. Stool samples were collected at baseline and the day of the end of Ramadan. 16S rRNA qPCR assay has been performed for quantification of Akkermansia muciniphila, Faecalibacterium prausnitzii, Bifidobacterium spp., Lactobacillus spp., Bacteroides fragilis group, and Enterobacteriaceae. Blood samples were also collected to test for metabolic and nutritional parameters. A significantly increased abundance of A. muciniphila and B. fragilis group was observed in all subjects after Islamic fasting when compared with the baseline levels (p=0.004 and 0.008, respectively). Serum fasting glucose and total cholesterol levels were also significantly reduced in all of the subjects (p<0.01 and p=0.009, respectively). Islamic fasting, which represents intermittent fasting, leads to an increase in A. muciniphila and B. fragilis group, which were considered as healthy gut microbiota members. Although this is a pilot study, which should be tested with larger sample size, there are a very limited number of studies in the literature on fasting and microbiota in human subjects. Thus, our present findings may contribute to the understanding of fasting-gut microbiota interaction.


Genetic discrimination and life insurance: a systematic review of the evidence.
Since the late 1980s, genetic discrimination has remained one of the major concerns associated with genetic research and clinical genetics. Europe has adopted a plethora of laws and policies, both at the regional and national levels, to prevent insurers from having access to genetic information for underwriting. Legislators from the United States and the United Kingdom have also felt compelled to adopt protective measures specifically addressing genetics and insurance. But does the available evidence really confirm the popular apprehension about genetic discrimination and the subsequent genetic exceptionalism? This paper presents the results of a systematic, critical review of over 20 years of genetic discrimination studies in the context of life insurance. The available data clearly document the existence of individual cases of genetic discrimination. The significance of this initial finding is, however, greatly diminished by four observations. First, the methodology used in most of the studies is not sufficiently robust to clearly establish either the prevalence or the impact of discriminatory practices. Second, the current body of evidence was mostly developed around a small number of 'classic' genetic conditions. Third, the heterogeneity and small scope of most of the studies prevents formal statistical analysis of the aggregate results. Fourth, the small number of reported genetic discrimination cases in some studies could indicate that these incidents took place due to occasional errors, rather than the voluntary or planned choice, of the insurers. Important methodological limitations and inconsistencies among the studies considered make it extremely difficult, at the moment, to justify policy action taken on the basis of evidence alone. Nonetheless, other empirical and theoretical factors have emerged (for example, the prevalence and impact of the fear of genetic discrimination among patients and research participants, the (un)importance of genetic information for the commercial viability of the private life insurance industry, and the need to develop more equitable schemes of access to life insurance) that should be considered along with the available evidence of genetic discrimination for a more holistic view of the debate.


Relationship between 8/9-yr-old school children BMI, parents' BMI and educational level: a cross sectional survey.
Parents are responsible not only for the genetic structure of their children, but also for passing onto them their behaviours and attitudes toward life. The aim of this study was to analyse the connection between school-age children's obesity and that of their parents as well as between child obesity and parents' educational level, as a proxy indicator of the socio-economic status (SES) of families in Tuscany. The children sample was selected from "OKkio alla Salute 2010" (a cross sectional survey carried out by the Italian Institute of Health) and consisted of 1,751 (922 males and 855 females) 8-9 year-old school children. Weight and height were measured by ad hoc trained personnel, and Body Mass Index (BMI) categories were calculated using Cole et al.'s cut-off. Parents' weight, height and educational level were collected by a self-administered questionnaire. The educational levels were classified as high, medium and low. The prevalence of obese children increased along the parents' BMI category: from 1.4% for underweight mothers to 30.3% for obese mothers and from 4% for under-normal-weight fathers to 23.9% for obese fathers (p < 0.001). An inverse relationship was observed between the parents' educational level and child obesity, the lowest educational level corresponding to the highest prevalence of obese children: 9.3% for mothers with a low educational level compared to 5.8% for mothers with a high educational level (p = 0.15); similarly, the corresponding prevalence for fathers was 9.5% compared to 4.5% (p = 0.03). Parents' obesity and the cultural resources of the family, particularly the father's, seem to influence the prevalence of overweight and obesity in Tuscan children.


SU-D-BRCD-05: Evaluation of New Exit Detector Based Transit Dosimetry Software for TomoTherapy Treatments.
The prospect of 3D transit dosimetry to verify treatment delivery is a novel and emerging technology in TomoTherapy. Math Resolutions, LLC, has expanded their Dosimetry Check (DC) quality control software to include transit dosimetry calculations for TomoTherapy treatments. The data recorded by the MVCT detectors during patient treatment is used in conjunction with the planning CT to calculate the delivered dose to the patient from each fraction. This study presents a summation of our experiences at the University of Virginia in collaboration with Math Resolutions in verifying and implementing the transit-dose calculation aspects of this new TomoTherapy specific product. Low and high modulation cheese phantom plans and clinical plans (prostate, GYN, pituitary, and thoracic vertebra) were used to evaluate the DC transit dosimetry software. The TomoTherapy planning CT, structure set, plan, and dose for each plan were imported into the DC software. The fluence maps were reconstructed from the exit detector data by correcting for patient attenuation and used to compute the delivered dose. The resulting dose distribution is compared with the TPS planned dose using isodose line comparison and gamma index. The percent difference between the planned and DC calculated doses ranged between 0.63% for a low modulation cheese phantom plan to 5.94% for a prostate plan. Using criteria of 3%, 3mm, the gamma index passing rate for the tested plans ranged from 94.7% to 99.1% <1 for the overall patient area and from 88% to 96.4% for the treatment area receiving at least 80% of the prescribed dose. The results from our evaluation of Math Resolutions' DC look promising and generally within an acceptable range for portal dosimetry programs. Further investigations will include developments to improve the DC algorithm and determine how it can best be implemented in a typical TomoTherapy clinical workflow. Research Grant from Math Resolutions LLC 01/12/2012-01/11/2013 Math Resolutions™ Dosimetry Checksoftware was given to UVa to assist with evaluating the precision of the product in reconstructing dose from the TomoTherapy exit detector data.


Biological activities of peptide concentrates obtained from hydrolysed eggshell membrane byproduct by optimisation with response surface methodology.
The increase of hen egg consumption demands profitable applications for eggshells, including their membranes, in order to minimize environmental and public health problems that could result from their accumulation. This work presents an innovative application for eggshell membranes to obtain an added-value food ingredient that combines maximized ACE-inhibitory and antioxidant activities. Firstly, the use of acetic acid 5% (v/v); and 3-mercaptopropionic acid 1.25 M enabled 63% recovery of eggshell membrane proteins. Secondly, the extracted proteins were hydrolysed by alcalase from Bacillus licheniformis, viscozyme L and protease from Bacillus amyloliquefaciens. Hydrolysis conditions were optimized using response surface methodology experimental design. The ACE-inhibitory activity (IC50) was 34.5 ± 2.1 μg mL-1, 63.0 ± 4.2 μg mL-1 and 43.0 ± 8.5 μg mL-1 for each enzyme, respectively, and the antioxidant activity was ca. 4.0 μmoltrolox equivalent mg-1hydrolysed protein. The combination of both bioactive properties is of potential interest to control cardiovascular diseases.


Integrated optical Young interferometer.
The integrated optical configuration of a Young interferometer is proposed for refractometry and chemical sensing. We coupled light into an integrated optical Ybranch by fixing a laser diode directly at the input of the optical device. We solved the problem of ambiguity in the interference order by operating the laser diode at currents below threshold, resulting in visibility modulation of the interference fringes caused by the low coherence length of the emitted light. A very compact device results that measures the refractive index of liquids or gases. An electronic scanning technique by means of a CCD array provides a fast readout without the need for moving parts.


Both mu and delta opiate receptors exist on the same neuron.
Low concentrations of the relatively selective opiate receptor agonists dihydromorphine and normorphine (mu receptor agonists) and D-Ala 2-D-Leu 5-enkephalin (a delta receptor agonist) were applied to single enteric neurons while the frequency of action potential firing was recorded. Most neurons that were inhibited by the mu agonists were also inhibited by the delta agonist, but the two receptors could be distinguished by the higher concentration of naloxone required to antagonize the delta agonist. The results indicate that enteric neurons bear both mu and delta receptors and that cell firing is inhibited if either receptor type is activated.


