Postoperative nomogram for invasive bladder cancer: does it really work? A multicenter cohort study.
Nomograms are statistical models designed to maximize predictive accuracy. We have tested the statistical correlation between the predictions of International Bladder Cancer Nomogram Consortium and the clinical outcomes in a multicenter Italian cohort of patients treated with radical cystectomy (RC) and pelvic lymph-nodes dissection. Two hundred four patients who underwent RC were selected for multiple variable and then enrolled in the study. Patients were tested by the "online tool" based on the nomogram, then stratified and risk grouped for 5-year predicted disease-free survival (pDFS): low risk (67%-100%), intermediate risk (34%-66%), and high risk group (0%-33%). Receiving operating characteristic curve (ROC) quantified the area under curve (AUC) as predictive accuracy. Actual overall survival (aOS) and actual disease-free survival (aDFS) were calculated with Kaplan-Meyer analysis. Median of pDFS was compared with 5-year aDFS. AUC was 0.69 (P < 0.001). The aOS is 50% (95% confidence interval (95% CI, -7.68/+8.23) at 5-years after RC, the aDFS is 65.5% (95% CI, -7.56/+8.98). The 5-year aDFS is 75.3% (-8.82/+12.53) in low risk group; 67.3% (-12/+16.4) in intermediate risk group; 28.3% (-20/+17.2) in high risk group. The 5-year aDFS was well calculated by the nomogram but in all groups the nomogram slightly underestimated the prediction. In intermediate risk group, 5-year aDFS overscored both the nomogram pDFS and the pDFS range of this group (34%-66%). In all patients investigated, the pDFS was 65%, a value close to the 5-year aDFS found (65.6%). Statistical correlation between postoperative nomogram prediction and the clinical reality was observed.


Epitope mapping of broadly neutralizing HIV-2 human monoclonal antibodies.
Recent studies have shown that natural infection by HIV-2 leads to the elicitation of high titers of broadly neutralizing antibodies (NAbs) against primary HIV-2 strains (T. I. de Silva, et al., J. Virol. 86:930-946, 2012; R. Kong, et al., J. Virol. 86:947-960, 2012; G. Ozkaya Sahin, et al., J. Virol. 86:961-971, 2012). Here, we describe the envelope (Env) binding and neutralization properties of 15 anti-HIV-2 human monoclonal antibodies (MAbs), 14 of which were newly generated from 9 chronically infected subjects. All 15 MAbs bound specifically to HIV-2 gp120 monomers and neutralized heterologous primary virus strains HIV-2(7312A) and HIV-2(ST). Ten of 15 MAbs neutralized a third heterologous primary virus strain, HIV-2(UC1). The median 50% inhibitory concentrations (IC(50)s) for these MAbs were surprisingly low, ranging from 0.007 to 0.028 μg/ml. Competitive Env binding studies revealed three MAb competition groups: CG-I, CG-II, and CG-III. Using peptide scanning, site-directed mutagenesis, chimeric Env constructions, and single-cycle virus neutralization assays, we mapped the epitope of CG-I antibodies to a linear region in variable loop 3 (V3), the epitope of CG-II antibodies to a conformational region centered on the carboxy terminus of V4, and the epitope(s) of CG-III antibodies to conformational regions associated with CD4- and coreceptor-binding sites. HIV-2 Env is thus highly immunogenic in vivo and elicits antibodies having diverse epitope specificities, high potency, and wide breadth. In contrast to the HIV-1 Env trimer, which is generally well shielded from antibody binding and neutralization, HIV-2 is surprisingly vulnerable to broadly reactive NAbs. The availability of 15 human MAbs targeting diverse HIV-2 Env epitopes can facilitate comparative studies of HIV/SIV Env structure, function, antigenicity, and immunogenicity.


High Photoresponsivity in Ultrathin 2D Lateral Graphene:WS2:Graphene Photodetectors Using Direct CVD Growth.
We show that reducing the degree of van der Waals overlapping in all 2D ultrathin lateral devices composed of graphene:WS2:graphene leads to significant increase in photodetector responsivity. This is achieved by directly growing WS2 using chemical vapor deposition (CVD) in prepatterned graphene gaps to create epitaxial interfaces. Direct-CVD-grown graphene:WS2:graphene lateral photodetecting transistors exhibit high photoresponsivities reaching 121 A/W under 2.7 × 105 mW/cm2 532 nm illumination, which is around 2 orders of magnitude higher than similar devices made by the layer-by-layer transfer method. The photoresponsivity of our direct-CVD-grown device shows negative correlation with illumination power under different gate voltages, which is different from similar devices made by the transfer method. We show that the high photoresponsivity is due to the lowering of effective Schottky barrier height by improving the contact between graphene and WS2. Furthermore, the direct CVD growth reduces overlapping sections of WS2:Gr and leads to more uniform lateral systems. This approach provides insights into scalable manufacturing of high-quality 2D lateral electronic and optoelectronic devices.


