Interdisciplinary COPD intervention in primary care: a cluster randomised controlled trial.
We evaluated the effectiveness of an interdisciplinary, primary care-based model of care for chronic obstructive pulmonary disease (COPD).A cluster randomised controlled trial was conducted in 43 general practices in Australia. Adults with a history of smoking and/or COPD, aged ≥40 years with two or more clinic visits in the previous year were enrolled following spirometric confirmation of COPD. The model of care comprised smoking cessation support, home medicines review (HMR) and home-based pulmonary rehabilitation (HomeBase). Main outcomes included changes in St George's Respiratory Questionnaire (SGRQ) score, COPD Assessment Test (CAT), dyspnoea, smoking abstinence and lung function at 6 and 12 months.We identified 272 participants with COPD (157 intervention, 115 usual care); 49 (31%) out of 157 completed both HMR and HomeBase. Intention-to-treat analysis showed no statistically significant difference in change in SGRQ at 6 months (adjusted between-group difference 2.45 favouring intervention, 95% CI -0.89-5.79). Per protocol analyses showed clinically and statistically significant improvements in SGRQ in those receiving the full intervention compared to usual care (difference 5.22, 95% CI 0.19-10.25). No statistically significant differences were observed in change in CAT, dyspnoea, smoking abstinence or lung function.No significant evidence was found for the effectiveness of this interdisciplinary model of care for COPD in primary care over usual care. Low uptake was a limitation.


Unraveling the genetic etiology of adult antisocial behavior: a genome-wide association study.
Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about half of the variance in antisocial behavior can be explained by genetic factors. In order to identify the specific common genetic variants underlying this behavior, we conduct the first genome-wide association study (GWAS) on adult antisocial behavior. Our sample comprised a community sample of 4816 individuals who had completed a self-report questionnaire. No genetic polymorphisms reached genome-wide significance for association with adult antisocial behavior. In addition, none of the traditional candidate genes can be confirmed in our study. While not genome-wide significant, the gene with the strongest association (p-value = 8.7×10(-5)) was DYRK1A, a gene previously related to abnormal brain development and mental retardation. Future studies should use larger, more homogeneous samples to disentangle the etiology of antisocial behavior. Biosocial criminological research allows a more empirically grounded understanding of criminal behavior, which could ultimately inform and improve current treatment strategies.


The F-BAR domain protein PACSIN2 associates with Rac1 and regulates cell spreading and migration.
The Rac1 GTPase controls cytoskeletal dynamics and is a key regulator of cell spreading and migration mediated by signaling through effector proteins, such as the PAK kinases and the Scar and WAVE proteins. We previously identified a series of regulatory proteins that associate with Rac1 through its hypervariable C-terminal domain, including the Rac1 activator β-Pix (also known as Rho guanine-nucleotide-exchange factor 7) and the membrane adapter caveolin-1. Here, we show that Rac1 associates, through its C-terminus, with the F-BAR domain protein PACSIN2, an inducer of membrane tubulation and a regulator of endocytosis. We show that Rac1 localizes with PACSIN2 at intracellular tubular structures and on early endosomes. Active Rac1 induces a loss of PACSIN2-positive tubular structures. By contrast, Rac1 inhibition results in an accumulation of PACSIN2-positive tubules. In addition, PACSIN2 appears to regulate Rac1 signaling; siRNA-mediated loss of PACSIN2 increases the levels of Rac1-GTP and promotes cell spreading and migration in a wound healing assay. Moreover, ectopic expression of PACSIN2 reduces Rac1-GTP levels in a fashion that is dependent on the PACSIN2-Rac1 interaction, on the membrane-tubulating capacity of PACSIN2 and on dynamin. These data identify the BAR-domain protein PACSIN2 as a Rac1 interactor that regulates Rac1-mediated cell spreading and migration.


Individualised Estimation of Quality-adjusted Survival Benefit and Cost-effectiveness of Proton Beam Therapy in Intermediate-stage Hodgkin Lymphoma.
Radiotherapy for Hodgkin lymphoma leads to the irradiation of organs at risk (OAR), which may confer excess risks of late effects. Comparative dosimetry studies show that proton beam therapy (PBT) may reduce OAR irradiation compared with photon radiotherapy, but PBT is more expensive and treatment capacity is limited. The purpose of this study is to inform the appropriateness of PBT for intermediate-stage Hodgkin lymphoma (ISHL). A microsimulation model simulating the course of ISHL, background mortality and late effects was used to estimate comparative quality-adjusted life years (QALYs) lived and healthcare costs after consolidative pencil beam scanning PBT or volumetric modulated arc therapy (VMAT), both in deep-inspiration breath-hold. Outcomes were compared for 606 illustrative patients covering a spectrum of clinical presentations, varying by two age strata (20 and 40 years), both sexes, three smoking statuses (never, former and current) and 61 pairs of OAR radiation doses from a comparative planning study. Both undiscounted and discounted outcomes at 3.5% yearly discount were estimated. The maximum excess cost of PBT that might be considered cost-effective by the UK's National Institute for Health and Care Excellence was calculated. OAR doses, smoking status and discount rate had large impacts on QALYs gained with PBT. Current smokers benefited the most, averaging 0.605 undiscounted QALYs (range -0.341 to 2.171) and 0.146 discounted QALYs (range -0.067 to 0.686), whereas never smokers benefited the least, averaging 0.074 undiscounted QALYs (range -0.196 to 0.491) and 0.017 discounted QALYs (range -0.030 to 0.086). For the gain in discounted QALYs to be considered cost-effective, PBT would have to cost at most £4812 more than VMAT for current smokers and £645 more for never smokers. This is below preliminary National Health Service cost estimates of PBT over photon radiotherapy. In a UK setting, PBT for ISHL may not be considered cost-effective. However, the degree of unquantifiable uncertainty is substantial.


Sedation versus general anaesthesia for provision of dental treatment to patients younger than 18 years.
A significant proportion of children have caries requiring restorations or extractions, and some of these children will not accept this treatment under local anaesthetic. Historically this has been managed by the use of a general anaesthetic in children; however, use of sedation may lead to reduced morbidity and cost. The aim of this review was to compare the efficiency of sedation versus general anaesthesia (GA) for provision of dental treatment to children and adolescents younger than 18 years. This review was originally published in 2009 and was updated in 2012 and again in 2015. We will evaluate morbidity and effectiveness of sedation versus GA for provision of dental treatment to patients younger than 18 years. If data become available, we will analyse the cost-effectiveness of different interventions. If data are not available, we will obtain crude estimates of cost.Morbidity can be defined as 'an undesired result or complication'. For the purposes of this review, 'postoperative morbidity' refers to undesired results or complications such as nausea following a procedure, once the patient had been restored to consciousness and could breathe unaided. 'Intraoperative morbidity' refers to any complications that occur during the procedure that may necessitate action by the anaesthetist or the sedationist, such as respiratory arrest. In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7); MEDLINE Ovid SP (1950 to July 2015); EMBASE Ovid SP (1974 to July 2015); System for Information on Grey Literature in Europe (SIGLE) (1980 to October July 2012); Latin American & Caribbean Health Sciences Literature (LILACS) (1982 to July 2015); and Institute for Scientific Information (ISI) Web of Science (1945 to July 2015).We also carried out handsearching of relevant journals to July 2015. We imposed no language restriction. We planned to include randomized controlled clinical trials that compared sedative agents versus general anaesthesia in children and adolescents up to 18 years of age undergoing dental treatment. We excluded complex surgical procedures and pseudo-randomized trials. Two review authors assessed titles and abstracts for inclusion in the review. We recorded information relevant to objectives and outcome measures by using a specially designed 'data extraction form'. We will employ the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) approach to interpret findings. In our original review, we identified 16 studies for potential inclusion after searching available databases and screening titles and abstracts. After retrieving full-text studies, we found none to be eligible. We identified no additional studies in the updated search of July 2012. We identified two studies for possible inclusion in the updated search of July 2015; again we found these to be ineligible. Randomized controlled studies comparing use of dental general anaesthesia versus sedation are needed to quantify differences such as morbidity and cost.


IDO chronic immune activation and tryptophan metabolic pathway: A potential pathophysiological link between depression and obesity.
Obesity and depression are among the most pressing health problems in the contemporary world. Obesity and depression share a bidirectional relationship, whereby each condition increases the risk of the other. By inference, shared pathways may underpin the comorbidity between obesity and depression. Activation of cell-mediated immunity (CMI) is a key factor in the pathophysiology of depression. CMI cytokines, including IFN-γ, TNFα and IL-1β, induce the catabolism of tryptophan (TRY) by stimulating indoleamine 2,3-dioxygenase (IDO) resulting in the synthesis of kynurenine (KYN) and other tryptophan catabolites (TRYCATs). In the CNS, TRYCATs have been related to oxidative damage, inflammation, mitochondrial dysfunction, cytotoxicity, excitotoxicity, neurotoxicity and lowered neuroplasticity. The pathophysiology of obesity is also associated with a state of aberrant inflammation that activates aryl hydrocarbon receptor (AHR), a pathway involved in the detection of intracellular or environmental changes as well as with increases in the production of TRYCATs, being KYN an agonists of AHR. Both AHR and TRYCATS are involved in obesity and related metabolic disorders. These changes in the TRYCAT pathway may contribute to the onset of neuropsychiatric symptoms in obesity. This paper reviews the role of immune activation, IDO stimulation and increased TRYCAT production in the pathophysiology of depression and obesity. Here we suggest that increased synthesis of detrimental TRYCATs is implicated in comorbid obesity and depression and is a new drug target to treat both diseases.