Chronic Physical Disturbance Substantially Alters the Response of Biological Soil Crusts to a Wetting Pulse, as Characterized by Metatranscriptomic Sequencing.
Biological soil crusts (biocrusts) are microbial communities that are a feature of arid surface soils worldwide. In drylands where precipitation is pulsed and ephemeral, the ability of biocrust microbiota to rapidly initiate metabolic activity is critical to their survival. Community gene expression was compared after a short duration (1 h) wetting pulse in both intact and soils disturbed by chronic foot trampling. Across the metatranscriptomes the majority of transcripts were cyanobacterial in origin, suggesting that cyanobacteria accounted for the bulk of the transcriptionally active cells. Chronic trampling substantially altered the functional profile of the metatranscriptomes, specifically resulting in a significant decrease in transcripts for nitrogen fixation. Soil depth (biocrust and below crust) was a relatively small factor in differentiating the metatranscriptomes, suggesting that the metabolically active bacteria were similar between shallow soil horizons. The dry samples were consistently enriched for hydrogenase genes, indicating that molecular hydrogen may serve as an energy source for the desiccated soil communities. The water pulse was associated with a restructuring of the metatranscriptome, particularly for the biocrusts. Biocrusts increased transcripts for photosynthesis and carbon fixation, suggesting a rapid resuscitation upon wetting. In contrast, the trampled surface soils showed a much smaller response to wetting, indicating that trampling altered the metabolic response of the community. Finally, several biogeochemical cycling genes in carbon and nitrogen cycling were assessed for their change in abundance due to wetting in the biocrusts. Different transcripts encoding the same gene product did not show a consensus response, with some more abundant in dry or wet biocrusts, highlighting the challenges in relating transcript abundance to biogeochemical cycling rates. These observations demonstrate that metatranscriptome sequencing was able to distinguish alterations in the function of arid soil microbial communities at two varying temporal scales, a long-term ecosystems disturbance through foot trampling, and a short term wetting pulse. Thus, community metatranscriptomes have the potential to inform studies on the response and resilience of biocrusts to various environmental perturbations.


European surveillance of antimicrobial resistance in Neisseria gonorrhoeae.
To perform a European sentinel surveillance study for antimicrobial resistance (AMR) in Neisseria gonorrhoeae as part of the European Surveillance of Sexually Transmitted Infections Programme. From 2006 to 2008 17 countries participated in the AMR surveillance programme. The susceptibility of a total of 3528 consecutive isolates was tested using the agar dilution breakpoint technique or Etests for ciprofloxacin, penicillin, tetracycline, azithromycin, spectinomycin and ceftriaxone. Nitrocefin was used to detect β-lactamase activity. Rates of resistance to ciprofloxacin, the previously recommended treatment, were high across Europe (42-52%), indicating that usage is no longer appropriate. Although resistance to the currently recommended treatment, ceftriaxone, was not demonstrated, a concerning upward drift in the minimal inhibitory concentration (MIC) distribution was identified since an earlier European study in 2004. No resistance to spectinomycin was seen, whereas azithromycin resistance varied from 2% to 7% and isolates from Scotland (n=4) and Ireland (n=1) showed high-level resistance (MIC >256 mg/l). High-level resistance to tetracycline and penicillin remained relatively constant at 16% and 12%, respectively. AMR is an ongoing problem in Europe, with high rates of resistance to many previously recommended therapeutic agents observed in many European countries. Continual European and global surveillance of AMR in N gonorrhoeae is essential to monitor for increasing, emerging and high-level resistance to therapeutically relevant agents and to inform treatment guidelines so optimum treatments are administered.


Determination of two-dimensional planar displacement by moiré fringes of concentric-circle gratings.
We investigate the moiré fringe pattern of two concentric-circle gratings with the aim of measuring the relative two-dimensional planar displacement induced between the gratings. In the first stage we give a comprehensive mathematical approach for the analysis of fringe patterns. Then we suggest a fast computational measurement algorithm that uses a Fourier transformation technique. Finally, our experimental results prove that a measuring accuracy of 0.01 µm can be achieved with this method.


Chemical characteristics and enhanced hepatoprotective activities of Maillard reaction products derived from milk protein-sugar system.
The objective of this study was to investigate the characteristics, antioxidative properties, and hepatoprotective effects of Maillard reaction products (MRP) from milk protein reacted with sugars. The MRP were obtained from milk protein, whey protein concentrates and sodium caseinate, using 2 types of sugars, lactose and glucose, by heating the mixture at 55°C for 7d in a sodium phosphate buffer (pH 7.4). Changes in the chemical modification of the milk protein were monitored by measuring the protein-bound carbonyls and PAGE protein profiles. The results showed that the amount of protein-bound carbonyls increased after Maillard reaction (MR). In addition, sodium dodecyl sulfate-PAGE analysis indicated a formation of high-molecular weight complexes through MR. The modification sites induced by MR of milk protein were monitored by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of tryptic-digested gel spots of MRP. As a result, modification and their localization in AA sequence of MRP was identified. Also, the MRP showed higher antioxidant activities than the intact milk protein, and they reduced intracellular reactive oxygen species production and inhibited the depletion of the reduced glutathione concentrations in the HepG2 cells. In particular, glucose-sodium caseinate MRP showed the highest biological activities among all MRP. Therefore, these results suggest that the MRP from milk protein reacting with sugars possess effective antioxidant activity and have a protective ability against oxidative damage.


Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population.
The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPR(mt)). UPR(mt) shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes.


In vivo differences in inputs and spiking between neurons in lobules VI/VII of neocerebellum and lobule X of archaeocerebellum.
The cerebellum plays an important role in the coordination and refinement of movements and cognitive processes. Recently, it has been shown that the main output neuron of the cerebellar cortex, i.e., the Purkinje cell, can show a different firing behavior dependent on its intrinsic electrophysiological properties. Yet, to what extent a different nature of mossy fiber inputs can influence the firing behavior of cerebellar cortical neurons remains to be elucidated. Here, we compared the firing rate and regularity of mossy fibers and neurons in two different regions of cerebellar cortex. One region intimately connected with the cerebral cortex, i.e., lobules VI/VII of the neocerebellum, and another one strongly connected with the vestibular apparatus, i.e., lobule X of the archaeocerebellum. Given their connections, we hypothesized that activity in neurons in lobules VI/VII and lobule X may be expected to be more phasic and tonic, respectively. Using whole-cell and cell-attached recordings in vivo in anesthetized mice, we show that the mossy fiber inputs to these functionally distinct areas of the cerebellum differ in that the irregularity and bursty character of their firing is significantly greater in lobules VI/VII than in lobule X. Importantly, this difference in mossy fiber regularity is propagated through the granule cells at the input stage to the Purkinje cells and molecular layer interneurons, ultimately resulting in different regularity of simple spikes. These data show that the firing behavior of cerebellar cortical neurons does not only reflect particular intrinsic properties but also an interesting interplay with the innate activity at the input stage.


The Cost of Melanoma and Kidney, Prostate, and Ovarian Cancers in Russia.
The objective of this study was to assess the total annual economic burden of melanoma and kidney, prostate, and ovarian cancers in Russia using the unified methods. The general prevalence-based cost-of-illness model was developed to evaluate the annual health and social care costs and value of lost productivity attributable to the following cancers: melanoma and kidney, prostate, and ovarian cancers from the perspective of the overall governmental budget. All costs were calculated using the "bottom-up" costing technique for the total population of patients with studied cancer, including both newly diagnosed patients stratified by cancer stage and patients diagnosed in previous years who were still alive in the study year. The lowest aggregate annual cost was found for melanoma-€17.48 million (52.4% health care costs, 34.9% social care costs, 12.7% attributed to productivity loss) and the highest-€84.52 million-for prostate cancer (72.0%, 19.0%, and 9.0%, respectively). Estimations for kidney and ovarian cancers were €45.33 and €45.56 million, respectively, with a similar distribution (42.5%-45.2% health care costs, 39.0%-40.3% social care costs, 14.5%-18.5% lost productivity). Cost for a newly diagnosed patient was several times higher than for a patient diagnosed in previous years (€1144- €1947 vs. €145-€417, respectively). For patients in the first year after diagnosis, the major part of economic burden was attributed to health care costs, whereas for those diagnosed before the study year, costs not related to health were more prominent, except for prostate cancer. The economic impact of cancers is more prominent during the first year after diagnosis. A considerable part of the economic burden of cancer lies outside the health sector.


Impact of Caries Severity/Activity and Psychological Aspects of Caregivers on Oral Health-Related Quality of Life among 5-Year-Old Children.
The aim of the present study was to evaluate the influence of the severity/activity of dental caries as well as sense of coherence (SOC) and locus of control (LOC) on oral health-related quality of life (OHRQoL) among 5-year-old children. A cross-sectional study was conducted involving 769 children at schools in a city in northeast Brazil. Parents/caregivers answered validated questionnaires addressing SOC and LOC. The children and parents/caregivers answered their respective modules of the Brazilian version of the Scale of Oral Health Outcomes for 5-year-old children (SOHO-5). Data were also collected on sociodemographic characteristics, visits to the dentist, and the occurrence of toothache. Clinical examinations were performed by 2 trained examiners. A directed acyclic graph was used to select covariates for statistical adjustment, and logistic regression for complex samples was used to test associations between the dependent and independent variables (α = 5%). For parents/caregivers, the variables associated with a negative impact on OHRQoL were the occurrence of toothache (odds ratio, OR: 10.53; 95% confidence interval, CI: 6.34-17.51; p < 0.001) and a low SOC (OR: 2.17; 95% CI: 1.37-3.43; p = 0.001). According to the children's perceptions, the following variables were associated with a negative impact on OHRQoL: toothache (OR: 3.58; 95% CI: 2.30-5.55; p < 0.001), caries activity (OR: 1.97; 95% CI: 1.07-3.62; p = 0.028), and traumatic dental injury (OR: 1.71; 95% CI: 1.15-2.53; p = 0.007). Among parents/caregivers, a low SOC led to poorer OHRQoL. For the children, however, neither psychological aspect affected OHRQoL. In the perception of both the parents/caregivers and children, toothache was the oral condition that exerted a negative impact on OHRQoL.


Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative sigma factor, SigH.
The pathogenesis of tuberculosis involves multiple phases and is believed to involve both a carefully deployed series of adaptive bacterial virulence factors and inappropriate host immune responses that lead to tissue damage. A defined Mycobacterium tuberculosis mutant strain lacking the sigH-encoded transcription factor showed a distinctive infection phenotype. In resistant C57BL/6 mice, the mutant achieved high bacterial counts in lung and spleen that persisted in tissues in a pattern identical to those of wild-type bacteria. Despite a high bacterial burden, the mutant produced a blunted, delayed pulmonary inflammatory response, and recruited fewer CD4(+) and CD8(+) T cells to the lung in the early stages of infection. In susceptible C3H mice, the mutant again showed diminished immunopathology and was nonlethal at over 170 days after intravenous infection, in contrast to isogenic wild-type bacilli, which killed with a median time to death of 52 days. Complete genomic microarray analysis revealed that M. tuberculosis sigH may mediate the transcription of at least 31 genes directly and that it modulates the expression of about 150 others; the SigH regulon governs thioredoxin recycling and may be involved in the maintenance of intrabacterial reducing capacity. These data show that the M. tuberculosis sigH gene is dispensable for bacterial growth and survival within the host, but is required for the production of immunopathology and lethality. This phenotype demonstrates that beyond an ability to grow and persist within the host, M. tuberculosis has distinct virulence mechanisms that elicit deleterious host responses and progressive pulmonary disease.


Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.
We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.


Effects of low-intensity resistance exercise under acute systemic hypoxia on hormonal responses.
Previous studies have shown that low-intensity resistance exercises with vascular occlusion and slow movement effectively increase muscular size and strength. Researchers have speculated that local hypoxia by occlusion and slow movement may contribute to such adaptations via promoting anabolic hormone secretions by the local accumulation of metabolites. In this study, we determined the effects of low-intensity resistance exercise under acute systemic hypoxia on metabolic and hormonal responses. Eight male subjects participated in 2 experimental trials: (a) low-intensity resistance exercise while breathing normoxic air (normoxic resistance exercise [NR]), (b) low-intensity resistance exercise while breathing 13% oxygen (hypoxic resistance exercise [HR]). The resistance exercises (bench press and leg press) consisted of 14 repetitions for 5 sets at 50% of maximum strength with 1 minute of rest between sets. Blood lactate (LA), serum growth hormone (GH), norepinephrine (NE), testosterone, and cortisol concentrations were measured before normoxia and hypoxia exposures; 15 minutes after the exposures; and at 0, 15, and 30 minutes after the exercises. The LA levels significantly increased after exercises in both trials (p ≤ 0.05). The area under the curve for LA after exercises was significantly higher in the HR trial than in the NR trial (p ≤ 0.05). The GH significantly increased only after the HR trial (p ≤ 0.05). The NE and testosterone significantly increased after the exercises in both trials (p ≤ 0.05). Cortisol did not significantly change in both trials. These results suggest that low-intensity resistance exercise in the hypoxic condition caused greater metabolic and hormonal responses than that in the normoxic condition. Coaches may consider low-intensity resistance exercise under systemic hypoxia as a potential training method for athletes who need to maintain muscle mass and strength during the long in-season.


Omega-3 fatty acids and traumatic neurological injury: from neuroprotection to neuroplasticity?
Omega-3 polyunsaturated fatty acids (PUFAs) are compounds that have a structural role in the nervous system and are essential for neurodevelopment. Results obtained with docosahexaenoic acid and eicosapentaenoic acid show therapeutic potential in neurotrauma. Traumatic brain injury (TBI) and spinal cord injury (SCI) can lead to major disability and have a significant socioeconomic cost. Thus, there is an unmet need for acute neuroprotection and for treatments that promote neuroregeneration. Acute administration of omega-3 PUFAs after injury and dietary exposure before or after injury improve neurological outcomes in experimental SCI and TBI. The mechanisms involved include decreased neuroinflammation and oxidative stress, neurotrophic support, and activation of cell survival pathways. This review raises questions that must be addressed before successful clinical translation.


Analysis of functional coupling: mitochondrial creatine kinase and adenine nucleotide translocase.
The mechanism of functional coupling between mitochondrial creatine kinase (MiCK) and adenine nucleotide translocase (ANT) in isolated heart mitochondria is analyzed. Two alternative mechanisms are studied: 1), dynamic compartmentation of ATP and ADP, which assumes the differences in concentrations of the substrates between intermembrane space and surrounding solution due to some diffusion restriction and 2), direct transfer of the substrates between MiCK and ANT. The mathematical models based on these possible mechanisms were composed and simulation results were compared with the available experimental data. The first model, based on a dynamic compartmentation mechanism, was not sufficient to reproduce the measured values of apparent dissociation constants of MiCK reaction coupled to oxidative phosphorylation. The second model, which assumes the direct transfer of substrates between MiCK and ANT, is shown to be in good agreement with experiments--i.e., the second model reproduced the measured constants and the estimated ADP flux, entering mitochondria after the MiCK reaction. This model is thermodynamically consistent, utilizing the free energy profiles of reactions. The analysis revealed the minimal changes in the free energy profile of the MiCK-ANT interaction required to reproduce the experimental data. A possible free energy profile of the coupled MiCK-ANT system is presented.


Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).
The gene encoding C/EBP-homologous protein (CHOP), also known as growth arrest and DNA-damage-inducible gene 153 (GADD153), is activated by agents that adversely affect the function of the endoplasmic reticulum (ER). Because of the pleiotropic effects of such agents on other cellular processes, the role of ER stress in inducing CHOP gene expression has remained unclear. We find that cells with conditional (temperature-sensitive) defects in protein glycosylation (CHO K12 and BHK tsBN7) induce CHOP when cultured at the nonpermissive temperature. In addition, cells that are defective in initiating the ER stress response, because of overexpression of an exogenous ER chaperone, BiP/GRP78, exhibit attenuated inducibility of CHOP. Surprisingly, attenuated induction of CHOP was also noted in BiP-overexpressing cells treated with methyl methanesulfonate, an agent thought to activate CHOP by causing DNA damage. The roles of DNA damage and growth arrest in the induction of CHOP were therefore reexamined. Induction of growth arrest by culture to confluence or treatment with the enzymatic inhibitor N-(phosphonacetyl)-L-aspartate did not induce CHOP. Furthermore, both a DNA-damage-causing nucleoside analog (5-hydroxymethyl-2'-deoxyuridine) and UV light alone did not induce CHOP. These results suggest that CHOP is more responsive to ER stress than to growth arrest or DNA damage and indicate a potential role for CHOP in linking stress in the ER to alterations in gene expression.


Random local temporal structure of category fluency responses.
The Category Fluency Test (CFT) provides a sensitive measurement of cognitive capabilities in humans related to retrieval from semantic memory. In particular, it is widely used to assess progress of cognitive impairment in patients with dementia. Previous research shows that, in the first approximation, the intensity of tested individuals' responses within a standard 60-s test period decays exponentially with time, with faster decay rates for more cognitively impaired patients. Such decay rate can then be viewed as a global (macro) diagnostic parameter of each test. In the present paper we focus on the statistical properties of the properly de-trended time intervals between consecutive responses (inter-call times) in the Category Fluency Test. In a sense, those properties reflect the local (micro) structure of the response generation process. We find that a good approximation for the distribution of the de-trended inter-call times is provided by the Weibull Distribution, a probability distribution that appears naturally in this context as a distribution of a minimum of independent random quantities and is the standard tool in industrial reliability theory. This insight leads us to a new interpretation of the concept of "navigating a semantic space" via patient responses.


Is Tumor Size Really Important for Prediction of Lymphatic Dissemination in Grade 1 Endometrial Carcinoma With Superficial Myometrial Invasion?
Selection of patients with endometrioid endometrial cancer (EEC), in whom systematic lymph node dissection (LND) is indicated, is an important part of management to maintain optimal oncological outcomes, while avoiding unnecessary morbidities. According to the current approach, LND is recommended for the patients with International Federation of Gynecology and Obstetrics (FIGO) grade 1 to 2 tumors and a primary tumor diameter (PTD) greater than 2 cm, even with myometrial invasion (MMI) of less than 50%. We aimed to determine incidence of LN metastasis in this particular group of patients with grade 1 tumors, superficial MMI, and a PTD greater than 2 cm. This study only focused on women with FIGO grade 1 EEC having less than 50% MMI. Therefore, women with grade 2 or 3 tumors were excluded, as well as patients with 50% or greater MMI. We also excluded women with macroscopic extrauterine disease, as well as patients with cervical stromal involvement. Patients were divided into subgroups with regard to PTD; group 1 was composed of patients with PTD of 20 mm or less, whereas group 2 was composed of patients with PTD greater than 20 mm. All clinical and pathological variables were compared between the groups. Final pathology reports of 484 women with EEC who underwent surgical staging were analyzed. Among these women, there were 123 women in group 1 (PTD ≤ 20 mm) and 120 women in group 2 (PTD > 20 mm), with FIGO grade 1 tumors and superficial MMI. The median number of total LNs removed was 54 (range, 20-151). There were no women with pelvic and/or para-aortic LN metastasis in group 2, as well as in group 1. Our results suggest that lymphadenectomy may be omitted in women with FIGO grade 1 EEC having superficial MMI regardless of PTD. Deferral of systematic LND in this subgroup of patients may lead to reductions in costs and surgical morbidity.