Sealed-cell mercury resonance ionization imaging detector.
A sealed, compact mercury atomic-absorption resonance ionization imaging detector has been developed and evaluated. The sensitivity of the detector as well as its ability to form two-dimensional images has been demonstrated. Images of faint light (1000 photons) have been recorded by image summation. It is shown that one can obtain high-quality images with a spatial resolution of at least 130 mum by detecting the ionic component of the imaging signal. Distortion, more noise, and poorer spatial resolution were observed when the electron component of the signal was detected. We studied the influence of voltage on the cell electrodes to find the conditions for optimum signal-to-noise ratio.


Pediatric outpatient utilization by differing Medicaid payment models in the United States.
In the United States (US), Medicaid capitated managed care costs are controlled by optimizing patients' healthcare utilization. Adults in capitated plans utilize primary care providers (PCP) more than emergency departments (ED), compared to fee-for-service (FFS). Pediatric data are lacking. We aim to determine the association between US capitated and FFS Medicaid payment models and children's outpatient utilization. This retrospective cohort compared outpatient utilization between two payment models of US Medicaid enrollees aged 1-18 years using Truven's 2014 Marketscan Medicaid database. Children enrolled > 11 months were included, and were excluded for eligibility due to disability/complex chronic condition, lack of outpatient utilization, or provider capitation penetration rate < 5% or > 95%. Negative binomial and logistic regression assessed relationships between payment model and number of visits or odds of utilization, respectively. Of 711,008 children, 66,980(9.4%) had FFS and 644,028(90.6%) had capitated plans. Children in capitated plans had greater odds of visits to urgent care, PCP-acute, and PCP-well-child care (aOR 1.21[95%CI 1.15-1.26]; aOR 2.07[95%CI 2.03-2.13]; aOR 1.86 [95%CI 1.82-1.91], respectively), and had lower odds of visits to EDs and specialty care (aOR 0.82 [95%CI 0.8-0.83]; aOR 0.61 [95%CI 0.59-0.62], respectively), compared to FFS. The majority of children in this US Medicaid population had capitated plans associated with higher utilization of acute care, but increased proportion of lower-cost sites, such as PCP-acute visits and UC. Health insurance programs that encourage capitated payment models and care through the PCP may improve access to timely acute care in lower-cost settings for children with non-complex chronic conditions.


Hypertonic saline solution for renal failure prevention in patients with decompensated heart failure.
Hyponatremia and congestive phenomena indicate a bad prognosis in decompensated heart failure. The occurrence of renal failure is associated to an increased death risk. To evaluate the safety and efficacy of the hypertonic saline solution in patients with decompensated heart failure for renal failure prevention. Patients with decompensated heart failure, congestion and hyponatremia participated in the study. In addition to the standard treatment, the patients received hypertonic saline solution and were submitted to clinical as well as laboratory assessment. Nine patients were enrolled in the study. Mean age was 55 + 14.2 years, being 5 male (55.5%) and 4 (44.5%) female patients. All of them presented functional class III-IV of the New York Heart Association (NYHA), and 5 (55.5%) received dobutamine. All of them presented initial creatinine > 1.4 mg/dl. The mean tonicity of the solution was 4.39% + 0.018% (2.5% to 7.5%) and the duration of treatment was 4.9 days + 4.1 days (1-15 days). There were no severe adverse effects; none of the patients presented clinical worsening or neurologic disorders; hypokalemia occurred in 4 cases (44.5%). The comparison of the variables before and after treatment showed a decrease in urea (105 mg/dl + 74.8 mg/dl vs. 88 mg/dl + 79.4 mg/dl; p = 0.03) and increase in the urinary volume (1,183 ml/day vs. 1,778 ml/day; p = 0.03); there was no tendency to creatinine decrease (2.0 mg/dl + 0.8 mg/dl vs. 1.7 mg/dl + 1.0 mg/dl; p = 0.08). Despite the elevation in sodium levels (131 mEq/l + 2.8 mEq/l vs. 134 mEq/l + 4.9 mEq/l) and weight decrease (69.5 kg + 18.6 kg vs. 68.2 kg + 17.1 kg), there was no statistically significant difference. The use of hypertonic saline solution in patients with decompensated heart failure can be a safe therapeutic method and potentially related to clinical improvement and renal failure prevention.


Acceptance of SARS-CoV-2 vaccination and the associated factors among dental health care professionals: A cross-sectional survey.
One of the greatest inventions of the 21st century is the development of vaccines against the life-threatening pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whenever a new medication or treatment modality is introduced globally, it is accompanied by anxiety in the general public and among health care professionals. The aim of the study was to explore factors that may influence the acceptance of COVID-19 vaccination among dental health care professionals, as they are the first subgroup in the population to receive the vaccine. A survey-based cross-sectional study was conducted on 164 health care professionals (general dentists, dental specialists with 2 years of experience after graduation and dental assistants). Data was collected by sending a URL link to the hardand soft-copy questionnaire on Google Forms through all social media platforms. The questionnaire had 2 sections - the 1st part concerned the demographic details and the 2nd part was designed to assess the acceptance of SARS-CoV-2 vaccination among dental health care professionals and the related factors. The normality of the data was assessed with the Shapiro-Wilk test. The Cox regression algorithm was applied to evaluate the factors associated with the acceptance of SARS-CoV-2 vaccination. Out of 164 participants, 85.37% showed a positive attitude toward vaccination and only 7.32% of dental health care professionals were not willing to get vaccinated; out of them, 5 were males and 7 were females. Those who refused to get vaccinated included 3.6% of general dentists, 21.1% of dental specialists and 11.7% of dental assistants. The complications of major concern were fever, myalgia and the lethargic condition immediately after vaccination. A small percentage of health care professionals declined to get vaccinated against COVID-19 and the main reason was uncertainty about the associated side effects. The respondents were mostly concerned about such side effects as fever, myalgia and the lethargic condition immediately after vaccination.


Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors.
Metastatic dissemination of cancer cells from the primary tumor and their spread to distant sites in the body is the leading cause of mortality in breast cancer patients. While researchers have identified treatments that shrink or slow metastatic tumors, no treatment that permanently eradicates metastasis exists at present. Here, we show that the ABL kinase inhibitors imatinib, nilotinib, and GNF-5 impede invadopodium precursor formation and cortactin-phosphorylation dependent invadopodium maturation, leading to decreased actin polymerization in invadopodia, reduced extracellular matrix degradation, and impaired matrix proteolysis-dependent invasion. Using a mouse xenograft model we demonstrate that, while primary tumor size is not affected by ABL kinase inhibitors, the in vivo matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs are significantly impaired in inhibitor-treated mice. Further proteogenomic analysis of breast cancer patient databases revealed co-expression of the Abl-related gene (Arg) and cortactin across all hormone- and human epidermal growth factor receptor 2 (HER2)-receptor status tumors, which correlates synergistically with distant metastasis and poor patient prognosis. Our findings establish a prognostic value for Arg and cortactin as predictors of metastatic dissemination and suggest that therapeutic inhibition of ABL kinases may be used for blocking breast cancer metastasis.


Workup and indications for polysomnography in patients with sleep-related complaints.
A significant proportion of the population has chronic sleep problems necessitating an increasing involvement by the primary care physician. Also, the general patient population is becoming more familiar with these disorders and is seeking assistance. Because sleep studies are expensive and time consuming, adhering to the recognized indications for testing reduces the number of inappropriate studies. Under most circumstances, individuals with excessive daytime sleepiness and symptoms suggestive of obstructive sleep apnea are candidates for polysomnography. Other individuals with parasomnias or difficult-to-treat insomnia are also candidates for testing. In some circumstances, procedures designed to assess sleepiness may also need to be used to ascertain the impact of the disorder on daytime functioning and may be part of evaluations involving the transportation industry. Only after taking a thorough history and doing a physical examination can the physician make an accurate determination of the appropriate study type.


Regulators encoded in the Escherichia coli type III secretion system 2 gene cluster influence expression of genes within the locus for enterocyte effacement in enterohemorrhagic E. coli O157:H7.
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 subverts host cells through a type III secretion system encoded by the locus for enterocyte effacement (LEE). Genome sequencing of this pathotype revealed the existence of a gene cluster encoding components of a second cryptic type III secretion system, E. coli type III secretion system 2 (ETT2). Recently, we showed that the ETT2 gene cluster is present in whole or in part in the majority of E. coli strains but is unable to encode a functional secretion system in most strains, including EHEC O157:H7. However, here we show that mutational inhibition of two regulatory genes (ECs3720 or etrA and ECs3734 or eivF) from the ETT2 cluster in EHEC O157:H7 leads to greatly increased secretion of proteins encoded by the LEE and to increased adhesion to human intestinal cells. Studies in which transcriptional fusions and microarrays were used indicated that EtrA and EivF exert profound negative effects on gene transcription within the LEE. Consistent with these observations, expression of these regulators in an EHEC O26:H- strain led to suppression of protein secretion under LEE-inducing conditions. These findings provide fresh examples of the influence of mobile genetic elements on regulation of the LEE and of cross talk between type III secretion system gene clusters. In addition, they provide a cautionary tale because they show that the effects of regulatory genes can outlive widespread decay of other genes in a functionally coherent gene cluster, a phenomenon that we have named the "Cheshire cat effect." It also seems likely that variations in the ETT2 regulator repertoire might account for strain-to-strain variation in secretion of LEE-encoded proteins.


Recorded quadrant incidence of female breast cancer in Great Britain suggests a disproportionate increase in the upper outer quadrant of the breast.
The upper outer quadrant (UOQ) of the breast is the most frequent site for incidence of breast cancer, but the reported disproportionate incidence in this quadrant appears to rise with year of publication. In order to determine whether this increasing incidence in the UOQ is an artifact of different study populations or is chronological, data have been analysed for annual quadrant incidence of female breast cancer recorded nationally in England and Wales between 1979 and 2000 and in Scotland between 1980 and 2001. In England and Wales, the recorded incidence of female breast cancer in the UOQ rose from 47.9% in 1979 to 53.3% in 2000, and has done so linearly over time with a correlation coefficient R of +0.71 +/- SD 0.01 (p < 0.001). Analysis of independent data from Scotland showed a similar trend in that recorded female breast cancer had also increased in the UOQ from 38.3% in 1980 to 54.7% in 2001, with a correlation coefficient R for the linear annual increase of +0.80 +/- SD 0.03 (p < 0.001). These results are inconsistent with current views that the high level of UOQ breast cancer is due solely to a greater amount of target epithelial tissue in that region. Identification of the reasons for such a disproportionate site-specific increase could provide clues as to causative factors in breast cancer.