Acute aortic syndromes: new insights from electrocardiographically gated computed tomography.
The development of retrospective electrocardiographic (ECG)-gating has proved to be a diagnostic and therapeutic boon for computed tomography (CT) imaging of patients with acute thoracic aortic diseases, such as aortic dissection/intramural hematoma (AD/IMH), penetrating atherosclerotic ulcer (APU), and ruptured/leaking aneurysm. The notorious pulsation motion artifacts in the ascending aorta confounding regular CT scanning can be eliminated, and involvement of the sinuses of Valsalva, the valve cusps, the aortic annulus, and the coronary arteries in aortic dissection can be clearly depicted or excluded. Motion-free images also allow reliable identification of the site of the primary intimal tear, the location, and extent of the intimomedial flap, and branch artery involvement. ECG-gated CTA also allows the detection of more subtle lesions and variants of aortic dissection, which may ultimately expand our understanding of these complex, life-threatening disorders.


A comparison between slaughter traits and meat quality of various sheep breeds: wool, dual-purpose and mutton.
The slaughter and meat quality traits of 20-month-old wool (Merino), dual-purpose (Dohne Merino and South African Mutton Merino [SAMM]) and mutton (Dormer) type sheep were compared. Average live weights of SAMM and Dormer sheep were 23% heavier than those of Dohne Merinos which were 28% heavier than Merinos. Fat depths at the thirteenth rib and lumbar regions of Merino and Dohne Merino sheep were lower than those of SAMM and Dormer sheep. The cooking loss, drip loss and shearing value from the M. longissimus dorsi did not differ between breeds. The initial juiciness and sustained juiciness of meat from Merinos were rated significantly lower by sensory analysis. Meat from Dohne Merino was rated significantly more tender for the attribute first bite. It was demonstrated that Dormer and SAMM sheep had heavier but fatter carcasses than Merinos and Dohne Merinos, with differences in meat quality between breeds.


Patient-Specific Network Connectivity Combined With a Next Generation Neural Mass Model to Test Clinical Hypothesis of Seizure Propagation.
Dynamics underlying epileptic seizures span multiple scales in space and time, therefore, understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. In this view, mathematical models have been developed, ranging from single neuron to neural population. In this study, we consider a neural mass model able to exactly reproduce the dynamics of heterogeneous spiking neural networks. We combine mathematical modeling with structural information from non invasive brain imaging, thus building large-scale brain network models to explore emergent dynamics and test the clinical hypothesis. We provide a comprehensive study on the effect of external drives on neuronal networks exhibiting multistability, in order to investigate the role played by the neuroanatomical connectivity matrices in shaping the emergent dynamics. In particular, we systematically investigate the conditions under which the network displays a transition from a low activity regime to a high activity state, which we identify with a seizure-like event. This approach allows us to study the biophysical parameters and variables leading to multiple recruitment events at the network level. We further exploit topological network measures in order to explain the differences and the analogies among the subjects and their brain regions, in showing recruitment events at different parameter values. We demonstrate, along with the example of diffusion-weighted magnetic resonance imaging (dMRI) connectomes of 20 healthy subjects and 15 epileptic patients, that individual variations in structural connectivity, when linked with mathematical dynamic models, have the capacity to explain changes in spatiotemporal organization of brain dynamics, as observed in network-based brain disorders. In particular, for epileptic patients, by means of the integration of the clinical hypotheses on the epileptogenic zone (EZ), i.e., the local network where highly synchronous seizures originate, we have identified the sequence of recruitment events and discussed their links with the topological properties of the specific connectomes. The predictions made on the basis of the implemented set of exact mean-field equations turn out to be in line with the clinical pre-surgical evaluation on recruited secondary networks.


Escaping peril: perceived predation risk affects migratory propensity.
Although migratory plasticity is increasingly documented, the ecological drivers of plasticity are not well understood. Predation risk can influence migratory dynamics, but whether seasonal migrants can adjust their migratory behaviour according to perceived risk is unknown. We used electronic tags to record the migration of individual roach (Rutilus rutilus), a partially migratory fish, in the wild following exposure to manipulation of direct (predator presence/absence) and indirect (high/low roach density) perceived predation risk in experimental mesocosms. Following exposure, we released fish in their lake summer habitat and monitored individual migration to connected streams over an entire season. Individuals exposed to increased perceived direct predation risk (i.e. a live predator) showed a higher migratory propensity but no change in migratory timing, while indirect risk (i.e. roach density) affected timing but not propensity showing that elevated risk carried over to alter migratory behaviour in the wild. Our key finding demonstrates predator-driven migratory plasticity, highlighting the powerful role of predation risk for migratory decision-making and dynamics.


Immobilisation of TiO2 for combined photocatalytic-biological azo dye degradation.
The biodegradability of the azo dye Remazol Red RR (100 mg/l) was evaluated using unadapted activated sludge and the experiment confirmed the recalcitrance of the dye. Using a combination of photocatalysis and an aerobic biological step, the biodegradability was improved significantly and complete removal of both colour and COD were achieved. Furthermore, TiO2 was successfully immobilised on borosilicate glass slides by calcination, which facilitates reuse of the catalyst. The catalytic activity of the immobilised TiO2 was close to that of suspended TiO2. A reduced activity was however observed when the TiO2 slides were used repeatedly. When comparing NaOH, calcination and UV irradiation for regeneration of the TiO2 slides, immersion in NaOH was shown to be the most efficient method.


Improving nutritional status of children with cystic fibrosis at Red Cross War Memorial Children's Hospital.
To determine the nutritional status of children attending a cystic fibrosis clinic in a tertiary hospital in South Africa and compare it to previously reported 10-year rates. Weights and heights were measured of 69 (37 male and 32 female) children aged between 1 year and 18 years. Expected weight-for-age, expected height-for-age, expected weight-for-height and body mass index (BMI) were compared with international standards for underweight, stunting, wasting and BMI goal. The nutritional status of the patients has improved over the last 10 years, most significantly for wasting, which decreased from 58.3% in 1996 to 15.9% in 2006 (95% confidence interval (CI), 1.315-14.09, P < 0.05). Fifty-two percent of the children were underweight in 2006, compared with 66.7% in 1996 (95% CI, 0.044-13.96, P < 0.05). Stunting was found in 31.9% of the current sample. Females over 15 years had expected weight-for-age 25.9% lower than those between 10 years and 15 years, while no difference was found between the male age groups. Female height-for-age was 7.06 percentage points greater than males between 10 years and 15 years (95% CI, 2.16-11.96, P < 0.01). Males between 10 years and 15 years had significantly lower BMIs than the corresponding female group. Coloured patients had significantly lower BMIs than white patients in all age groups. These children demonstrated continuing improvement in nutritional status, although deficits remain. The normalisation of mean weight-for-age and weight-for-height with far fewer wasted patients is encouraging. Interventions are needed in some areas to ensure that all children show progress.


Measuring capability for healthy diet and physical activity.
Patterns of diet and physical activity, major drivers of morbidity and mortality, are contingent on people's feasible opportunities to pursue healthy behaviors. Our objective for this mixed methods study was to develop measures of feasible opportunities for diet and activity. The Capability Approach framework for evaluating people's real freedoms to pursue their values guided the research. A community-based participatory model was applied to conduct focus groups of adults with obesity or diabetes mellitus from an economically disadvantaged Latino community. Focus group themes were developed into survey items that assess how individual circumstances and neighborhood contexts influence opportunities for diet and activity. The prevalence of different influences was explored in a sample of 300 patients from a primary care safety net clinic. Scales measuring different aspects of opportunity were created through principal components analysis. Availability, convenience, safety, cost of food, and activity resources interact with individual circumstances, such as illness, depression, family and nonfamily supports, and scope of personal agency, to shape practical opportunities. Multiple vulnerabilities in availability of resources and moderators of resource use commonly occur together, intensifying challenges and creating difficult trade-offs. Only one-half of participants reported that physicians understood their difficulties pursuing activity, and just one-third for diet. Our results suggest that practical opportunities for healthy behavior can be measured as a primary target for clinical and public health assessment and intervention. The Capability Approach holds promise as a framework for developing interventions responsive to both personal and environmental determinants.


Effects of wolves on elk and cattle behaviors: implications for livestock production and wolf conservation.
In many areas, livestock are grazed within wolf (Canis lupus) range. Predation and harassment of livestock by wolves creates conflict and is a significant challenge for wolf conservation. Wild prey, such as elk (Cervus elaphus), perform anti-predator behaviors. Artificial selection of cattle (Bos taurus) might have resulted in attenuation or absence of anti-predator responses, or in erratic and inconsistent responses. Regardless, such responses might have implications on stress and fitness. We compared elk and cattle anti-predator responses to wolves in southwest Alberta, Canada within home ranges and livestock pastures, respectively. We deployed satellite- and GPS-telemetry collars on wolves, elk, and cattle (n = 16, 10 and 78, respectively) and measured seven prey response variables during periods of wolf presence and absence (speed, path sinuosity, time spent head-up, distance to neighboring animals, terrain ruggedness, slope and distance to forest). During independent periods of wolf presence (n = 72), individual elk increased path sinuosity (Z = -2.720, P = 0.007) and used more rugged terrain (Z = -2.856, P = 0.004) and steeper slopes (Z = -3.065, P = 0.002). For cattle, individual as well as group behavioral analyses were feasible and these indicated increased path sinuosity (Z = -2.720, P = 0.007) and decreased distance to neighbors (Z = -2.551, P = 0.011). In addition, cattle groups showed a number of behavioral changes concomitant to wolf visits, with variable direction in changes. Our results suggest both elk and cattle modify their behavior in relation to wolf presence, with potential energetic costs. Our study does not allow evaluating the efficacy of anti-predator behaviors, but indicates that artificial selection did not result in their absence in cattle. The costs of wolf predation on livestock are often compensated considering just the market value of the animal killed. However, society might consider refunding some additional costs (e.g., weight loss and reduced reproduction) that might be associated with the changes in cattle behaviors that we documented.


Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease.
Autophagy, an intracellular system for delivering portions of cytoplasm and damaged organelles to lysosomes for degradation/recycling, plays a role in many physiological processes and is disturbed in many diseases. We recently provided evidence for the role of autophagy in Pompe disease, a lysosomal storage disorder in which acid alphaglucosidase, the enzyme involved in the breakdown of glycogen, is deficient or absent. Clinically the disease manifests as a cardiac and skeletal muscle myopathy. The current enzyme replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from skeletal muscle. In our Pompe model, the poor muscle response to therapy is associated with the presence of pools of autophagic debris. To clear the fibers of the autophagic debris, we have generated a Pompe model in which an autophagy gene, Atg7, is inactivated in muscle. Suppression of autophagy alone reduced the glycogen level by 50–60%. Following ERT, muscle glycogen was reduced to normal levels, an outcome not observed in Pompe mice with genetically intact autophagy. The suppression of autophagy, which has proven successful in the Pompe model, is a novel therapeutic approach that may be useful in other diseases with disturbed autophagy.


Lung tissue responses and sites of particle retention differ between rats and cynomolgus monkeys exposed chronically to diesel exhaust and coal dust.
Several chronic inhalation bioassays of poorly soluble, nonfibrous particles have resulted in an increased incidence of lung tumors in rats, no increase in lung tumors in Syrian hamsters, and inconsistent results in mice. These results have raised concerns that rats may be more prone than other species to develop persistent pulmonary epithelial hyperplasia, metaplasia, and tumors in response to the accumulation of inhaled particles. In addition, particle deposition and the rate of particle clearance from the lung differ between rats and primates, as does the anatomy of the centriacinar region. For these reasons, the usefulness of pulmonary carcinogenicity data from rats exposed to high concentrations of particles for quantitatively predicting lung cancer risk in humans exposed to much lower environmental or occupational concentrations has been questioned. The purpose of this investigation was to directly compare the anatomical patterns of particle retention and the lung tissue responses of rats and monkeys exposed chronically to high occupational concentrations of poorly soluble particles. Lung sections from male cynomolgus monkeys and F344 rats exposed 7 hr/day, 5 days/week for 24 months to filtered ambient air, diesel exhaust (2 mg soot/m3), coal dust (2 mg respirable particulate material/m3), or diesel exhaust and coal dust combined (1 mg soot and 1 mg respirable coal dust/m3) were examined histopathologically. The relative volume density of particulate material and the volume percentage of the total particulate material in defined pulmonary compartments were determined morphometrically to assess the relative amount and the anatomic distribution of retained particulate material. In all groups, relatively more particulate material was retained in monkey than in rat lungs. After adjustment for differences between rat and monkey controls, the coal dust- and the combined diesel exhaust and coal dust-exposed monkeys retained more particulate material than the coal dust- and the combined diesel exhaust and coal dust-exposed rats, respectively. There was no significant difference in the relative amount of retained particulate material between diesel exhaust-exposed monkeys and rats. Within each species, the sites of particle retention and lung tissue responses were the same for diesel soot, coal dust, and the combined material. Rats retained a greater portion of the particulate material in lumens of alveolar ducts and alveoli than monkeys. Conversely, monkeys retained a greater portion of the particulate material in the interstitium than rats. Rats, but not monkeys, had significant alveolar epithelial hyperplastic, inflammatory, and septal fibrotic responses to the retained particles. These results suggest that intrapulmonary particle retention patterns and tissue reactions in rats may not be predictive of retention patterns and tissue responses in primates exposed to poorly soluble particles at concentrations representing high occupational exposures.


A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients.
Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45 mg/m(2), and has been recommended as a standard of care. However, 60 mg/m(2) is widely used and has never been directly compared with 90 mg/m(2). As part of the UK National Cancer Research Institute (NCRI) AML17 trial, 1206 adults with untreated AML or high-risk myelodysplastic syndrome, mostly younger than 60 years of age, were randomized to a first-induction course of chemotherapy, which delivered either 90 mg/m(2) or 60 mg/m(2) on days 1, 3, and 5 combined with cytosine arabinoside. All patients then received a second course that included daunorubicin 50 mg/m(2) on days 1, 3, and 5. There was no overall difference in complete remission rate (73% vs 75%; odds ratio, 1.07 [0.83-1.39]; P = .6) or in any recognized subgroup. The 60-day mortality was increased in the 90 mg/m(2) arm (10% vs 5% (hazard ratio [HR] 1.98 [1.30-3.02]; P = .001), which resulted in no difference in overall 2-year survival (59% vs 60%; HR, 1.16 [0.95-1.43]; P = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535.


A whole-mount immunocytochemical analysis of the expression of the intermediate filament protein vimentin in Xenopus.
We have developed a whole-mount immunocytochemical method for Xenopus and used it to map the expression of the intermediate filament protein vimentin during early embryogenesis. We used two monoclonal antibodies, 14h7 and RV202. Both label vimentin filaments in Xenopus A6 cells, RV202 reacts specifically with vimentin (Mr, 55 x 10(3] on Western blots of A6 cells and embryos. 14h7 reacts with vimentin and a second, insoluble polypeptide of 57 x 10(3) Mr found in A6 cells. The 57 x 10(3) Mr polypeptide appears to be an intermediate filament protein immunochemically related to vimentin. In the whole-mount embryo, we first found vimentin at the time of neural tube closure (stage 19) in cells located at the lateral margins of the neural tube. By stage 26, these cells, which are presumably radial glia, are present along the entire length of the neural tube and in the tail bud. Cells in the optic vesicles express vimentin by stage 24. Vimentin-expressing mesenchymal cells appear on the surface of the somites at stage 22/23; these cells appear first on anterior somites and on progressively more posterior somites as development continues. Beginning at stage 24, vimentin appears in mesenchymal cells located ventral to the somites and associated with the pronephric ducts; these ventral cells first appear below the anterior somites and later appear below more posterior somites. The dorsal fin mesenchyme expresses vimentin at stage 26. In the head, both mesodermally-derived and neural-crest-derived mesenchymal tissues express vimentin by stage 26. These include the mesenchyme of the branchial arches, the mandibular arch, the corneal epithelium, the eye, the meninges and mesenchyme surrounding the otic vesicle. By stage 33, vimentin-expressing mesenchymal cells are present in the pericardial cavity and line the vitelline veins. Vimentin expression appears to be a marker for the differentiation of a subset of central nervous system cells and of head and body mesenchyme in the early Xenopus embryo.


Trends in the Application of Postmastectomy Radiotherapy for Breast Cancer With 1 to 3 Positive Axillary Nodes and Tumors ≤5 cm in the Modern Treatment Era: A Retrospective Korean Breast Cancer Society Report.
Despite high-level evidence, the benefit of postmastectomy RT in these patients in recent years has not been fully elucidated. We investigated postmastectomy radiotherapy (RT) use and evaluated clinicopathologic and treatment factors influencing RT use in Korean women with pT1-2N1 breast cancer.We identified women diagnosed with pT1-2N1 breast cancer between 1994 and 2009 using the Korean Breast Cancer Registry. Factors associated with RT use were evaluated using logistic regression analysis. The median follow-up was 95 months.Of the 6196 women, 11.9% underwent postmastectomy RT. RT was applied more frequently in women with 3 positive lymph nodes (adjusted odds ratio [OR], 2.69) and larger tumors (OR per centimeter, 1.10). RT use was not significantly associated with well-established risk factors (e.g., tumor grade, hormone receptor status, and lymphovascular space invasion). Although RT utilization increased gradually during the study period (OR per year, 1.07), factors associated with RT were similar over time. The estimated 5-year overall survival increased significantly from 84.1% in 1994 to 2000 to 94.6% in 2005 to 2009.This population-based analysis revealed that the indications for postmastectomy RT in pT1-2N1 breast cancer in Korea are based solely on conventional anatomical factors, although their survival has increased significantly in the modern treatment era. There is a significant unmet need for better risk stratification in these patients and for tailored RT with the incorporation of tumor biology-associated factors.


A case report of a 53-year-old female with rheumatoid arthritis and osteoporosis: focus on lab testing and CAM therapies.
A 53-year-old female presented with rheumatoid arthritis and osteoporosis. Additional conditions and symptoms included Raynaud syndrome, fatigue, irritable bowel syndrome associated constipation (IBS-C), gastroesophageal reflux (GERD), menopausal symptoms, chronic urinary tract and upper respiratory infections, and weight gain. She was taking Arthrotec (a combination of diclofenac and misoprostol - for pain and inflammation), Fosamax Plus D (alendronate with vitamin D3 - recently prescribed because of low bone density), and Catapres (clonidine - for menopausal symptoms). Against the advice of her rheumatologist, she had recently discontinued taking Plaquenil (hydroxychloroquine), methotrexate, and prednisone due to significant side effects. Lab tests to identify underlying imbalances and to direct treatment were ordered. Treatment included dietary, nutritional, hormonal, and mind/body support. After one year of therapy, the patient experienced improvement with all of her presenting conditions and symptoms, which enabled her to discontinue several medications. She became versed in identifying and avoiding the environmental triggers of her disease, including foods (dairy, wheat, eggs, and soy), molds, and emotional stress. Antinuclear antibodies were normalized. She experienced a 7.5-percent improvement in left trochanteric bone density - comparable to bisphosphonate therapy. Mild improvements were also noted in the spine and bilateral femoral neck.