Do independent geriatric outpatients with nocturnal polyuria profit from desmopressin?
To compare the efficacy of desmopressin and placebo in independent geriatric outpatients with nocturnal polyuria (NP). A prospective, randomized, single-center, national, double blind, placebo-controlled, fixed-dose, parallel group comparative trial was carried out. The study included 110 geriatric outpatients, 55 patients per treatment group using desmopressin acetate nasal spray (strength: 0.1 mg/ml) once daily of 10 μg/spray blast or placebo. The NP positive geriatric outpatients with >33% nocturnal urine output volume, antidiuretic hormone (ADH) positive or negative were treated over 10 days with intranasal spray in the evening time (7 p.m.), drug or placebo. On day 1 voiding frequency, voiding volumes day and night, serum osmolarity and arginine-vasopressin (AVP) were measured at 7 p.m. On days 2, 5 and 10 creatinine, blood urea nitrogen (bun), blood count and C‑reactive protein (CrP), vena cava diameter and bioimpedance were measured and a structured interview was implemented (voiding frequency, sleeping behavior and subjective and cognitive behavior). The NP patients showed a mean night voiding volume of 50.60%, 39.21% (n = 102) showed a low AVP level at baseline with no correlation to sodium concentration or voiding frequencies. The primary efficacy criterion, a decrease of the nocturnal voiding frequency during the course of the clinical trial as change from baseline at day 10 (visit 4) was 50% versus 41.40% in the verum versus placebo group, respectively but the differences were not significant. The U‑test showed superiority of AVP-positive NP patients to a positive reaction on desmopressin. Sleeping time hours increased in both groups without significant differences. In this 10-day clinical trial desmopressin was not proven to be therapeutically superior to placebo with respect to micturition frequency or sleeping hours. Independent geriatric outpatients with decreased ADH levels seemed to respond and benefit from active treatment with desmopressin. The unexpected results in the placebo group may be due to the effect of intensive outpatient care and information on NP outpatients with normal AVP levels.


Antibiotics to prevent complications following tooth extractions.
The most frequent indications for tooth extractions are dental caries and periodontal infections, and these extractions are generally done by general dental practitioners. Antibiotics may be prescribed to patients undergoing extractions to prevent complications due to infection. To determine the effect of antibiotic prophylaxis on the development of infectious complications following tooth extractions. The following electronic databases were searched: the Cochrane Oral Health Group's Trials Register (to 25 January 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE via OVID (1948 to 25 January 2012), EMBASE via OVID (1980 to 25 January 2012) and LILACS via BIREME (1982 to 25 January 2012). There were no restrictions regarding language or date of publication. We included randomised double-blind placebo-controlled trials of antibiotic prophylaxis in patients undergoing tooth extraction(s) for any indication. Two review authors independently assessed risk of bias for the included studies and extracted data. We contacted trial authors for further details where these were unclear. For dichotomous outcomes we calculated risk ratios (RR) and 95% confidence intervals (CI) using random-effects models. For continuous outcomes we used mean differences (MD) with 95% CI using random-effects models. We examined potential sources of heterogeneity. The quality of the body of evidence has been assessed using the GRADE tool. This review included 18 double-blind placebo-controlled trials with a total of 2456 participants. Five trials were assessed at unclear risk of bias, thirteen at high risk, and none at low risk of bias. Compared to placebo, antibiotics probably reduce the risk of infection in patients undergoing third molar extraction(s) by approximately 70% (RR 0.29 (95% CI 0.16 to 0.50) P < 0.0001, 1523 participants, moderate quality evidence) which means that 12 people (range 10-17) need to be treated with antibiotics to prevent one infection following extraction of impacted wisdom teeth. There is evidence that antibiotics may reduce the risk of dry socket by 38% (RR 0.62 (95% CI 0.41 to 0.95) P = 0.03, 1429 participants, moderate quality evidence) which means that 38 people (range 24-250) need to take antibiotics to prevent one case of dry socket following extraction of impacted wisdom teeth. There is also some evidence that patients who have prophylactic antibiotics may have less pain (MD -8.17 (95% CI -11.90 to -4.45) P < 0.0001, 372 participants, moderate quality evidence ) overall 7 days after the extraction compared to those receiving placebo, which may be a direct result of the lower risk of infection. There is no evidence of a difference between antibiotics and placebo in the outcomes of fever (RR 0.34, 95% CI 0.06 to 1.99), swelling (RR 0.92, 95% CI 0.65 to 1.30) or trismus (RR 0.84, 95% CI 0.42 to 1.71) 7 days after tooth extraction.Antibiotics are associated with an increase in generally mild and transient adverse effects compared to placebo (RR 1.98 (95% CI 1.10 to 3.59) P = 0.02) which means that for every 21 people (range 8-200) who receive antibiotics, an adverse effect is likely. Although general dentists perform dental extractions because of severe dental caries or periodontal infection, there were no trials identified which evaluated the role of antibiotic prophylaxis in this group of patients in this setting. All of the trials included in this review included healthy patients undergoing extraction of impacted third molars, often performed by oral surgeons. There is evidence that prophylactic antibiotics reduce the risk of infection, dry socket and pain following third molar extraction and result in an increase in mild and transient adverse effects. It is unclear whether the evidence in this review is generalisable to those with concomitant illnesses or immunodeficiency, or those undergoing the extraction of teeth due to severe caries or periodontitis. However, patients at a higher risk of infection are more likely to benefit from prophylactic antibiotics, because infections in this group are likely to be more frequent, associated with complications and be more difficult to treat. Due to the increasing prevalence of bacteria which are resistant to treatment by currently available antibiotics, clinicians should consider carefully whether treating 12 healthy patients with antibiotics to prevent one infection is likely to do more harm than good.


Priority of Risk (But Not Perceived Magnitude of Risk) Predicts Improved Sun-Protection Behavior Following Genetic Counseling for Familial Melanoma.
Understanding multiple components of risk perceptions is important because perceived risk predicts engagement in prevention behaviors. To examine how multiple components of risk perceptions (perceived magnitude of and worry about risk, prioritization of the management of one's risk) changed following genetic counseling with or without test reporting, and to examine which of these components prospectively predicted improvements in sun-protection behavior 1 year later. A prospective, nonrandomized study design was used. Participants were 114 unaffected members of melanoma-prone families who (i) underwent genetic testing for a CDKN2A/p16 mutation (n = 69) or (ii) were at comparably elevated risk based on family history and underwent genetic counseling but not testing (no-test controls, n = 45). Participants reported risk perception components and sun-protection behavior at baseline, immediately following counseling, and 1 month and 1 year after counseling. Factor analysis indicated three risk components. Carriers reported increased perceived magnitude and priority of risk, but not cancer worry. No-test controls showed no changes in any risk perception. Among noncarriers, priority of risk remained high at all assessments, whereas magnitude of risk and cancer worry decreased. Of the three risk components, greater priority of risk uniquely predicted improved self-reported sun protection 1 year post-counseling. Priority of risk (i) seems to be a component of risk perceptions distinguishable from magnitude of risk and cancer worry, (ii) may be an important predictor of daily prevention behavior, and (iii) remained elevated 1 year following genetic counseling only for participants who received a positive melanoma genetic test result.


Electrically induced optical emission from a carbon nanotube FET.
Polarized infrared optical emission was observed from a carbon nanotube ambipolar field-effect transistor (FET). An effective forward-biased p-n junction, without chemical dopants, was created in the nanotube by appropriately biasing the nanotube device. Electrical measurements show that the observed optical emission originates from radiative recombination of electrons and holes that are simultaneously injected into the undoped nanotube. These observations are consistent with a nanotube FET model in which thin Schottky barriers form at the source and drain contacts. This arrangement is a novel optical recombination radiation source in which the electrons and holes are injected into a nearly field-free region. Sucha source may form the basis for ultrasmall integrated photonic devices.


Guanyl nucleotides modulate binding to steroid receptors in neuronal membranes.
The recently characterized corticosteroid receptor on amphibian neuronal membranes appears to mediate rapid, stress-induced changes in male reproductive behaviors. Because the transduction mechanisms associated with this receptor are unknown, we performed radioligand binding studies to determine whether this steroid receptor is negatively modulated by guanyl nucleotides. The binding of [3H]corticosterone to neuronal membranes was inhibited by nonhydrolyzable guanyl nucleotides in both equilibrium saturation binding and titration studies. The addition of guanyl nucleotide plus unlabeled corticosterone induced a rapid phase of [3H]corticosterone dissociation from membranes that was not induced by addition of unlabeled ligand alone. Furthermore, the equilibrium binding of [3H]corticosterone and the sensitivity of the receptor to modulation by guanyl nucleotides were both enhanced by Mg2+. These results are consistent with the formation of a ternary complex of steroid, receptor, and guanine nucleotide-binding protein that is subject to regulation by guanyl nucleotides. Therefore, rapid signal transduction through corticosteroid receptors on neuronal membranes appears to be mediated by guanine nucleotide-binding proteins.