Construction and expression of a chimeric gene encoding human terminal deoxynucleotidyltransferase and DNA polymerase beta.
A domain substitution experiment was carried out between the structurally related DNA-polymerizing enzymes Pol beta and TdT to investigate the region of Pol beta required for template utilization. Site-directed mutagenesis and recombinant DNA procedures were used for construction of a gene encoding a chimeric form of the two enzymes and termed TDT::POLB, in which the DNA region encoding amino acids (aa) 154-212 of TdT was replaced by the corresponding region encoding aa 1-60 of POL beta. The construction was confirmed by restriction analysis and DNA sequencing. Since this region of POL beta represents most of the N-terminal domain of the enzyme possessing single-stranded DNA (ssDNA)-binding activity, it was hypothesized that the chimeric protein, unlike TdT, might possess template-dependent DNA polymerase activity. The chimeric gene product was produced in Escherichia coli, purified and subjected to preliminary enzymological characterization. The finding that the chimeric TdT::Pol beta protein possessed significant template-dependent polymerase activity suggests that aa 1-60 of Pol beta are involved in template utilization during the polymerization reaction, as suggested by the previous finding that the 8-kDa N-terminal domain of Pol beta possesses ssDNA-binding activity [Kumar et al., J. Biol. Chem. 265 (1990a) 2124-2131; Kumar et al., Biochemistry 29 (1990b) 7156-7159; Prasad et al., J. Biol. Chem. 268 (1993) 22746-22755].


The World report on ageing and health: a policy framework for healthy ageing.
Although populations around the world are rapidly ageing, evidence that increasing longevity is being accompanied by an extended period of good health is scarce. A coherent and focused public health response that spans multiple sectors and stakeholders is urgently needed. To guide this global response, WHO has released the first World report on ageing and health, reviewing current knowledge and gaps and providing a public health framework for action. The report is built around a redefinition of healthy ageing that centres on the notion of functional ability: the combination of the intrinsic capacity of the individual, relevant environmental characteristics, and the interactions between the individual and these characteristics. This Health Policy highlights key findings and recommendations from the report.


45,X product of conception after preimplantation genetic diagnosis and euploid embryo transfer: evidence of a spontaneous conception confirmed by DNA fingerprinting.
Preimplantation genetic screening (PGS) provides an opportunity to eliminate a potential implantation failure due to aneuploidy in infertile couples. Some studies clearly show that twins following single embryo transfer (SET) can be the result of a concurrent natural conception and an incidence as high as 1 in 5 twins has been reported. In our case PGS was performed on trophectoderm (TE) biopsies by quantitative polymerase chain reaction (qPCR). The product of conception (POC) was cytogenetically investigated after selection of the placental villi by means of the direct method. Molecular cytogenetic characterization of the POC was performed by fluorescence in situ hybridization (FISH) and array-comparative genomic hybridization (a-CGH) analyses. To investigate the possibility of a spontaneous conception, a panel of 40 single nucleotide polymorphisms (SNPs) was used to compare genetic similarity between the DNA of the POC and the DNA leftover of the TE biopsy. We describe a 36-year old infertile woman undergoing PGS who had a spontaneous abortion after a single euploid embryo transfer on a spontaneous cycle. The POC showed a 45,X karyotype confirmed by FISH and a-CGH. DNA fingerprinting demonstrated a genetic similarity of 75 % between the DNA of the POC and TE biopsy, consistent with a sibling status. All supernumerary euploid embryos were also tested showing a non-self relationship with the POC, excluding a mix-up event at the time of fetal embryo transfer. DNA fingerprinting of the transferred blastocyst and POC, confirmed the occurrence of a spontaneous conception. This case challenges the assumption that a pregnancy after assisted reproductive technology (ART) is always a result of ART, and strengthens the importance to avoid intercourses during PGS and natural transfer cycles. Moreover, cytogenetic analysis of the POCs is strongly recommended along with fingerprinting children born after PGS to see what the concordance is between the embryo transferred and the resultant child.


Multiple imputation using an iterative hot-deck with distance-based donor selection.
Hot-deck imputation offers advantages in reflecting salient features of data distributions in missing-data problems, but previous implementations have lacked the appeal associated with modern Bayesian statistical-computing techniques. We outline a strategy of iterative hot-deck multiple imputation with distance-based donor selection. With distance defined as a monotonic function of the difference in predictive means between cases, donors are chosen with probability inversely proportional to their distance from the donee. This method retains the implementation ease of ad hoc techniques, while incorporating the desirable features of Bayesian approaches. Special cases of our method include nearest-neighbor imputation and a simple random hot-deck. Iterating the procedure provides an analogy to Markov Chain Monte Carlo methods and is intended to mitigate dependence on starting values. Results from imputing missing values in a longitudinal depression treatment trial as well as a simulation study are presented. We evaluate how different definitions of distance, choices of starting values, the order in which variables are chosen for imputation, and the number of iterations impact inferences. We show that our measure of distance controls the tradeoff between bias and variance of our estimates. We find that inferences from the depression treatment trial are not sensitive to most definitions of distance. In addition, while differences exist between 1 iteration and 10 iterations, there are no meaningful differences between inferences based on 10 iterations and those based on 500 iterations. The choice of starting value did not have an impact on inferences but the order in which the variables were chosen for imputation was significant even after iteration.