Epigenomic Modifications Mediating Antibody Maturation.
Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches. It has been shown that alternate chromatin modifications, in concert with ncRNAs and potentially DNA methylation, regulate AID recruitment and stabilize DNA repair factors. We, hereby, assess the combination of these distinct modifications and discuss how they contribute to initiating differential DNA repair pathways at the Ig locus, which ultimately leads to enhanced antibody-antigen binding affinity (SHM) or antibody isotype switching (CSR). We will also highlight how misregulation of epigenomic regulation during DNA repair can compromise antibody development and lead to a number of immunological syndromes and cancer.


Development and testing of an expectations survey for patients undergoing lumbar spine surgery.
Patients' expectations of lumbar spine surgery have not been obtained with valid and reliable scales derived from patients' perspectives. The objective of this cross-sectional study was to develop and to test a patient-derived expectations survey. The survey was developed in three phases. Phase 1 involved interviews with patients with open-ended questions about expectations and assembly of a draft survey. Phase 2 involved administering the survey twice to assess test-retest reliability. Phase 3 involved selection of final items based on concordance of responses and clinical relevance, and the development of a scoring rubric. In Phase 1, 118 preoperative patients with diverse lumbar spine diagnoses volunteered 583 expectations, from which thirty-one discrete categories were discerned and became the items for the draft survey. In Phase 2, another fifty-six preoperative patients completed the draft survey twice, four days apart. In Phase 3, twenty-one items were retained for the final survey addressing symptom relief, return to basic mobility, resumption of activities, and improvement in psychosocial well-being. An overall score was calculated on the basis of the number of expectations and amount of improvement expected and ranged from 0 to 100 points; a higher score indicates more expectations. For patients in Phase 2, the mean scores for both administrations were 66 and 65 points, the Cronbach alpha coefficients for both administrations were 0.90 and 0.92, and the intraclass correlation coefficient between scores was 0.86. We developed a patient-derived survey that is valid, reliable, and applicable to diverse diagnoses and includes physical and psychosocial expectations. The survey generates an overall score that is easy to calculate and to interpret, and thus fills a gap in the assessment of lumbar spine surgery by offering a practical and comprehensive way to record patients' expectations.


Sleep hygiene awareness: Its relation to sleep quality among medical students in King Saud University, Riyadh, Saudi Arabia.
Sleep hygiene (SH) is considered to be an effective method to treat sleep disturbances, especially among adolescents and young adults. This study aimed to find out the relationship of SH awareness and its importance in overall sleep quality among medical students and to assess the prevalence of sleep disturbance among them. This was a cross-sectional study conducted in the College of Medicine, King Saud University during the period between April and July 2016. A total of 225 students participated in this study and were recruited by a convenience sampling method. Two validated questionnaires were used, Pittsburg Sleep Quality Index (PSQI) to assess sleep quality and the Sleep Beliefs Scale (SBS) to assess the awareness of students about SH. Data were entered into, and analyzed by SPSS Version 20. Overall, more than half of the participants, 113 (56.5%), had a poor sleep quality. Sixty one (30.5%) students got excellent score in SH awareness and the rest of the participants (n = 139; 69.5%) scored poor/intermediate. Thirty-five (57.4%) poor sleepers and 42.6% of good sleepers scored excellent in SH awareness. This study showed a higher prevalence of sleep disturbance among medical students and no significant correlation between SH awareness and good sleep quality, which means that SH awareness may not necessarily ensure a good sleep quality.


Does Fluoride Affect Serum Testosterone and Androgen Binding Protein with Age-Specificity? A Population-Based Cross-Sectional Study in Chinese Male Farmers.
Many studies have demonstrated that exposure to excess fluoride was associated with a variety of diseases. Little is known about the variation of testosterone (T) levels caused by fluoride exposure. The aim of this study is to explore the association of fluoride exposure and age with serum T and androgen-binding protein (ABP) levels in male farmers. A cross-sectional study was conducted in a county of Henan Province, China, including high fluoride exposure from drinking water villages and control villages. Male farmers aged 18-55 years old who lived in these villages were recruited by cluster sampling and divided into a higher fluoride exposure group (HFG) and a lower fluoride exposure group (LFG) according to the level of urinary fluoride. Levels of T and ABP in serum were measured using chemiluminescence immunoassay (CLIA) and enzyme-linked immunosorbent assay (ELISA) respectively. Markedly lower T levels were observed in male farmers from the HFG than in those from the LFG (t = 2.496, P < 0.05). Furthermore, younger farmers, 18-29 and 30-39 years old, may be the most likely to have lower T levels when exposed to fluoride (P < 0.05). No significant differences were observed in serum ABP levels in all male farmers between the two groups with different fluoride exposure. These results supported that excess fluoride exposure decreased serum T levels of male farmers with age-specificity.


pH-responsive micelles based on (PCL)2(PDEA-b-PPEGMA)2 miktoarm polymer: controlled synthesis, characterization, and application as anticancer drug carrier.
Amphiphilic A2(BC)2 miktoarm star polymers [poly(ϵ-caprolactone)]2-[poly(2-(diethylamino)ethyl methacrylate)-b- poly(poly(ethylene glycol) methyl ether methacrylate)]2 [(PCL)2(PDEA-b-PPEGMA)2] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC50 of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)2(PDEA-b-PPEGMA)2 micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.


Vaccination with Mycobacterium bovis BCG strains Danish and Pasteur in white-tailed deer (Odocoileus virginianus) experimentally challenged with Mycobacterium bovis.
Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis in domestic livestock and the cause for many faltering bovine tuberculosis eradication programmes. One approach in dealing with wildlife reservoirs of disease is to interrupt inter-species and intraspecies transmission through vaccination of deer or cattle. To evaluate the efficacy of BCG vaccination in white-tailed deer, 35 deer were assigned to one of three groups; one s.c. dose of 10(7) CFU of M. bovis BCG Pasteur (n = 12); 1 s.c. dose of 10(7) CFU of M. bovis BCG Danish (n = 11); or unvaccinated deer (n = 12). After vaccination, deer were inoculated intratonsilarly with virulent M. bovis. Lesion severity scores of the medial retropharyngeal lymph node, as well as all lymph nodes combined, were reduced in vaccinated deer compared to unvaccinated deer. BCG Danish vaccinated deer had no late stage granulomas characterized by coalescent caseonecrotic granulomas containing numerous acid-fast bacilli compared to BCG Pasteur vaccinated or unvaccinated deer where such lesions were present. Both BCG strains were isolated as late as 250 days after vaccination from deer that were vaccinated but not challenged. In white-tailed deer, BCG provides protection against challenge with virulent M. bovis. Issues related to vaccine persistence, safety and shedding remain to be further investigated.


Kawasaki disease in East Mazandaran, Islamic Republic of Iran, 1997-2002.
We conducted a retrospective review of all cases of Kawasaki disease admitted to the major referral centres in Sari, East Mazandaran from 1 November 1997 to 30 October 2002. Of 29 probable cases, 25 were confirmed, giving an average annual incidence rate of 7.3 per 100 000 in children 0-5 years. The mean age of all cases was 38 months (range: 3.5-80 months). There was a male predominance. The mean time between the onset of illness and diagnosis was 8.2 +/- 3.1 days. Five of the 25 patients had cardiovascular abnormalities before treatment. All patients were treated with intravenous immunoglobulin and 22 (88%) responded to a single dose of treatment and high doses of acetylsalicylic acid; 2 patients needed a second dose of IVIG, and 1 patient required a third. Complete recovery was noted in all patients except for 1, who is under follow-up and treatment.


Perceived deterrents to being a plasmapheresis donor in a voluntary, nonremunerated environment.
As demand for plasma-derived products increases internationally, maintaining a committed plasmapheresis panel membership is critical for blood collection agencies. This study addresses the current lack of knowledge regarding deterrents to the recruitment and retention of plasmapheresis donors in a voluntary nonremunerated environment. Nine focus groups (n = 84) and six individual interviews were conducted using semistructured schedules. Three focus groups were conducted with each category of eligible whole blood (WB) donors: those who had 1) declined to convert to plasmapheresis (DTC), 2) converted but lapsed to WB (LWB), and 3) converted and lapsed from the panel completely (LFP). Transcript analysis revealed distinct deterrent categories. The time required for plasmapheresis was a universally identified deterrent, with concerns of donation frequency expectations shared between DTC and LWB. LWB and LFP both reported excessive questioning and paperwork, and eligibility requirements as deterrents. Unique deterrents for DTC were a lack of accurate knowledge about safety and process. LWB reported concerns about plasmapheresis donation outcomes; however, they were more committed to continuing donation than LFP, who reported donation not being salient, being too busy, and poorer donation experiences. Providing information to address safety and health concerns should be the focus for successful conversion to plasmapheresis. Setting donation frequency expectations at levels to which donors are accustomed may improve evaluations of the cost/benefit ratio of conversion and retention. Involvement levels (i.e., importance, personal meaning of donation) may be the key differentiator between those donors who return to WB and those that lapse altogether.


Relation between cell wall turnover and cell growth in Bacillus subtilis.
The kinetics of cell wall turnover in Bacillus subtilis have been examined in detail. After pulse labeling of the peptidoglycan with N-acetylglucosamine, the newly formed peptidoglycan is stable for approximately three-quarters of a generation and is then degraded by a process that follows first-order kinetics. Deprivation of an auxotroph of amino acids required for protein synthesis results in a cessation of turnover. If a period of amino acid starvation occurs during the lag phase of turnover, then the initiation of turnover is delayed for a period of time equivalent to the starvation period. During amino acid starvation, new cell wall peptidoglycan is synthesized and added to preexisting cell wall. This peptidoglycan after resumption of growth is also subject to degradation (turnover). It is suggested that cell wall turnover is dependent on cell growth and elongation. Several possible control mechanisms for cell wall autolytic enzymes are discussed in light of these observations.