Capillary wave propagation during the delamination of graphene by the precursor films in electro-elasto-capillarity.
Molecular dynamics simulations were carried out to explore the capillary wave propagation induced by the competition between one upper precursor film (PF) on the graphene and one lower PF on the substrate in electro-elasto-capillarity (EEC). During the wave propagation, the graphene was gradually delaminated from the substrate by the lower PF. The physics of the capillary wave was explored by the molecular kinetic theory. Besides, the dispersion relation of the wave was obtained theoretically. The theory showed that the wave was controlled by the driving work difference of the two PFs. Simulating the EEC process under different electric field intensities (E), the wave velocity was found insensitive to E. We hope this research could expand our knowledge on the wetting, electrowetting and EEC. As a potential application, the electrowetting of the PF between the graphene and the substrate is a promising candidate for delaminating graphene from substrate.


Randomized controlled trial of acupuncture for prevention of radiation-induced xerostomia among patients with nasopharyngeal carcinoma.
Xerostomia (dry mouth) after head/neck radiation is a common problem among cancer patients, and available treatments are of little benefit. The objective of this trial was to determine whether acupuncture can prevent xerostomia among head/neck patients undergoing radiotherapy. A randomized, controlled trial among patients with nasopharyngeal carcinoma was conducted comparing acupuncture to standard care. Participants were treated at Fudan University Shanghai Cancer Center, Shanghai, China. Forty patients were randomized to acupuncture treatment and 46 to standard care. Patients were treated 3×/wk on the same days they received radiotherapy. Subjective measures included the Xerostomia Questionnaire and MD Anderson Symptom Inventory-Head and Neck (MDASI-HN). Objective measures were unstimulated and stimulated whole salivary flow rates. Patients were followed for 6 months after the end of radiotherapy. Xerostomia Questionnaire scores for acupuncture were statistically significantly lower than for controls starting in week 3 through the 6 months (P = .003 at week 3, all other P < .0001), with clinically significant differences as follows: week 11, relative risk (RR) 0.63 (95% confidence interval [CI], 0.45-0.87); 6 months, RR 0.38 (95% CI, 0.19-0.76). Similar findings were seen for MDASI-HN scores. Group differences emerged as early as 3 weeks into treatment for saliva (unstimulated whole salivary flow rate, P = .0004), with greater saliva flow in the acupuncture group at week 7 (unstimulated whole salivary flow rate, P < .0001; stimulated whole salivary flow rate, P = .002) and 11 (unstimulated whole salivary flow rate, P < .02; stimulated whole salivary flow rate, P < .03) and at 6 months (stimulated whole salivary flow rate, P < .003). Acupuncture given concurrently with radiotherapy significantly reduced xerostomia and improved quality of life.


Bovine tuberculosis prevalence survey on cattle in the rural livestock system of Torodi (Niger).
Bovine tuberculosis (BTB) is a widespread zoonosis in developing countries but has received little attention in sub-Saharan Africa, especially in Niger. Recent investigations confirmed the high incidence of the disease in cattle slaughtered in an abattoir in Niamey. The fact that most of the animals in which M. bovis has been identified were from the rural area of Torodi implied the existence of a probable source of BTB in this region. This study aimed to determine the prevalence of BTB infection in cattle and to identify risk factors for infection in human and cattle populations in Torodi. A survey was carried out at the level of households keeping livestock (n = 51). The questionnaire was related to the potential risk factors and the presence of clinical signs of TB both in animals and humans. Comparative Intradermal Tuberculin Test was conducted to determine the TB status in cattle (n = 393). The overall apparent individual animal prevalence of tuberculin reactors was 3.6% (CI: 95%, 1.9-5.9), whereas the individual true prevalence was estimated at 0.8% (CI: 95%, 0.0-5.0). Using a multivariate logistic regression analysis and a classification tree analysis, the only household level risk factor that significantly influenced the presence of BTB in cattle was the presence of animals coughing in the herd (OR = 4.7, 95% CI: 1.12-19.71, p-value = 0.034). The lack of the practice of quarantine was borderline significant (OR = 4.2, 95% CI: 0.96-18.40, p-value = 0.056). The study confirmed that BTB is endemic in cattle in Torodi and the risk of the transmission of the disease to humans is potentially high. For the control of the disease in livestock, slaughtering of infected animals and the compensation of the owners is needed. Collaboration between the veterinary and the medical sectors, in the diagnosis, monitoring, prevention and control of BTB is strongly encouraged.


Tracheal tube biofilm as a source of bacterial colonization of the lung.
Biofilm formation in tracheal tubes, its bacterial content, and its interaction with ventilator gas flow were investigated. At least 50 mg (dry weight) of biofilm was found in 30 of 40 tracheal tubes used in intensive care patients for 2 h to 10 days. Electron microscopy showed bacteria in this layer, and quantitative studies showed that bacterial counts could reach up to 10(6)/cm of tube length. Bacteria were cultured from the patient side of 18 of 78 heat and moisture exchanger-microbiological filter units removed from ventilator circuits. Particles were shown to detach from tracheal tube luminal biofilm and were projected up to 45 cm from the tracheal tube tip. Following contamination of the tracheal tube biofilm with a patient's own gastrointestinal flora, entrainment of bacteria in the inspiratory gas flow provides a mechanism for initial and repeated lung colonization.


Tilted superstructure fiber grating used as a Fourier-transform spectrometer.
We propose and demonstrate a new method for fabricating a compact all-fiber spectrometer by using a tilted superstructure fiber grating to couple light out of a fiber core and produce an interference pattern in the near field. The Fourier transform of the interference pattern serves as a direct measurement of the optical input spectrum, and the superstructure grating design offers several degrees of freedom that permit control over the resolution and bandwidth of the spectrometer. For single-wavelength operation, the proposed scheme offers the possibility of making wavelength measurements with picometer-level precision over a broad 80-nm wavelength range while simultaneously providing coarser precision over a 160-nm range.


The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration.
Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca(2+)) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration.


Evaluation of the Antiviral Activity of Sephin1 Treatment and Its Consequences on eIF2α Phosphorylation in Response to Viral Infections.
The guanabenz derivative Sephin1 has recently been proposed to increase the levels of translation initiation factor 2 (eIF2α) phosphorylation by inhibiting dephosphorylation by the protein phosphatase 1-GADD34 (PPP1R15A) complex. As phosphorylation of eIF2α by protein kinase R (PKR) is a prominent cellular antiviral pathway, we evaluated the consequences of Sephin1 treatment on virus replication. Our results provide evidence that Sephin1 downregulates replication of human respiratory syncytial virus, measles virus, human adenovirus 5 virus, human enterovirus D68, human cytomegalovirus, and rabbit myxoma virus. However, Sephin1 proved to be inactive against influenza virus, as well as against Japanese encephalitis virus. Sephin1 increased the levels of phosphorylated eIF2α in cells exposed to a PKR agonist. By contrast, in virus-infected cells, the levels of phosphorylated eIF2α did not always correlate with the inhibition of virus replication by Sephin1. This work identifies Sephin1 as an antiviral molecule in cell culture against RNA, as well as DNA viruses belonging to phylogenetically distant families.


A case of Wiskott-Aldrich syndrome with de novo mutation at exon 4.
Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, eczema and immunodeficiency. Clinical features of the disease are highly varied; therefore, the diagnosis is sometimes difficult, especially in solitary cases or cases with milder forms of the disease. However, the identification of the WASP gene has made possible a definite WAS diagnosis for these cases. In this report, we present a 26-month-old boy who had received several ineffective treatments for chronic immune thrombocytopenic purpura. He was then suspected to have WAS because of the early onset of thrombocytopenia and small platelets. The diagnosis became definite with the detection of a de novo mutation at exon 4 of the WASP gene, Arg138Pro, through mutation analysis.


Quantifying shark distribution patterns and species-habitat associations: implications of marine park zoning.
Quantifying shark distribution patterns and species-specific habitat associations in response to geographic and environmental drivers is critical to assessing risk of exposure to fishing, habitat degradation, and the effects of climate change. The present study examined shark distribution patterns, species-habitat associations, and marine reserve use with baited remote underwater video stations (BRUVS) along the entire Great Barrier Reef Marine Park (GBRMP) over a ten year period. Overall, 21 species of sharks from five families and two orders were recorded. Grey reef Carcharhinus amblyrhynchos, silvertip C. albimarginatus, tiger Galeocerdo cuvier, and sliteye Loxodon macrorhinus sharks were the most abundant species (>64% of shark abundances). Multivariate regression trees showed that hard coral cover produced the primary split separating shark assemblages. Four indicator species had consistently higher abundances and contributed to explaining most of the differences in shark assemblages: C. amblyrhynchos, C. albimarginatus, G. cuvier, and whitetip reef Triaenodon obesus sharks. Relative distance along the GBRMP had the greatest influence on shark occurrence and species richness, which increased at both ends of the sampling range (southern and northern sites) relative to intermediate latitudes. Hard coral cover and distance across the shelf were also important predictors of shark distribution. The relative abundance of sharks was significantly higher in non-fished sites, highlighting the conservation value and benefits of the GBRMP zoning. However, our results also showed that hard coral cover had a large effect on the abundance of reef-associated shark species, indicating that coral reef health may be important for the success of marine protected areas. Therefore, understanding shark distribution patterns, species-habitat associations, and the drivers responsible for those patterns is essential for developing sound management and conservation approaches.


Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases.
High-grade versions of appendiceal goblet cell carcinoids ('adenocarcinoma ex-goblet cell carcinoids') are poorly characterized. We herein document 77 examples. Tumors occurred predominantly in females (74%), mean age 55 years (29-84), most with disseminated abdominal (77% peritoneal, 58% gynecologic tract involvement) and stage IV (65%) disease. Many presented to gynecologic oncologists, and nine had a working diagnosis of ovarian carcinoma. Metastases to liver (n=3) and lung (n=1) were uncommon and none arose in adenomatous lesions. Tumors had various histologic patterns, in variable combinations, most of which were fairly specific, making them recognizable as appendiceal in origin, even at metastatic sites: I: Ordinary goblet cell carcinoid/crypt pattern (rounded, non-luminal acini with well-oriented goblet cells), in variable amounts in all cases. II: Poorly cohesive goblet cell pattern (diffusely infiltrative cords/single files of signet ring-like/goblet cells). III: Poorly cohesive non-mucinous cell (diffuse-infiltrative growth of non-mucinous cells). IV: Microglandular (rosette-like glandular) pattern without goblet cells. V: Mixed 'other' carcinoma foci (including ordinary intestinal/mucinous). VI: goblet cell carcinoid pattern with high-grade morphology (marked nuclear atypia). VII: Solid sheet-like pattern punctuated by goblet cells/microglandular units. Ordinary nested/trabecular ('carcinoid pattern') was very uncommon. In total, 33(52%) died of disease, with median overall survival 38 months and 5-year survival 32%. On multivariate analysis perineural invasion and younger age (<55) were independently associated with worse outcome while lymph-vascular invasion, stage, and nodal status trended toward, but failed to reach, statistical significance. Worse behavior in younger patients combined with female predilection and ovarian-affinity raise the possibility of hormone-assisted tumor progression. In conclusion, 'adenocarcinoma ex-goblet cell carcinoid' is an appendix-specific, high-grade malignant neoplasm with distinctive morphology that is recognizable at metastatic sites and recapitulates crypt cells (appendiceal crypt cell adenocarcinoma). Unlike intestinal-type adenocarcinoma, it occurs predominantly in women, is disguised as gynecologic malignancy, and spreads along peritoneal surfaces with only rare hematogenous metastasis. It appears to be significantly more aggressive than appendiceal mucinous neoplasms.


Effect of ovariectomy and alendronate on implant osseointegration in rat maxillary bone.
Bisphosphonates such as alendronate (ALD), although controversial, are worthy of investigation for the enhancement of implant osseointegration in patients with low bone mass who are already taking bisphosphonates for osteoporosis. These patients may receive additional benefits and be acceptable candidates for dental implants without needing to change their medication regimen and possibly as a result of their medication regimen. The purpose of this study was to compare implant osseointegration in maxillary bone of normal rats with a rat model of postmenopausal estrogen deficiency (ovariectomized [OVX]), with and without ALD. An experimental group of 32 rats was divided in 4 groups: ALD-OVX (n=8 OVX with ALD), OVX (n=8 OVX without ALD), ALD (n=8 normal rats with ALD), and control (n=8 normal rats). All rats received one titanium microscrew implant in the left edentulous region of the maxillary arch. The ALD-OVX and ALD groups received subcutaneous injections of ALD 3 times a week. On the fourth week after ALD administration, an implant was placed in all 32 rats. The maxilla of each rat was radiographed 4 times: at 0, 7, 14, and 28 days. On day 28 after implant placement, all rats were killed, and the peri-implant tissue was embedded in plastic or paraffin for histological examination. The X rays were used for a chronologic calculation of the contact ratio between implant and bone surfaces. Radiographic bone density was determined at 3 points: mesial, apical, and distal. The results show that osseointegration of the implants was impaired in the estrogen-deficient OVX rats compared with the ALD-OVX rats. Fifty percent of the implants were lost at 2 weeks in the OVX group. Radiographic evidence suggested that none of the implants in the OVX group osseointegrated. In the histologic examination more bone was observed around implants from the ALD-OVX and ALD groups than around implants from the OVX group. The OVX group presented a dramatic reduction in implant bone contact at 2 weeks and a significant 13% reduction at 4 weeks vs day of implant (P = .006). The ALD-OVX group presented 50% more bone density than the OVX group (P = .0003). Both ALD groups (ALD and ALD-OVX) had significantly higher radiographic bone density than the other groups (P < .01 for each comparison). In conclusion, osseointegration of implants was enhanced by ALD. Radiographic bone density and contact ratio improved with ALD administration. Implant osseointegration was impaired by estrogen deficiency in the OVX group.


Characterizing the community structure of complex networks.
Community structure is one of the key properties of complex networks and plays a crucial role in their topology and function. While an impressive amount of work has been done on the issue of community detection, very little attention has been so far devoted to the investigation of communities in real networks. We present a systematic empirical analysis of the statistical properties of communities in large information, communication, technological, biological, and social networks. We find that the mesoscopic organization of networks of the same category is remarkably similar. This is reflected in several characteristics of community structure, which can be used as "fingerprints" of specific network categories. While community size distributions are always broad, certain categories of networks consist mainly of tree-like communities, while others have denser modules. Average path lengths within communities initially grow logarithmically with community size, but the growth saturates or slows down for communities larger than a characteristic size. This behaviour is related to the presence of hubs within communities, whose roles differ across categories. Also the community embeddedness of nodes, measured in terms of the fraction of links within their communities, has a characteristic distribution for each category. Our findings, verified by the use of two fundamentally different community detection methods, allow for a classification of real networks and pave the way to a realistic modelling of networks' evolution.


Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease.
Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.


Development of a positive youth development program: promoting the mental health of stressful adolescents using principles of Problem Solving Therapy.
This paper outlines the proposal for the development, implementation, and evaluation of a positive youth development program that attempts to promote the mental health of stressful Chinese adolescents using principles of Problem Solving Therapy (PST). There are two general aims of PST: to help clients identify life difficulties and resolve them, as well as to teach them skills on how to deal with future problems. The proposed project will utilize the principles of PST as the guiding framework to run two mental health promotion courses for adolescents who are experiencing disturbing stressful responses and students who want to improve their stress management style. Both objective and subjective outcome evaluation strategies will be carried out to assess the effectiveness of the intervention to promote the psychological well-being in adolescents who are experiencing stress. A related sample proposal is described that can give social workers some insight on how to prepare a proposal for developing the Tier 2 Program of the Project PATHS (Positive Adolescent Training through Holistic Social Programs).


Robotic Surgery for Benign and Low-Grade Malignant Diseases of the Duodenum.
Robotic duodenal surgery (RDS) is a treatment option for many benign and low-grade malignant duodenal conditions that are not amenable to endoscopic intervention and can avoid morbidity related to open surgery. A retrospective review of all patients undergoing RDS (non-Whipple) at a tertiary care center from 2010-2017 was carried out. Indications, procedural details, and outcomes were reviewed. Twenty-four patients underwent RDS during the study period: transduodenal resection in 6 patients (25%), wedge resection in 6 patients (25%), transduodenal ampullectomy in 5 patients (21%), sleeve (segmental) resection in 5 patients (21%), duodenojejunostomy bypass in 1 patient (4%), and duodenal diverticulectomy in 1 patient (4%). Median age was 68 years, 54 per cent were male, and median BMI was 27. Adenoma was the most common diagnosis (68%) followed by neuroendocrine tumor (25%), duodenal diverticulum (4%), and refractory superior mesenteric artery syndrome (4%). Seventy-one per cent were symptomatic with gastroinstestinal bleed being the most common presentation. Median tumor size was 27 mm, and the most common location was D2 (58%) followed by D3/D4 (25%) and D1 (17%). Median operating time was 205 minutes and estimated blood loss was 50cc with no patient requiring intraoperative transfusion. Median length of stay was five days (3-21 days). Overall complication rate was 41 per cent (10/24): minor biliopancreatic leak in three patients; ileus in three patients; bleeding, arrhythmia, hypoxia, and headache in one patient each. Three (12%) patients had significant complications (Clavien-Dindo grade ≥ 3) requiring laparoscopic or robotic reoperation, but all three were discharged on or before POD 6 with resolution of complication. Ninety-day readmission rate was 8 per cent and 90-day mortality was 0. Recurrent disease or strictures were not seen in any patient after a median follow-up of 16 months. It has been concluded that RDS is a safe alternative to open or laparoscopic duodenal resection for benign and low-grade malignant conditions not amenable to endoscopic intervention.