Molecular alterations underlying eosinophilic and mast cell malignancies.
Eosinophilic and mast cell disorders are uncommon hematologic entities, but they can carry significant morbidity and lead to devastating end-organ sequelae. In the past ten years, extensive work has led to the discovery of certain molecular abnormalities underlying a subset of these diseases. A significant minority of patients with clonal eosinophilia carry abnormal gene fusions involving PDGFRA, PDGFRB, and FGFR1. These findings have been quite significant, as those individuals with a FIP1L1-PDGFRA fusion have an exquisite susceptibility to tyrosine kinase inhibitors (TKIs), such as imatinib mesylate. Imatinib leads to a rapid remission in these patients and aborts the clinical trajectory of the disease. Unfortunately, TKIs have not been shown to be particularly active in the case of mastocytosis, although the majority of patients with mastocytosis carry a c-KIT alteration, a target of agents such as imatinib. The reason for this decreased sensitivity to TKIs is related to the resistance of the D816V variant of c-KIT, found in the majority of patients with mastocytosis. Nevertheless, investigation is ongoing to define new molecular lesions in these diseases, and potentially new targets for therapy. Clinical trials are also investigating other novel small molecules that may have efficacy against targets currently resistant to imatinib and other TKIs.


Health coaching by telephony to support self-care in chronic diseases: clinical outcomes from The TERVA randomized controlled trial.
The aim was to evaluate the effect of a 12-month individualized health coaching intervention by telephony on clinical outcomes. An open-label cluster-randomized parallel groups trial. Pre- and post-intervention anthropometric and blood pressure measurements by trained nurses, laboratory measures from electronic medical records (EMR). A total of 2594 patients filling inclusion criteria (age 45 years or older, with type 2 diabetes, coronary artery disease or congestive heart failure, and unmet treatment goals) were identified from EMRs, and 1535 patients (59%) gave consent and were randomized into intervention or control arm. Final analysis included 1221 (80%) participants with data on primary end-points both at entry and at end. Primary outcomes were systolic and diastolic blood pressure, serum total and LDL cholesterol concentration, waist circumference for all patients, glycated hemoglobin (HbA1c) for diabetics and NYHA class in patients with congestive heart failure. The target effect was defined as a 10-percentage point increase in the proportion of patients reaching the treatment goal in the intervention arm. The proportion of patients with diastolic blood pressure initially above the target level decreasing to 85 mmHg or lower was 48% in the intervention arm and 37% in the control arm (difference 10.8%, 95% confidence interval 1.5-19.7%). No significant differences emerged between the arms in the other primary end-points. However, the target levels of systolic blood pressure and waist circumference were reached non-significantly more frequently in the intervention arm. Individualized health coaching by telephony, as implemented in the trial was unable to achieve majority of the disease management clinical measures. To provide substantial benefits, interventions may need to be more intensive, target specific sub-groups, and/or to be fully integrated into local health care. ClinicalTrials.gov Identifier: NCT00552903.


Carotid stiffness is associated with incident stroke: a systematic review and individual participant data meta-analysis.
Carotid stiffening is considered a key element in the pathogenesis of stroke. However, results of studies evaluating the association between carotid stiffness and incident stroke have been inconsistent. This study investigated whether carotid stiffness (as determined by ultrasonography) is associated with incident stroke and whether this association is independent of aortic stiffness as estimated by carotid-femoral pulse wave velocity (cfPWV). Additionally, we evaluated the incremental value of carotid stiffness for stroke risk prediction beyond Framingham risk factors and cfPWV. This study included a systematic review and meta-analyses of aggregate and individual participant data (IPD), the latter of which was obtained by requesting individual-level data of all cohort studies with available data on carotid stiffness and cfPWV. Ten studies (n = 22,472) were included in the aggregate data meta-analysis and 4 (n = 4,540) in the IPD meta-analysis. After adjusting for cardiovascular (CV) factors, the aggregate data meta-analysis showed that greater carotid stiffness (per SD) was associated with stroke (hazard ratio: 1.18; 95% confidence interval: 1.05 to 1.33). In addition, carotid stiffness was associated with total CV events and CV and all-cause mortality, but not with coronary heart disease events. In the IPD meta-analysis, additional adjustment for cfPWV did not materially change these associations. Carotid stiffness did improve stroke risk prediction beyond Framingham and cfPWV (integrative discrimination improvement: 0.4 percentage point [95% confidence interval: 0.1 to 0.6 percentage point] and continuous net reclassification improvement: 18.6% [95% confidence interval: 5.8% to 31.3%]). Carotid stiffness is associated with incident stroke independently of CV factors and aortic stiffness. In addition, carotid stiffness improves stroke risk prediction beyond Framingham and aortic stiffness.