Widely Tunable Two-Color Free-Electron Laser on a Storage Ring.
With a wide wavelength tuning range, free-electron lasers (FELs) are well suited for producing simultaneous lasing at multiple wavelengths. We present the first experimental results of a novel two-color storage ring FEL. With three undulators and a pair of dual-band mirrors, the two-color FEL can lase simultaneously in infrared (IR) around 720 nm and in ultraviolet (UV) around 360 nm. We have demonstrated independent wavelength tuning in a wide range (60 nm in IR and 24 nm in UV). We have also realized two-color harmonic operation with the UV lasing tuned to the second harmonic of the IR lasing. Furthermore, we have demonstrated good power stability with two-color lasing, and good control of the power sharing between the two colors.


A clinical evaluation of Kanchanara Guggulu and Bala Taila Matra Basti in the management of Mutraghata with special reference to benign prostatic hyperplasia.
Mutraghata a disease of Mutravaha Srotasa (urinary system) described in Ayurveda, closely resembles with benign prostatic hyperplasia (BPH) of the modern medicine. It affects man above the age of 40 years. Conservative management with hormonal therapy, open prostatectomy and TURP are the options available in modern medicine. In Ayurveda, the drugs having Vata Kapha pacifying action, Shothahara (anti-inflammatory) and Mutrala (diuretic) are recommended for its management. The aim of this study was to evaluate the clinical efficacy of Kanchanara Guggulu orally and Bala Taila Matra Basti in the management of Mutraghata (BPH). A total of 32 selected patients were divided into two groups. In group A, Bala Taila 60 ml, Matra Basti, once a day, was administered just before breakfast for 21 days. In group B, Bala Taila (60 ml), Matra Basti, once a day, was administered just before breakfast for 21 days and Kanchanara Guggulu Vati 1g (2 tab, 500mg each) three times a day, orally with lukewarm water was administered for 21 days. Findings were recorded in research proforma at weekly interval and patients were followed up till 1 month. In group A, the maximum improvement was seen in 3 patients (25.00%), moderate improvement was seen in 8 patients (66.67%) and mild improvement was observed in 1 patient (8.34%). Similarly, in group B, the maximum improvement was found in 10 patients (55.56%), moderate improvement in 7 patients (38.89%) and mild improvement in 1 patient (5.56%) only. None of the patients got complete remission or remained unchanged in either of the groups. Significant reduction was observed in postvoidal residual urine volume and the size of the prostate in both the groups. It was concluded that Matra Basti along with Kanchanara Guggulu orally showed Mutraghata comparatively better symptomatic relief as compared to Matra Basti alone in cases of Mutraghata (BPH).


The effects of spatial stability and cue type on spatial learning: Implications for theories of parallel memory systems.
Some theories of spatial learning predict that associative rules apply under only limited circumstances. For example, learning based on a boundary has been claimed to be immune to cue competition effects because boundary information is the basis for the formation of a cognitive map, whilst landmark learning does not involve cognitive mapping. This is referred to as the cue type hypothesis. However, it has also been claimed that cue stability is a prerequisite for the formation of a cognitive map, meaning that whichever cue type was perceived as stable would enter a cognitive map and thus be immune to cue competition, while unstable cues will be subject to cue competition, regardless of cue type. In experiments 1 and 2 we manipulated the stability of boundary and landmark cues when learning the location of two hidden goals. One goal location was constant with respect to the boundary, and the other constant with respect to the landmark cues. For both cue types, the presence of distal orientation cues provided directional information. For half the participants the landmark cues were unstable relative to the boundary and orientation cues, whereas for the remainder of the participants the boundary was unstable relative to landmarks and orientation cues. In a second stage of training, all cues remained stable so that both goal locations could be learned with respect to both landmark and boundary information. According to the cue type hypothesis, boundary information should block learning about landmarks regardless of cue stability. According to the cue stability hypothesis, however, landmarks should block learning about the boundary when the landmarks appear stable relative to the boundary. Regardless of cue type or stability the results showed reciprocal blocking, contrary to both formulations of incidental cognitive mapping. Experiment 3 established that the results of Experiments 1 and 2 could not be explained in terms of difficulty in learning certain locations with respect to different cue types. In a final experiment, following training in which both landmarks and boundary cues signalled two goal locations, a new goal location was established with respect to the landmark cues, before testing with the boundary, which had never been used to define the new goal location. The results of this novel test of the interaction between boundary and landmark cues indicated that new learning with respect to the landmark had a profound effect on navigation with respect to the boundary, counter to the predictions of incidental cognitive mapping of boundaries.


Shape registration with learned deformations for 3D shape reconstruction from sparse and incomplete point clouds.
Shape reconstruction from sparse point clouds/images is a challenging and relevant task required for a variety of applications in computer vision and medical image analysis (e.g. surgical navigation, cardiac motion analysis, augmented/virtual reality systems). A subset of such methods, viz. 3D shape reconstruction from 2D contours, is especially relevant for computer-aided diagnosis and intervention applications involving meshes derived from multiple 2D image slices, views or projections. We propose a deep learning architecture, coined Mesh Reconstruction Network (MR-Net), which tackles this problem. MR-Net enables accurate 3D mesh reconstruction in real-time despite missing data and with sparse annotations. Using 3D cardiac shape reconstruction from 2D contours defined on short-axis cardiac magnetic resonance image slices as an exemplar, we demonstrate that our approach consistently outperforms state-of-the-art techniques for shape reconstruction from unstructured point clouds. Our approach can reconstruct 3D cardiac meshes to within 2.5-mm point-to-point error, concerning the ground-truth data (the original image spatial resolution is ∼1.8×1.8×10mm3). We further evaluate the robustness of the proposed approach to incomplete data, and contours estimated using an automatic segmentation algorithm. MR-Net is generic and could reconstruct shapes of other organs, making it compelling as a tool for various applications in medical image analysis.


Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells.
Successful grafting of tissues or cells from mismatched donors requires systemic immunosuppression. It is yet to be determined whether immunosuppressive manipulations perturb transplanted cell engraftment or proliferation. We used syngeneic and allogeneic cell transplantation assays based on F344 recipient rats lacking dipeptidyl peptidase IV enzyme activity to identify transplanted hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate dehydrogenase inhibitor). First, suitable drug doses capable of inducing long-term survival of allografted hepatocytes were identified. In pharmacologically effective doses, rapamycin enhanced cell engraftment by downregulating hepatic expression of selected inflammatory cytokines but profoundly impaired proliferation of transplanted cells, which was necessary for liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil perturbed neither transplanted cell engraftment nor their proliferation. Therefore, mTOR-dependent extracellular and intracellular mechanisms affected liver replacement with transplanted cells. In conclusion, insights into the biological effects of specific drugs on transplanted cells are critical in identifying suitable immunosuppressive strategies for cell therapy.


Use of laser tweezers to analyze sperm motility and mitochondrial membrane potential.
We combine laser tweezers with custom computer tracking software and robotics to analyze the motility [swimming speed, VCL (curvilinear velocity), and swimming force in terms of escape laser power (Pesc)] and energetics [mitochondrial membrane potential (MP)] of individual sperm. Domestic dog sperm are labeled with a cationic fluorescent probe, DiOC2(3), that reports the MP across the inner membrane of the mitochondria located in the sperm's midpiece. Individual sperm are tracked to calculate VCL. Pesc is measured by reducing the laser power after the sperm is trapped using laser tweezers until the sperm is capable of escaping the trap. The MP is measured every second over a 5-s interval during the tracking phase (sperm is swimming freely) and continuously during the trapping phase. The effect of the fluorescent probe on sperm motility is addressed. The sensitivity of the probe is measured by assessing the effects of a mitochondrial uncoupling agent (CCCP) on MP of free swimming sperm. The effects of prolonged exposed to the laser tweezers on VCL and MP are analyzed. The system's capabilities are demonstrated by measuring VCL, Pesc, and MP simultaneously for individual sperm. This combination of imaging tools is useful to quantitatively assess sperm quality and viability.


The use of pressure and silicone in hypertrophic scar management in burns patients: a pilot randomized controlled trial.
This pilot study investigates whether pressure and silicone therapy used simultaneously are more effective in treating multiple characteristics of hypertrophic scars than pressure alone. A pilot randomized controlled trial was conducted. Twenty-two participants with hypertrophic burn scars were randomized to receive Jobskin pressure garments and Mepiform silicone sheeting or Jobskin pressure garments alone. The Vancouver Scar Scale (VSS) was used to measure multiple scar characteristics at baseline, week 12, and week 24. No statistically significant difference was found in the rate of change of the VSS scores between the pressure therapy (PT) group and the pressure therapy and silicone group at week 12 or week 24; however, the mean scores of both groups reduced over 24 weeks. There were no statistically significant changes in the VSS subscores (scar height, vascularity, pliability, and pigmentation) from baseline to week 12 or week 24. A statistically significant relationship was observed between the VSS score and TBSA burned (<30%) in the PT group at baseline (P<.05), over 12 weeks (P<.05), and over 24 weeks (P<.05). Given the limitations of this study, especially the small sample size, further research is necessary before any firm conclusions can be drawn on this therapy approach. However, this pilot study has discussed the recurring issues in the research regarding these controversial treatments and has yielded potential for further investigation in a fully powered randomized controlled trial.