Critical factors in fatal collisions of adult cyclists with automobiles.
This article evaluates, by means of multivariate regression, critical factors influencing the collisions of motor vehicles with adult (over 17 years) cyclists that result in fatal injury of cyclists. The analysis is based on the database of the Traffic Police of Czech Republic from the time period 1995-2007. The results suggest that the most consequential categories of factors under study are: inappropriate driving speed of automobile; the head-on crash; and night-time traffic in places without streetlights. The cyclists' faults are of most serious consequence on crossroads when cyclists deny the right of way. Males are more likely to suffer a fatal injury due to a collision with a car than females. The most vulnerable age group are cyclists above 65 years. A fatal injury of a cyclist is more often driver's fault than cyclist's (598 vs. 370). In order to reduce the fatal risk, it is recommended to separate the road traffic of motor vehicles from bicyclists in critical road-sections; or, at least, to reduce speed limits there.


A MAM7 peptide-based inhibitor of Staphylococcus aureus adhesion does not interfere with in vitro host cell function.
Adhesion inhibitors that block the attachment of pathogens to host tissues may be used synergistically with or as an alternative to antibiotics. The wide-spread bacterial adhesin Multivalent Adhesion Molecule (MAM) 7 has recently emerged as a candidate molecule for a broad-spectrum adhesion inhibitor which may be used to prevent bacterial colonization of wounds. Here we have tested if the antibacterial properties of a MAM-based inhibitor could be used to competitively inhibit adhesion of methicillin-resistant Staphylococcus aureus (MRSA) to host cells. Additionally, we analyzed its effect on host cellular functions linked to the host receptor fibronectin, such as migration, adhesion and matrix formation in vitro, to evaluate potential side effects prior to advancing our studies to in vivo infection models. As controls, we used inhibitors based on well-characterized bacterial adhesin-derived peptides from F1 and FnBPA, which are known to affect host cellular functions. Inhibitors based on F1 or FnBPA blocked MRSA attachment but at the same time abrogated important cellular functions. A MAM7-based inhibitor did not interfere with host cell function while showing good efficacy against MRSA adhesion in a tissue culture model. These observations provide a possible candidate for a bacterial adhesion inhibitor that does not cause adverse effects on host cells while preventing bacterial infection.


Preferences for rehabilitation service delivery: a comparison of the views of patients, occupational therapists and other rehabilitation clinicians using a discrete choice experiment.
Understanding the differences in preferences of patients and occupational therapists for the way in which rehabilitation services are provided is important. In particular, it is unknown whether new approaches to rehabilitation such as high intensity therapy and virtual reality programs are more or less acceptable than traditional approaches. A discrete choice experiment was conducted to assess and compare the acceptability of these new approaches, relative to other characteristics of the rehabilitation program. The study included patients participating in a stroke or medical rehabilitation program (n = 100), occupational therapists (n = 23) and other clinicians (n = 91) working in rehabilitation settings at three hospitals in South Australia. Data were analysed using a conditional (fixed-effects) logistic regression model. The model coefficient attached to very high intensity therapy programs (defined as six hours per day) was negative and highly statistically significant for both patients and therapists indicating aversion for this option. In addition, other rehabilitation clinicians and patients were strongly averse to the use of virtual reality programs (as evidenced by the negative and highly statistically significant coefficient attached to this attribute for both groups) relative to occupational therapists. The comparison of the views of patients, occupational therapists and other rehabilitation clinicians revealed some differences. All participants (patients and clinicians) showed an inclination for programs that resulted in the best recovery. However, patients expressed stronger preferences than clinicians for traditional therapy approaches. As a group, occupational therapists were most likely to accept approaches such as virtual reality suggesting changes away from traditional delivery methods will be more readily integrated into practice.


Acoustically sticky topographic metasurfaces for underwater sound absorption.
A class of metasurfaces for underwater sound absorption, based on a design principle that maximizes thermoviscous loss, is presented. When a sound meets a solid surface, it leaves a footprint in the form of thermoviscous boundary layers in which energy loss takes place. Considered to be a nuisance, this acoustic to vorticity/entropy mode conversion and the subsequent loss are often ignored in the existing designs of acoustic metamaterials and metasurfaces. The metasurface created is made of a series of topographic meta-atoms, i.e., intaglios and reliefs engraved directly on the solid object to be concealed. The metasurface is acoustically sticky in that it rather facilitates the conversion of the incident sound to vorticity and entropy modes, hence the thermoviscous loss, leading to the desired anechoic property. A prototype metasurface machined on a brass object is tested for its anechoicity, and shows a multitude of absorption peaks as large as unity in the 2-5 MHz range. Computations also indicate that a topographic metasurface is robust to hydrostatic pressure variation, a quality much sought-after in underwater applications.


M2 Muscarinic acetylcholine receptor modulates rat airway smooth muscle cell proliferation.
Airways chronic inflammatory conditions in asthma and COPD are characterized by tissue remodeling, being smooth muscle hyperplasia, the most important feature. Non-neuronal and neuronal Acetylcholine acting on muscarinic receptors (MAChRs) has been postulated as determinant of tissue remodeling in asthma and COPD by promoting proliferation and phenotypic changes of airway smooth muscle cells (ASMC). The objective was to evaluate proliferative responses to muscarinic agonist as carbamylcholine (Cch) and to identify the MAchR subtype involved. ASMC were isolated from tracheal fragments of Sprague-Dawley rats by enzymatic digestion. Proliferation assays were performed by MTS-PMS method. Viability was confirmed by trypan blue exclusion method. Mitogens as, epidermal growth factor (EGF), Tumor necrosis factor-alpha (TNF-α) and fetal bovine serum (FBS) increased ASMC proliferation (p < 0.05, n = 5). Cch alone increased ASMC proliferation at 24 and 48 hrs. However, combination of Cch with other mitogens exhibited a dual effect, synergistic proliferation effect in the presence of EGF (5 ng/mL) and 5% FBS and inhibiting the proliferation induced by 10% FBS, EGF (10 ng/mL) and TNF-α (10 ng/mL). To determine the MAChR subtype involved in these biological responses, a titration curve of selective muscarinic antagonists were performed. The Cch stimulatory and inhibitory effects on ASCM proliferation was blocked by AF-DX-116 (M2AChR selective antagonist), in greater proportion than 4-DAMP (M3AChR selective antagonist), suggesting that the modulation of muscarinic agonist-induced proliferation is M2AChR mediated responses. Thus, M2AChR can activate multiple signal transduction systems and mediate both effects on ASMC proliferation depending on the plethora and variable airway microenvironments existing in asthma and COPD.


Genetic modification of cassava for enhanced starch production.
To date, transgenic approaches to biofortify subsistence crops have been rather limited. This is particularly true for the starchy root crop cassava (Manihot esculenta Crantz). Cassava has one of the highest rates of CO(2) fixation and sucrose synthesis for any C3 plant, but rarely reaches its yield potentials in the field. It was our hypothesis that starch production in cassava tuberous roots could be increased substantially by increasing the sink strength for carbohydrate. To test this hypothesis, we generated transgenic plants with enhanced tuberous root ADP-glucose pyrophosphorylase (AGPase) activity. This was achieved by expressing a modified form of the bacterial glgC gene under the control of a Class I patatin promoter. AGPase catalyses the rate-limiting step in starch biosynthesis, and therefore the expression of a more active bacterial form of the enzyme was expected to lead to increased starch production. To facilitate maximal AGPase activity, we modified the Escherichia coli glgC gene (encoding AGPase) by site-directed mutagenesis (G336D) to reduce allosteric feedback regulation by fructose-1,6-bisphosphate. Transgenic plants (three) expressing the glgC gene had up to 70% higher AGPase activity than control plants when assayed under conditions optimal for plant and not bacterial AGPase activity. Plants having the highest AGPase activities had up to a 2.6-fold increase in total tuberous root biomass when grown under glasshouse conditions. In addition, plants with the highest tuberous root AGPase activity had significant increases in above-ground biomass, consistent with a possible reduction in feedback inhibition on photosynthetic carbon fixation. These results demonstrate that targeted modification of enzymes regulating source-sink relationships in crop plants having high carbohydrate source strengths is an effective strategy for increasing carbohydrate yields in sink tissues.


Subcortical Shape Changes, Hippocampal Atrophy and Cortical Thinning in Future Alzheimer's Disease Patients.
Efficacy of future treatments depends on biomarkers identifying patients with mild cognitive impairment at highest risk for transitioning to Alzheimer's disease. Here, we applied recently developed analysis techniques to investigate cross-sectional differences in subcortical shape and volume alterations in patients with stable mild cognitive impairment (MCI) (n = 23, age range 59-82, 47.8% female), future converters at baseline (n = 10, age range 66-84, 90% female) and at time of conversion (age range 68-87) compared to group-wise age and gender matched healthy control subjects (n = 23, age range 61-81, 47.8% female; n = 10, age range 66-82, 80% female; n = 10, age range 68-82, 70% female). Additionally, we studied cortical thinning and global and local measures of hippocampal atrophy as known key imaging markers for Alzheimer's disease. Apart from bilateral striatal volume reductions, no morphometric alterations were found in cognitively stable patients. In contrast, we identified shape alterations in striatal and thalamic regions in future converters at baseline and at time of conversion. These shape alterations were paralleled by Alzheimer's disease like patterns of left hemispheric morphometric changes (cortical thinning in medial temporal regions, hippocampal total and subfield atrophy) in future converters at baseline with progression to similar right hemispheric alterations at time of conversion. Additionally, receiver operating characteristic curve analysis indicated that subcortical shape alterations may outperform hippocampal volume in identifying future converters at baseline. These results further confirm the key role of early cortical thinning and hippocampal atrophy in the early detection of Alzheimer's disease. But first and foremost, and by distinguishing future converters but not patients with stable cognitive abilities from cognitively normal subjects, our results support the value of early subcortical shape alterations and reduced hippocampal subfield volumes as potential markers for the early detection of Alzheimer's disease.