Chemopotentiation by PARP inhibitors in cancer therapy.
Poly(ADP-ribose) polymerases (PARP) constitute a family of enzymes involved in the regulation of many cellular processes such as DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability. Among the 18 members identified so far, PARP-1 and PARP-2 are the only proteins stimulated by DNA strand breaks and implicated in the repair of DNA injury. Therefore, these molecules have been exploited as potential targets for the development of pharmacological strategies to increase the antitumor efficacy of chemotherapeutic agents, which induce DNA damage. PARP inhibitors have been shown to restore sensitivity of resistant tumors to methylating agents or topoisomerase I inhibitors, drugs presently used for the treatment of primary and secondary brain tumors or malignancies refractory to standard chemotherapy. Interestingly, PARP inhibitors may also provide protection from the untoward effects exerted by certain anticancer drugs, which cause oxidative stress and consequent PARP overactivation. The aim of this article is to provide a brief overview of the recent literature on preclinical studies with the specific and potent inhibitors newly synthesized.


Mental Health Policy in Brazil: federal expenditure evolution between 2001 and 2009.
To analyze the evolution of estimates of federal spending in Brazil's Mental Health Program since the promulgation of the national mental health law. The total federal outlay of the Mental Health Program and its components of hospital and extra-hospital expenses were estimated based on 21 expenses categories from 2001 to 2009. The expenses amount was updated to values in reais of 2009 by means of the use of the Índice de Preços ao Consumidor Amplo (Broad Consumer Price Index). The per capita/year value of the federal expenditure on mental health was calculated. The outlay on mental health rose 51.3% in the period. The breakdown of the expenditures revealed a significant increase in the extra-hospital value (404.2%) and a decrease in the hospital one (-39.5%). The per capita expenditures had a lower, but still significant, growth (36.2%). The historical series of the disaggregated per capita expenditures showed that in 2006, for the first time, the extra-hospital expenditure was higher than the hospital one. The extra-hospital per capita value increased by 354.0%; the per capita hospital value decreased by 45.5%. There was a significant increase in federal outlay on mental health between 2001 and 2009 and an expressive investment in extra-hospital actions. From 2006 onwards, resources allocation was shifted towards community services. The funding component played a crucial role as the inducer of the change of the mental health care model. The challenge for the coming years is maintaining and increasing the resources for mental health in a context of underfunding of the National Health System.


Avoiding sedation in research MRI and spectroscopy in infants: our approach, success rate and prevalence of incidental findings.
Performing magnetic resonance investigations in a paediatric population can be difficult; image acquisition is commonly complicated by movement artefact and non-compliance. Sedation is widely used for clinically indicated investigations, but there is controversy when used for research imaging. Over a 10-year period we have performed whole body MRI on over 450 infants and hepatic magnetic resonance spectroscopy on over 270 infants. These investigations have been accomplished without the use of sedation in infants up to 3 months of age. Our overall success rate in achieving good quality images free of movement artefact is 94%. The prevalence of incidental findings on whole body (excluding brain) MRI in our cohort was 0.8%. We conclude that the use of sedation for research MRI in this group is not necessary. Our approach to MRI in infancy is also described.


Differences between Dorsal and Ventral Striatum in the Sensitivity of Tonically Active Neurons to Rewarding Events.
Within the striatum, cholinergic interneurons, electrophysiologically identified as tonically active neurons (TANs), represent a relatively homogeneous group in terms of their functional properties. They display typical pause in tonic firing in response to rewarding events which are of crucial importance for reinforcement learning. These responses are uniformly distributed throughout the dorsal striatum (i.e., motor and associative striatum), but it is unknown, at least in monkeys, whether differences in the modulation of TAN activity exist in the ventral striatum (i.e., limbic striatum), a region specialized for processing of motivational information. To address this issue, we examined the activity of dorsal and ventral TANs in two monkeys trained on a Pavlovian conditioning task in which a visual stimulus preceded the delivery of liquid reward by a fixed time interval. We found that the proportion of TANs responding to the stimulus predictive of reward did not vary significantly across regions (58%-80%), whereas the fraction of TANs responding to reward was higher in the limbic striatum (100%) compared to the motor (65%) and associative striatum (52%). By examining TAN modulation at the level of both the population and the individual neurons, we showed that the duration of pause responses to the stimulus and reward was longer in the ventral than in the dorsal striatal regions. Also, the magnitude of the pause was greater in ventral than dorsal striatum for the stimulus predictive of reward but not for the reward itself. We found similar region-specific differences in pause response duration to the stimulus when the timing of reward was less predictable (fixed replaced by variable time interval). Regional variations in the duration and magnitude of the pause response were transferred from the stimulus to reward when reward was delivered in the absence of any predictive stimulus. It therefore appears that ventral TANs exhibit stronger responses to rewarding stimuli, compared to dorsal TANs. The high proportion of responsive neurons, combined with particular response features, support the notion that the ventral TAN system can be driven by specific synaptic inputs arising from afferent sources distinct from those targeting the dorsal TAN system.


Experimental demonstration of novel end-pumping method for double-clad fiber devices.
We present experimental demonstration of an end-pumping scheme based on splicing the multimode pump and single-mode signal fibers directly to a double-clad fiber with a tailored cross section. The method is used to pump a double-clad, erbium- and ytterbium-doped, fiber ring laser. The efficiency of the end-pumping method is tested by determining the slope efficiencies of the fiber ring laser and the fiber laser in a Fabry-Perot configuration. Comparable slope efficiencies are found when both laser configurations have similar output coupler ratios. The developed pumping scheme and double-clad fiber can find applications in cost-effective power fiber amplifiers and lasers.