Experience in a neonatal intensive care unit affects pain response.
To determine the effect of being in the neonatal intensive care unit (NICU) on pain responses in infants of 32 weeks' postconceptual age (PCA). A cross-sectional comparative design was used. Two level III NICUs, each in metropolitan, university teaching hospitals. Infants of 32 weeks' PCA born within the past 4 days (the newly born group; n = 53) were compared with infants of the same PCA who had been born 4 weeks earlier (the earlier-born group: n = 36) and had spent that time in an NICU. Heart rate, oxygen saturation levels, and facial actions were used as outcomes in a between-group repeated measures analysis of variance across the heel stick procedure. Background variables of Apgar, weight at birth and data collection, severity of illness, age group, and total number of invasive procedures were entered into a stepwise regression. The two groups responded differently to the heel stick: the earlier-born infants had less behavioral manifestations of pain than the newly born infants. The number of invasive procedures was the primary factor that explained those behavioral differences, with Apgar as a second explanatory factor. The earlier-born infants had higher heart rates and lower oxygen saturation than the newly born infants before as well as during the procedure. These physiological differences were explained by the perinatal factors of age at birth and birth weight. Preterm infants who spend PCA weeks 28 through 32 in an NICU are less mature in their pain response than newborn premature infants of 32 weeks' PCA. Greater frequency of invasive procedures is associated with behavioral immaturity, whereas birth factors are associated with physiological immaturity.


Insights to genetic characterization tools for epidemiological tracking of Francisella tularensis in Sweden.
Tularaemia, caused by the bacterium Francisella tularensis, is endemic in Sweden and is poorly understood. The aim of this study was to evaluate the effectiveness of three different genetic typing systems to link a genetic type to the source and place of tularemia infection in Sweden. Canonical single nucleotide polymorphisms (canSNPs), MLVA including five variable number of tandem repeat loci and PmeI-PFGE were tested on 127 F. tularensis positive specimens collected from Swedish case-patients. All three typing methods identified two major genetic groups with near-perfect agreement. Higher genetic resolution was obtained with canSNP and MLVA compared to PFGE; F. tularensis samples were first assigned into ten phylogroups based on canSNPs followed by 33 unique MLVA types. Phylogroups were geographically analysed to reveal complex phylogeographic patterns in Sweden. The extensive phylogenetic diversity found within individual counties posed a challenge to linking specific genetic types with specific geographic locations. Despite this, a single phylogroup (B.22), defined by a SNP marker specific to a lone Swedish sequenced strain, did link genetic type with a likely geographic place. This result suggests that SNP markers, highly specific to a particular reference genome, may be found most frequently among samples recovered from the same location where the reference genome originated. This insight compels us to consider whole-genome sequencing (WGS) as the appropriate tool for effectively linking specific genetic type to geography. Comparing the WGS of an unknown sample to WGS databases of archived Swedish strains maximizes the likelihood of revealing those rare geographically informative SNPs.


Evidence for lysosomotropic action of desipramine in cultured human fibroblasts.
The uptake and release of [3H]desipramine, an antidepressant drug, was investigated in cultures of human fibroblasts during single and repeated doses added to the culture medium. The resulting kinetics and the pH dependence suggest that desipramine is a lysosomotropic drug which is taken up into the cells by virtue of its amphiphilic character and concentrated in the acidic contents of the lysosomes by ion trapping. Similar to the lysosomotropic agent, chloroquine, desipramine interferes with the lysosomal degradation of endogenous sulfated mucopolysaccharides in a dose-dependent manner. In contrast to short time exposure, long-term treatment with desipramine produces intracellular granulation, possibly by interfering with the recycling of plasma membrane vesicles. The appearance of granular inclusions and the accumulation of intracellular desipramine which is difficult to exchange indicate a gradual formation of complexes with membrane phospholipids resulting in a lysosomal storage of desipramine.


Impact of Light Intensity on Control in Photoinduced Organocatalyzed Atom Transfer Radical Polymerization.
Organic photoredox catalysts have been shown to operate organocatalyzed atom transfer radical polymerizations (O-ATRP) using visible light as the driving force. In this work, the effect of light intensity from white LEDs was evaluated as an influential factor in control over the polymerization and the production of well-defined polymers. We posit the irradiation conditions control the concentrations of various catalyst states necessary to mediate a controlled radical polymerization. Systematic dimming of white LEDs allowed for consideration of the role of light intensity on the polymerization performance. The general effects of decreased irradiation intensity in photoinduced O-ATRP were investigated through comparing two different organic photoredox catalysts: perylene and an 3,7-di(4-biphenyl) 1-naphthalene-10-phenoxazine. Previous computational efforts have investigated catalyst photophysical and electrochemical characteristics, but the broad and complex effects of varied irradiation intensity as an experimental variable on the mechanism of O-ATRP have not been explored. This work revealed that perylene requires more stringent irradiation conditions to achieve controlled polymer molecular weight growth and produce polymers with dispersities <1.50. In contrast, the 3,7-di(4-biphenyl) 1-naphthalene-10-phenoxazine is more robust, achieving linear polymer molecular weight growth under relative irradiation intensity as low as 25%, to produce polymers with dispersities <1.50. This finding is significant, as the discovery of highly robust catalysts is necessary to allow for the adoption of successful O-ATRP in a wide scope of conditions, including those which necessitate low light intensity irradiation.


An evaluation of novel, lower-cost molecular screening tests for human papillomavirus in rural China.
New, lower-cost tests that target high-risk human papillomavirus (HR-HPV) have been developed for cervical cancer screening in lower-resource settings but large, population-based screening studies are lacking. Women ages 25 to 65 years and living in rural China (n = 7,543) self-collected a cervicovaginal specimen, had 2 cervical specimens collected by a clinician, and underwent visual inspection after acetic acid (VIA). The self- and one clinician-collected specimens underwent HR-HPV DNA testing by careHPV (QIAGEN) and Hybrid Capture 2 (HC2; QIAGEN) and the other clinician-collected specimen was tested for HPV16, 18, and 45 E6 using OncoE6 (Arbor Vita Corporation). Women who screened positive for any test and a random sample of those negative on all tests underwent colposcopic evaluation. The percent test positive was 1.8% for HPV E6 oncoprotein, between 14% and 18% for HR-HPV DNA testing, and 7.3% for VIA. The sensitivity for cervical intraepithelial neoplasia grade 3 or more severe (CIN3(+); n = 99) was 53.5% for OncoE6, 97.0% for both careHPV and HC2 testing of the clinician-collected specimen, 83.8% for careHPV testing and 90.9% for HC2 testing of the self-collected specimen, and 50.5% for VIA. OncoE6 had the greatest positive predictive value (PPV), at 40.8% for CIN3(+), compared with the other tests, which had a PPV of less than 10%. OncoE6 tested 70.3% positive for HPV16, 18, or 45-positive CIN3(+) and tested negative for all HPV16-, 18-, or 45-negative CIN3(+) (P < 0.0001). HPV E6 oncoprotein detection is useful for identifying women who have cervical precancer and cancer.


Influenza vaccination coverage rates in Germany a population-based cross-sectional analysis of the seasons 2002/2003 and 2003/2004.
Influenza continues to be a considerable health problem in Europe. Vaccination is the only preventive measure, reducing mortality and morbidity of influenza in all age groups. The objectives of this survey were to assess the level of influenza vaccination coverage in the 2002/2003 season compared with the 2003/2004 season in Germany, to understand the driving forces and barriers to vaccination, and to determine vaccination intentions for the following winter. The authors conducted a random-sampling, telephone-based household survey among noninstitutionalized individuals representative of the population aged > or = 14. The surveys for 2002/2003 and 2003/2004 used the same questionnaire and were subsequently pooled. Four target groups were determined for analysis: (1) persons aged > or = 60; (2) people working in the medical field; (3) persons suffering from chronic illness; and (4) a group composed of persons aged > or = 60 or working in the medical field or suffering from a chronic illness. The overall sample consisted of 4,011 people. The influenza vaccination coverage rate in Germany increased from 22.3% in 2002/2003 to 25.1% in 2003/2004. This increase is not significant. The most frequent reasons for being vaccinated given by vaccinees were: influenza considered to be a serious illness, which people wanted to avoid (90.1%), having received advice from the family doctor or nurse to be vaccinated (71.3%), and not wanting to infect family and friends (70.4%). Reasons for not being vaccinated mentioned by people who have never been vaccinated were: thinking about it, however, not being vaccinated in the end (47.7%), not expecting to catch influenza (43.6%), and not having received a recommendation from the family doctor to be vaccinated (36.6%). Options encouraging influenza vaccination are: recommendation by the family doctor or nurse (66.6%), more available information on the vaccine regarding efficacy and tolerance (54.2%), and more information available about the disease (52.4%). The vaccination coverage in the 2003/2004 season increased in comparison to the 2002/2003 season, although not significantly. The family doctor is the most important source of encouragement for people to be vaccinated against influenza. It seems that the public would be more likely to be vaccinated if they had more information on the efficacy and tolerance of the vaccine, as well as the disease. It is therefore suggested that family doctors be better informed on influenza vaccine and the disease itself, so that they can actively inform their patients on these topics.


Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein.
Genetic alteration of one or more components of the p16(INK4A)-CDK4,6/cyclin D-retinoblastoma pathway is found in more than half of all human cancers. Therefore, CDK4 is an attractive target for the development of a novel anticancer agent. However, it is difficult to make CDK4-specific inhibitors that do not possess activity for other kinases, especially CDK2, because the CDK family has high structural homology. The three-dimensional structure of CDK2, particularly that bound with the inhibitor, has provided useful information for the synthesis of CDK2-specific inhibitors. The same approach used to make CDK4-specific inhibitors was hindered by the failure to obtain a crystal structure of CDK4. To overcome this problem, we synthesized a CDK4 mimic CDK2 protein in which the ATP binding pocket of CDK2 was replaced with that of CDK4. This CDK4 mimic CDK2 was crystallized both in the free and inhibitor-bound form. The structural information thus obtained was found to be useful for synthesis of a CDK4-specific inhibitor that does not have substantial CDK2 activity. Namely, the data suggest that CDK4 has additional space that will accommodate a large substituent such as the CDK4 selective inhibitor. Inhibitors designed to bind into this large cavity should be selective for CDK4 without having substantial CDK2 activity. This design principle was confirmed in the x-ray crystal structure of the CDK4 mimic CDK2 with a new CDK4 selective inhibitor bound.