Spinal mechanical load as a risk factor for low back pain: a systematic review of prospective cohort studies.
Systematic review. To review and critically evaluate the past literature for spinal mechanical load as risk factor for low back pain (LBP). LBP is a costly health problem worldwide, and treatments are often unsuccessful. Therefore, prevention might be more beneficial in the management of LBP. With respect to prevention, the knowledge of risk factors is essential. From the literature, exposures involving spinal mechanical load is frequently discussed as a potential risk factor for LBP. For a better understanding of this risk factor, we performed a systematic review of the literature. Additionally, we evaluated exposures of spinal mechanical load for possible dose-response relations with LBP. We systematically searched Medline, Embase, PsycINFO, and CINAHL databases (without language restriction) for full-report publications of prospective cohort studies, evaluating spinal mechanical load during work and/or leisure time activities as risk factors for nonspecific LBP in patients (>18 years of age) free of LBP at baseline. We assessed the methodology of each article and extracted information on population, response rates, characteristics of LBP, exposures, and estimated association(s), using standardized forms. We performed a best evidence synthesis of the obtained information. In total, 18 studies were eligible (all rated as high methodologic quality) reporting on 24,315 subjects. We found strong evidence that leisure time sport or exercises, sitting, and prolonged standing/walking are not associated with LBP. Evidence for associations in leisure time activities (e.g., do-it-yourself home repair, gardening), whole-body vibration, nursing tasks, heavy physical work, and working with ones trunk in a bent and/or twisted position and LBP was conflicting. We found no studies, thus no evidence, for an association between sleeping or sporting on a professional level and LBP.


Surrogate utility estimation by long-term partners and unfamiliar dyads.
To what extent are people able to make predictions about other people's preferences and values?We report two experiments that present a novel method assessing some of the basic processes in surrogate decision-making, namely surrogate-utility estimation. In each experiment participants formed dyads who were asked to assign utilities to health related items and commodity items, and to predict their partner's utility judgments for the same items. In experiment one we showed that older adults in long-term relationships were able to accurately predict their partner's wishes. In experiment two we showed that younger adults who were relatively unfamiliar with one another were also able to predict other people's wishes. Crucially we demonstrated that these judgments were accurate even after partialling out each participant's own preferences indicating that in order to make surrogate utility estimations people engage in perspective-taking rather than simple anchoring and adjustment, suggesting that utility estimation is not the cause of inaccuracy in surrogate decision-making. The data and implications are discussed with respect to theories of surrogate decision-making.


Obesity is a strong determinant of hypertensive target organ damage in young-to-middle-age patients.
To examine the impact of overweight and obesity on development of target organ damage in the early stage of hypertension. Participants were 727 young-to-middle-age subjects screened for stage 1 hypertension and followed for 8 years. Ambulatory blood pressure (BP), albumin excretion rate and echocardiographic data were obtained at entry, every 5 years and/or before starting antihypertensive treatment. During the follow-up, hypertension needing treatment was developed by 54.7% of the subjects with normal weight, 66.6% of those with overweight and 73.0% of those with obesity (P<0.001). Kaplan-Meier curves showed that patients with obesity or overweight progressed to sustained hypertension earlier than those with normal weight (P<0.001). At study end, rate of organ damage was 10.7% in the normal weight, 16.4% in the overweight and 30.1% in the obese subjects (P<0.001). In a multivariable logistic regression analysis, overweight (P=0.008) and obesity (P<0.001) were significant predictors of final organ damage. Inclusion of changes in 24-h BP and body mass index, and of baseline organ damage did not virtually modify these associations (P=0.002 and <0.001, respectively). Obesity was a significant predictor of both left ventricular hypertrophy (P<0.001) and microalbuminuria (P=0.015) with an odds ratio (95% confidence interval) of 8.5 (2.7-26.8) and 3.5 (1.3-9.6), respectively. These data indicate that in hypertensive subjects obesity has deleterious effects on the cardiovascular system already at an early age. Preventive strategies addressed to achieve weight reduction should be implemented at a very early stage in young people with excess adiposity and high BP.


Test-retest resting-state fMRI in healthy elderly persons with a family history of Alzheimer's disease.
We present a test-retest dataset of resting-state fMRI data obtained in 80 cognitively normal elderly volunteers enrolled in the "Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease" (PREVENT-AD) Cohort. Subjects with a family history of Alzheimer's disease in first-degree relatives were recruited as part of an on-going double blind randomized clinical trial of Naproxen or placebo. Two pairs of scans were acquired ~3 months apart, allowing the assessment of both intra- and inter-session reliability, with the possible caveat of treatment effects as a source of inter-session variation. Using the NeuroImaging Analysis Kit (NIAK), we report on the standard quality of co-registration and motion parameters of the data, and assess their validity based on the spatial distribution of seed-based connectivity maps as well as intra- and inter-session reliability metrics in the default-mode network. This resource, released publicly as sample UM1 of the Consortium for Reliability and Reproducibility (CoRR), will benefit future studies focusing on the preclinical period preceding the appearance of dementia in Alzheimer's disease.


Cloning the differences between two complex genomes.
The analysis of the differences between two complex genomes holds promise for the discovery of infectious agents and probes useful for genetic studies. A system was developed in which subtractive and kinetic enrichment was used to purify restriction endonuclease fragments present in one population of DNA fragments but not in another. Application of this method to DNA populations of reduced complexity ("representations") resulted in the isolation of probes to viral genomes present as single copies in human DNA, and probes that detect polymorphisms between two individuals. In principle, this system, called representational difference analysis (RDA), may also be used for isolating probes linked to sites of genomic rearrangements, whether occurring spontaneously and resulting in genetic disorders or cancer, or programmed during differentiation and development.


Do general practitioners' attitudes towards depression predict their clinical behaviour?
GPs' attitudes towards depression vary, as do their abilities to detect and manage it effectively. Associations between attitudes and clinical behaviour have not yet been demonstrated directly. We tested two hypotheses: (1) that questionnaire measures of GPs' confidence in identifying depression predict their ability to identify depression in their patients; and (2) that GPs who prefer antidepressants prescribe more than those who prefer psychotherapy. Forty GPs in Liverpool and Manchester completed the Depression Attitude Questionnaire (DAQ) and were asked for prescribing (PACT) information. Attender surveys using the General Health Questionnaire (GHQ-12), in combination with GP ratings of patients' psychological status, generated indices for GPs' case identification, bias and accuracy. We tested associations between these indices and the four DAQ components, in particular GPs' confidence in diagnosis, across a total of 1436 patients. We also compared the DAQ component on attitudes to treatment with relevant PACT data. The DAQ assessment of GPs' ability to identify cases of depression bore no relationship to their observed ability, as measured by accuracy, bias, or identification indices. However, there were significant associations between observed diagnostic ability and: preference for psychotherapy; ease in managing depression; and, belief in successful treatment. PACT data were available for 26 (65%) GPs. There was an association between preference for antidepressants and prescription of SSRIs (rs 0.3981, P < 0.044), but not for overall antidepressant or tricyclic prescribing, or for dose of dothiepin. The DAQ measure of ease of identification is not valid when compared to actual clinical practice. The ability of GPs to identify depression may not be an independent variable, but may rather reflect other beliefs, attitudes and skills. This has considerable implications for educational interventions in primary care.


Occupational cumulative trauma disorders of the upper extremity.
The umbrella term cumulative trauma disorders (CTDs) (also known as repetitive strain injuries, overuse syndromes, and repetitive motion disorders) covers a number of similar conditions arising from overuse of the joints or soft tissues of the upper extremity. Occupational CTDs have become a common problem in the workplace. These disorders are costly to the employer, the worker, and society in terms of time lost from work and resulting disability. Within the past decade, occupational therapists and physical therapists specializing in rehabilitation of work-related musculoskeletal injuries have seen an increase in the incidence of CTDs of the upper extremity in the workplace. Therapists are called upon not just to treat these injured workers, but also to help them regain a functional level for work reentry and to educate them to prevent reinjury. This article reviews the literature on the epidemiology, etiology, pathophysiology, and management of upper-extremity occupational CTDs. Because the ultimate goal of the workplace is to maintain the health and safety of the employee, an educational approach to hand, wrist, elbow, and shoulder use is essential to prevent, decrease, or eliminate the risk of occupational CTDs of the upper extremity.