Improving the catalytic properties of immobilized Lecitase via physical coating with ionic polymers.
Lecitase Ultra has been immobilized on cyanogen bromide agarose (via covalent attachment) and on octyl agarose (via physical adsorption on the hydrophobic support by interfacial activation). Both immobilized preparations have been incubated in dextran sulfate (DS) or polyethylenimine (PEI) solutions to coat the enzyme surface. Then, the activity versus different substrates and under different experimental conditions was evaluated. The PEI coating generally produced a significant increase in enzyme activity, in some cases even by more than a 30-fold factor (using the octyl-Lecitase at pH 5 in the hydrolysis of methyl phenyl acetate). In opposition, the DS coating usually produced some negative effects on the enzyme activity. The rate of irreversible inhibition of the covalent preparation using diethyl p-nitrophenylphosphate did not increase after PEI coating suggesting that the increase in Lecitase activity is not a consequence of the stabilization of the open form of Lecitase. Moreover, the coating greatly increased the stability of the immobilized Lecitase, for example using DS and the covalent preparation, the half-life was increased by a 30-fold factor in 30% acetonitrile. The stabilizing effect was not found in all cases, in certain cases even a certain destabilization is found (e.g., octyl-Lecitase-DS at pH 7). Thus, the effects of the ionic polymer coating strongly depend on the substrate, experimental conditions and immobilization technique employed.


Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease.
This study determined the location and tissue density of cells immunoreactive for tumour necrosis factor alpha (TNF alpha) in intestinal specimens from 24 patients with chronic inflammatory bowel disease (15 with Crohn's disease, nine with ulcerative colitis) and 11 controls. There was significantly increased density of TNF alpha immunoreactive cells in the lamina propria of both ulcerative colitis and Crohn's disease specimens, although the distribution of these cells differed in the two conditions. In ulcerative colitis most of the TNF alpha immunoreactivity was seen in the subepithelial macrophages, with comparatively less in the deep lamina propria, while in Crohn's disease immunoreactive cells were distributed evenly throughout the lamina propria. Increased submucosal immunoreactivity was found only in Crohn's disease, in which TNF alpha positive macrophages tended to cluster around arterioles and venules, often infiltrating and disrupting vascular endothelium. It is suggested that this degree of TNF alpha production probably contributes significantly to the pathogenesis of both Crohn's disease and ulcerative colitis, by impairing the integrity of epithelial and endothelial membranes, increasing inflammatory cell recruitment, and by prothrombotic effects on the vascular endothelium.


Weighted fusion of multiple models for wavelength selection.
A new method based on the weighted fusion of multiple models is presented for wavelength selection in multivariate calibration of spectral data. It fuses the regression coefficients of multiple models with weights based on minimum mean square error to improve the accuracy and stability of the wavelength selection. To validate the performance of the proposed method, it was applied to the partial least squares (PLS) modeling of three near-infrared spectral datasets and compared with full-spectrum PLS, genetic algorithm-based PLS, and uninformative variable elimination-based PLS methods. Results show that the proposed method can effectively select the informative wavelength and enhance the prediction ability of the PLS model. On account of its simpler algorithm and higher efficiency, it can be widely used in practical applications.


Do drug advertisements provide therapeutic information?
In this study of advertisements appearing in medical periodicals and by direct mail advertising to general practitioners, Dr. Stimson, a sociologist, concludes that from what is intended to provide therapeutic information hardly any therapeutic information is provided. He reminds the reader of the safeguards which surround all drug advertising by law and by the code of practice of the Association of the British Pharmaceutical Industry but these safeguards do not appear to control real or potential sins of omission. Frequently in these advertisements the literature relating to the drug is quoted but Dr. Stimson found that it was difficult to trace all the papers quoted in different types of medical library. (Some references quoted were to unpublished papers but surely the blame should be shared in this situation?) Dr. Stimson also gives a vivid and fascinating glimpse of what he calls the 'images and stereotypes' of the patients who, it is claimed, would benefit from the drug being advertised. Certainly most general practitioners must be aware that when they prescribe that image is displaced by an individual but the portrait gallery is indeed depressing. However, to balance these advertisements drug companies issue data sheets which must be more informative than advertisements and conform to regulations in their format. Unfortunately data sheets are only issued every 15 months whereas the 'average general practitioner is potentially exposed to 1,300 advertisements every month'. In other words, the data sheet and not the advertisement should be the guideline but it arrives too infrequently to offset the lack of therapeutic information contained in advertisements.