Organic nitrogen uptake of Scots pine seedlings is independent of current carbohydrate supply.
In boreal forests, seedling establishment is limited by various factors including soil nitrogen (N) availability. Seedlings may absorb N from soil in a variety of inorganic and organic forms; however, the energy and thus carbohydrate requirements for uptake and assimilation of N vary with N source. We studied the importance of current photoassimilates for the acquisition and allocation of different N sources by Scots pine (Pinus sylvestris (L.)) seedlings. Girdling was used as a tool to impair phloem transport of photoassimilates, and hence gradually deprive roots of carbohydrates. Seedlings were cultivated in a greenhouse on equimolar N concentrations of one of the N sources-arginine, ammonium or nitrate-and then girdled prior to a pulse-chase uptake experiment with isotopically labeled N sources. Girdling proved to be efficient in decreasing levels of soluble sugars and starch in the roots. Uptake rate of arginine N was highest, intermediate for ammonium N and lowest for nitrate N. Moreover, the uptake of arginine N was unaffected by girdling, while the uptake of the two inorganic N sources decreased to 45-56% of the ungirdled controls. In arginine-treated seedlings, 95-96% of the acquired arginine N resided in the roots, whereas a significant shift in the N distribution toward the shoot was evident in girdled seedlings treated with inorganic N. This spatial shift was especially pronounced in nitrate-treated seedlings suggesting that the reduction and following incorporation into roots was limited by the availability of current photoassimilates. These results suggest that there are energetic benefits for seedlings to utilize organic N sources, particularly under circumstances where carbohydrate supply is limited. Hence, these putative benefits might be of importance for the survival and growth of seedlings when carbohydrate reserves are depleted in early growing season, or in light-limited environments, such as those sustained by continuous cover forestry systems.


Rehabilitation from sports injuries: from theory to practice.
A great number of injuries occur in the context of recreational physical activities and competitive athletics. Adherence to sport injury rehabilitation means an injured athlete's compliance (or not) to a sports medicine/injury personnel's instructions of participating in a rehabilitation programme in a clinic, and/or doing rehabilitation exercises at home. It has emerged as an area of interest among physiotherapists and other allied professionals (i.e. sport trainers, physicians). This article reviews compliance among injured athletes in the recovery process by presenting the protection motivation theory, personal investment theory and models of cognitive appraisal. Also it reviews key research findings about these three theoretical models. In addition practical guidelines and specific strategies are offered to sport injury rehabilitation personnel to enhance an athlete's adherence to injury rehabilitation. Sports medicine/injury personnel should educate athletes about their injuries and rehabilitation and increase effective communication and active listening. Also sports medicine/injury personnel should provide social support and encourage positive beliefs of injured athletes. In addition, coping with pain and setting short-term goals help athletes to increase their compliance to programmes of rehabilitation.


Concentration dependence of translational diffusion coefficients for globular proteins.
This investigation examines published results of traditional diffusion experiments on ovalbumin and bovine serum albumin to determine the extent to which assumed concentration independence of the translational diffusion coefficient is a reasonable approximation in the analysis of boundary spreading in sedimentation velocity experiments on proteins. Although significant positive concentration dependence of the diffusion coefficient (D) for both proteins is predicted by current theories, none has been detected in these experimental diffusion studies performed under the constraints of constant temperature and solvent chemical potential (those also pertinent to sedimentation velocity). Instead, the results are better described by the relatively minor concentration dependence predicted by considering solution viscosity to be an additional source of D-c dependence. Inasmuch as the predicted variation in D for solutions with concentrations below 10 mg mL(-1) is within the uncertainty of experimental estimates, these findings support use of the approximate solution of the Lamm equation developed by Fujita for the quantitative analysis of boundary spreading in sedimentation velocity experiments on proteins.


Entropic splitter for particle separation.
We present a particle separation mechanism which induces the motion of particles of different sizes in opposite directions. The mechanism is based on the combined action of a driving force and an entropic rectification of the Brownian fluctuations caused by the asymmetric form of the channel along which particles proceed. The entropic splitting effect shown could be controlled upon variation of the geometrical parameters of the channel and could be implemented in narrow channels and microfluidic devices.


Characterization of the non-native trifluoroethanol-induced intermediate conformational state of the Shiga toxin B-subunit.
The effect of increasing concentrations of 2,2,2-trifluoroethanol (TFE) on the conformational stability of the Shiga toxin B-subunit (STxB), a bacterial homopentameric protein involved in cell-surface binding and intracellular transport, has been studied by far-, near-UV circular dichroism (CD), intrinsic fluorescence, analytical ultracentrifugation, and differential scanning calorimetry (DSC) under equilibrium conditions. Our data show that the native structure of STxB is highly perturbed by the presence of TFE. In fact, at concentrations of TFE above 20% (v/v), the native pentameric conformation of the protein is cooperatively transformed into a helix-rich monomeric and partially folded conformational state with no significant tertiary structure. Additionally, no cooperative transition was detected upon a further increase in the TFE concentration (above 40% (v/v)). The thermal stability of STxB was investigated at several different TFE concentrations using DSC and CD spectroscopy. Thermal transitions at TFE concentrations of up to 20% (v/v) were successfully fitted to the two-state folding/unfolding coupled to oligomerization model consistent with the transition between a pentameric folded conformation to a monomeric state of the protein, which the presence of TFE stabilizes as a partially folded conformation.


Short communication: Relationships between physical form of oats in starter, rumen pH, and volatile fatty acids on hepatic expression of genes involved in metabolism and inflammation in dairy calves.
In early-weaning programs, dietary effects on calf rumen development have been studied extensively, but very little information is available about the effects of a solid diet on hepatic metabolism in preweaned dairy calves. The objective of this experiment was to determine the effect of physical form of oats in calf starter on the expression of key hepatic gluconeogenic, β-oxidation, and acute phase protein genes in preweaned dairy calves. Samples were analyzed from 3 experiments that fed either ground or whole oats in calf starters. Briefly, 7 calves were slaughtered at 5 wk of age in experiment 1, 6 were slaughtered at 6 wk in experiment 2, and 7 were slaughtered at 7 wk in experiment 3, and liver tissue was collected for gene expression analysis. Calves from experiments 1 and 2 were cannulated, and their rumen pH and volatile fatty acids were measured during treatment periods. The mRNA expression of gluconeogenic enzymes pyruvate carboxylase (PC), cytosolic and mitochondrial phosphoenolpyruvate carboxykinase (PCK1 and PCK2), fatty acid oxidation enzyme carnitine palmitoyltransferase I (CPT1), and positive acute phase protein haptoglobin (HPT) was measured by real-time quantitative reverse-transcriptase PCR. Expression of HPT was greater in calves fed whole oats than in calves fed ground oats; however, PC, PCK1, PCK2, and CPT1 were not affected by the physical form of oats. All enzymes (PCK1, PCK2, HPT, and CPT1) except PC were affected by experiment; PCK1 and CPT1 had greater expression in experiment 2 than in experiments 1 and 3. Expression of PCK2 was similar in experiments 2 and 3 but greater than experiment 1. Expression of HPT was similar in experiments 1 and 2 but greater than experiment 3. The mRNA expression of enzymes PCK1, PCK2, and CPT1 differed between experiments 1 and 2 and was negatively correlated with rumen propionate and butyrate but had a positive relationship with rumen acetate. Similarly, rumen pH was different in experiments 1 and 2, averaging 5.69 in experiment 1 and 4.81 in experiment 2, and there was a negative correlation between mRNA expression of rate-limiting gluconeogenic PCK1, PCK2, and β-oxidation CPT1 enzymes and rumen pH of calves in experiments 1 and 2. We concluded that the physical form of oats in calf starter did not affect gene expression of gluconeogenic and β-oxidation enzymes in preweaned dairy calves. However, lower rumen pH may be related to the upregulation of these enzymes.


Differential effects of hypothalamic long-chain fatty acid infusions on suppression of hepatic glucose production.
Our objective was to investigate whether the direct bilateral infusion of the monounsaturated fatty acid (MUFA) oleic acid (OA) within the mediobasal hypothalamus (MBH) is sufficient to reproduce the effect of administration of OA (30 nmol) in the third cerebral ventricle, which inhibits glucose production (GP) in rats. We used the pancreatic basal insulin clamp technique (plasma insulin ∼20 mU/ml) in combination with tracer dilution methodology to compare the effect of MBH OA on GP to that of a saturated fatty acid (SFA), palmitic acid (PA), and a polyunsaturated fatty acid (PUFA), linoleic acid (LA). The MBH infusion of 200 but not 40 pmol of OA was sufficient to markedly inhibit GP (by 61% from 12.6 ± 0.6 to 5.1 ± 1.6 mg·kg(-1)·min(-1)) such that exogenous glucose had to be infused at the rate of 6.0 ± 1.2 mg·kg(-1)·min(-1) to prevent hypoglycemia. MBH infusion of PA also caused a significant decrease in GP, but only at a total dose of 4 nmol (GP 5.8 ± 1.6 mg·kg(-1)·min(-1)). Finally, MBH LA at a total dose of 0.2 and 4 nmol failed to modify GP compared with rats receiving MBH vehicle. Increased availability of OA within the MBH is sufficient to markedly inhibit GP. LA does not share the effect of OA, whereas PA can reproduce the potent effect of OA on GP, but only at a higher dose. It remains to be determined whether SFAs need to be converted to MUFAs to exert this effect or whether they activate a separate signaling pathway to inhibit GP.


Policies for biosimilar uptake in Europe: An overview.
Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market.


Interviewing job applicants for a staff opening.
It can be very challenging to identify a potentially strong employee for your practice based upon a resume or written application alone. That is why a well-structured and carefully prepared interview is such an important part of the recruitment process. However, many interviewers have vague interview goals or do not know how to make their limited time with the applicant count. This article describes the key ingredients for a successful interview and offers practical tips for interview preparation. Sample interview questions, legal considerations, and interview follow-up tips are offered, as well as practical advice about involving members of your staff in the interview process.


The interplay between cognitive and motor functioning in healthy older adults: findings from dual-task studies and suggestions for intervention.
Reaching late adulthood is accompanied by losses in physical and mental resources, but lifestyle choices seem to have a considerable influence on the aging trajectory. This review deals with the interplay between cognitive and motor functioning in old age, focusing on two different lines of research, namely (a) dual-task studies requiring participants to perform a cognitive and a motor task simultaneously, and (b) intervention studies investigating whether increases in physical fitness also lead to improvements in cognitive performance. Dual-task studies indicate that healthy older adults show greater performance reductions in both domains than young adults when performing a cognitive and a motor task simultaneously. In addition, older adults often tend to protect their motor functioning at the expense of the cognitive task when the situation involves a threat to balance. This can be considered an adaptive behavior since fall-related injuries can have severe consequences. Fitness intervention studies which increased the aerobic fitness of previously sedentary older adults have demonstrated impressive performance improvements in the cognitive domain, especially for tasks involving executive control processes. These findings are interesting in light of cognitive intervention studies, which often fail to find significant transfer effects to tasks that have not been trained directly. The authors argue that future research should compare the effects of cognitive and aerobic fitness interventions in older adults, and they present a study design in which cognition and fitness are trained sequentially as well as simultaneously. Finally, methodological issues involved in this type of research and potential applications to applied settings are discussed.


Understanding how race/ethnicity and gender define age-trajectories of disability: an intersectionality approach.
A number of studies have demonstrated wide disparities in health among racial/ethnic groups and by gender, yet few have examined how race/ethnicity and gender intersect or combine to affect the health of older adults. The tendency of prior research to treat race/ethnicity and gender separately has potentially obscured important differences in how health is produced and maintained, undermining efforts to eliminate health disparities. The current study extends previous research by taking an intersectionality approach (Mullings & Schulz, 2006), grounded in life course theory, conceptualizing and modeling trajectories of functional limitations as dynamic life course processes that are jointly and simultaneously defined by race/ethnicity and gender. Data from the nationally representative 1994-2006 US Health and Retirement Study and growth curve models are utilized to examine racial/ethnic/gender differences in intra-individual change in functional limitations among White, Black and Mexican American Men and Women, and the extent to which differences in life course capital account for group disparities in initial health status and rates of change with age. Results support an intersectionality approach, with all demographic groups exhibiting worse functional limitation trajectories than White Men. Whereas White Men had the lowest disability levels at baseline, White Women and racial/ethnic minority Men had intermediate disability levels and Black and Hispanic Women had the highest disability levels. These health disparities remained stable with age-except among Black Women who experience a trajectory of accelerated disablement. Dissimilar early life social origins, adult socioeconomic status, marital status, and health behaviors explain the racial/ethnic disparities in functional limitations among Men but only partially explain the disparities among Women. Net of controls for life course capital, Women of all racial/ethnic groups have higher levels of functional limitations relative to White Men and Men of the same race/ethnicity. Findings highlight the utility of an intersectionality approach to understanding health disparities.


Multicenter Comparison of Lung and Oral Microbiomes of HIV-infected and HIV-uninfected Individuals.
Improved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly active antiretroviral therapy influences these microbiomes is unclear. We determined whether oral and lung microbiomes differed in clinically healthy groups of HIV-infected and HIV-uninfected subjects. Participating sites in the Lung HIV Microbiome Project contributed bacterial 16S rRNA sequencing data from oral washes and bronchoalveolar lavages (BALs) obtained from HIV-uninfected individuals (n = 86), HIV-infected individuals who were treatment naive (n = 18), and HIV-infected individuals receiving antiretroviral therapy (n = 38). Microbial populations differed in the oral washes among the subject groups (Streptococcus, Actinomyces, Rothia, and Atopobium), but there were no individual taxa that differed among the BALs. Comparison of oral washes and BALs demonstrated similar patterns from HIV-uninfected individuals and HIV-infected individuals receiving antiretroviral therapy, with multiple taxa differing in abundance. The pattern observed from HIV-infected individuals who were treatment naive differed from the other two groups, with differences limited to Veillonella, Rothia, and Granulicatella. CD4 cell counts did not influence the oral or BAL microbiome in these relatively healthy, HIV-infected subjects. The overall similarity of the microbiomes in participants with and without HIV infection was unexpected, because HIV-infected individuals with relatively preserved CD4 cell counts are at higher risk for lower respiratory tract infections, indicating impaired local immune function.


Sleep disparity, race/ethnicity, and socioeconomic position.
Sleep represents a set of biological functions necessary for the maintenance of life. Performing these functions, though, requires that an individual engage in behaviors, which are affected by social and environmental factors. Race/ethnicity and socioeconomic position represent categories of factors that likely play a role in the experience of sleep in the community. Previous studies have suggested that racial/ethnic minorities and the socioeconomically disadvantaged may be more likely to experience sleep patterns that are associated with adverse health outcomes. It is possible that disparities in sleep represent a pathway by which larger disparities in health emerge. This review (1) contextualizes the concept of race/ethnicity in biomedical research, (2) summarizes previous studies that describe patterns of sleep attainment across race/ethnicity groups, (3) discusses several pathways by which race/ethnicity may be associated with sleep, (4) introduces the potential role of socioeconomic position in the patterning of sleep, and (5) proposes future research directions to address this issue.


Psychometric validation of a multi-dimensional capability instrument for outcome measurement in mental health research (OxCAP-MH).
Patient reported outcome measures (PROMs) are widely used in mental healthcare research for quality of life assessment but most fail to capture the breadth of health and non-health domains that can be impacted. We report the psychometric validation of a novel, multi-dimensional instrument based on Amartya Sen's capability approach intended for use as an outcome measure in mental health research. The Oxford Capabilities Questionnaire for Mental Health (OxCAP-MH) is a 16-item self-complete capability measure that covers multiple domains of functioning and welfare. Data for validation of the instrument were collected through a national randomised controlled trial of community treatment orders for patients with psychosis. Complete OxCAP-MH data were available for 172 participants. Internal consistency was established with Cronbach's alpha; an interclass correlation coefficient was used to assess test-retest reliability in a sub-sample (N = 50) tested one week apart. Construct validity was established by comparing OxCAP-MH total scores with established instruments of illness severity and functioning: EuroQol (EQ-5D), Brief Psychiatric Rating Scale (BPRS), Global Assessment of Functioning (GAF) and Objective Social Outcomes Index (SIX). Sensitivity was established by calculating standard error of measurement using distributional methods. The OxCAP-MH showed good internal consistency (Cronbach's alpha 0.79) and test-retest reliability (ICC = 0.86). Convergent validity was evidenced by strong correlations with the EQ-5D (VAS 0.52, p < .001) (Utility 0.45, p < .001), and divergent validity through more modest associations with the BPRS (-0.41, p < .001), GAF (0.24, p < .001) and SIX (0.12, p = ns). A change of 9.2 points on a 0-100 scale was found to be meaningful on statistical grounds. The OxCAP-MH has demonstrable reliability and construct validity and represents a promising multi-dimensional alternative to existing patient-reported outcome measures for quality of life used in mental health research.


A genetic approach to the recruitment of PRC2 at the HoxD locus.
Polycomb group (PcG) proteins are essential for the repression of key factors during early development. In Drosophila, the polycomb repressive complexes (PRC) associate with defined polycomb response DNA elements (PREs). In mammals, however, the mechanisms underlying polycomb recruitment at targeted loci are poorly understood. We have used an in vivo approach to identify DNA sequences of importance for the proper recruitment of polycomb proteins at the HoxD locus. We report that various genomic re-arrangements of the gene cluster do not strongly affect PRC2 recruitment and that relatively small polycomb interacting sequences appear necessary and sufficient to confer polycomb recognition and targeting to ectopic loci. In addition, a high GC content, while not sufficient to recruit PRC2, may help its local spreading. We discuss the importance of PRC2 recruitment over Hox gene clusters in embryonic stem cells, for their subsequent coordinated transcriptional activation during development.


Investigating Holocene human population history in North Asia using ancient mitogenomes.
Archaeogenomic studies have largely elucidated human population history in West Eurasia during the Stone Age. However, despite being a broad geographical region of significant cultural and linguistic diversity, little is known about the population history in North Asia. We present complete mitochondrial genome sequences together with stable isotope data for 41 serially sampled ancient individuals from North Asia, dated between c.13,790 BP and c.1,380 BP extending from the Palaeolithic to the Iron Age. Analyses of mitochondrial DNA sequences and haplogroup data of these individuals revealed the highest genetic affinity to present-day North Asian populations of the same geographical region suggesting a possible long-term maternal genetic continuity in the region. We observed a decrease in genetic diversity over time and a reduction of maternal effective population size (Ne) approximately seven thousand years before present. Coalescent simulations were consistent with genetic continuity between present day individuals and individuals dating to 7,000 BP, 4,800 BP or 3,000 BP. Meanwhile, genetic differences observed between 7,000 BP and 3,000 BP as well as between 4,800 BP and 3,000 BP were inconsistent with genetic drift alone, suggesting gene flow into the region from distant gene pools or structure within the population. These results indicate that despite some level of continuity between ancient groups and present-day populations, the region exhibits a complex demographic history during the Holocene.