Effect of sample stratification on dairy GWAS results.
Artificial insemination and genetic selection are major factors contributing to population stratification in dairy cattle. In this study, we analyzed the effect of sample stratification and the effect of stratification correction on results of a dairy genome-wide association study (GWAS). Three methods for stratification correction were used: the efficient mixed-model association expedited (EMMAX) method accounting for correlation among all individuals, a generalized least squares (GLS) method based on half-sib intraclass correlation, and a principal component analysis (PCA) approach. Historical pedigree data revealed that the 1,654 contemporary cows in the GWAS were all related when traced through approximately 10-15 generations of ancestors. Genome and phenotype stratifications had a striking overlap with the half-sib structure. A large elite half-sib family of cows contributed to the detection of favorable alleles that had low frequencies in the general population and high frequencies in the elite cows and contributed to the detection of X chromosome effects. All three methods for stratification correction reduced the number of significant effects. EMMAX method had the most severe reduction in the number of significant effects, and the PCA method using 20 principal components and GLS had similar significance levels. Removal of the elite cows from the analysis without using stratification correction removed many effects that were also removed by the three methods for stratification correction, indicating that stratification correction could have removed some true effects due to the elite cows. SNP effects with good consensus between different methods and effect size distributions from USDA's Holstein genomic evaluation included the DGAT1-NIBP region of BTA14 for production traits, a SNP 45kb upstream from PIGY on BTA6 and two SNPs in NIBP on BTA14 for protein percentage. However, most of these consensus effects had similar frequencies in the elite and average cows. Genetic selection and extensive use of artificial insemination contributed to overlapped genome, pedigree and phenotype stratifications. The presence of an elite cluster of cows was related to the detection of rare favorable alleles that had high frequencies in the elite cluster and low frequencies in the remaining cows. Methods for stratification correction could have removed some true effects associated with genetic selection.


Physiological evidence for serial processing in somatosensory cortex.
Removal of the representation of a specific body part in the postcentral cortex of the macaque resulted in the somatic deactivation of the corresponding body part in the second somatosensory area. In contrast, removal of the entire second somatosensory area had no grossly detectable effect on the somatic responsivity of neurons in the postcentral cortex. This direct electrophysiological evidence for serial cortical processing in somesthesia is similar to that found earlier for vision and, taken together with recent anatomical evidence, suggests that there is a common cortical plan for the processing of sensory information in the various sensory modalities.


Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity.
The endoplasmic reticulum (ER) plays a critical role in protein, lipid, and glucose metabolism as well as cellular calcium signaling and homeostasis. Perturbation of ER function and chronic ER stress are associated with many pathologies ranging from diabetes and neurodegenerative diseases to cancer and inflammation. Although ER targeting shows therapeutic promise in preclinical models of obesity and other pathologies, the available chemical entities generally lack the specificity and other pharmacological properties required for effective clinical translation. To overcome these challenges and identify new potential therapeutic candidates, we first designed and chemically and genetically validated two high-throughput functional screening systems that independently measure the free chaperone content and protein-folding capacity of the ER. With these quantitative platforms, we characterized a small-molecule compound, azoramide, that improves ER protein-folding ability and activates ER chaperone capacity to protect cells against ER stress in multiple systems. This compound also exhibited potent antidiabetic efficacy in two independent mouse models of obesity by improving insulin sensitivity and pancreatic β cell function. Together, these results demonstrate the utility of this functional, phenotypic assay platform for ER-targeted drug discovery and provide proof of principle for the notion that specific ER modulators can be potential drug candidates for type 2 diabetes.


Hepatitis B infection among pregnant and post-partum women living with HIV and on antiretroviral therapy in Kinshasa, DR Congo: A cross-sectional study.
Hepatitis B virus (HBV) co-infection in HIV-infected individuals increases the risk of hepatic complications and mortality. Further, the risk of perinatal HBV transmission increases among HBV/HIV co-infected pregnant women. Although HBV is endemic in the Democratic Republic of Congo, there is little data on HBV/HIV co-infection. We aimed to assess the burden and risk factors of HBV surface antigen (HBsAg) positivity among HIV-infected pregnant and post-partum women. This cross-sectional study was conducted as part of an ongoing trial to assess the effect of data-driven continuous quality improvement interventions (CQI) for optimal prevention of mother-to-child transmission (PMTCT) of HIV (CQI-PMTCT study, NCT03048669). In each of the 35 health zones of Kinshasa province, all HIV-infected pregnant or breastfeeding women (≤1 year post-delivery) presenting for care in one of the three busiest maternal and child health clinics of the health zone were tested for HBsAg using Alere Determine, Japan. We used logistic regression with general estimating equation accounting for within-clinic clustering to assess risk factors of HBsAg positivity. Between November 2016 and June 2018, a total of 1377 women, all on antiretroviral therapy, were tested for HBsAg. Overall, 4.7% [95% binomial confidence interval (CI): 3.7%-5.7%] tested positive for HBsAg. HBsAg prevalence was 3.3% (95% CI: 2.1%-4.8%) for women tested during pregnancy, 4.5% (2.5%-7.4%) for those tested at delivery, and 8.5% (5.6%-12.2%) for those tested post-partum (Ptrend = 0.001). In multivariate models including socio-economic status (SES), type of care facility, duration of antiretroviral therapy, HIV viral load, and self-reported intimate partner violence (IPV), lowest tertile of SES, ≤ 6 months of ART, and IPV were all consistently and positively associated with higher prevalence of HBsAg across pregnancy, delivery, and postpartum period while been tested in a health centre or having a viral load ≥ 1000 copies/mL were consistently associated with lower prevalence. However, only the association with IPV (OR = 2.74, 95% CI: 1.10-6.84) and viral load between 40-1000 copies/ml (OR = 4.28, 95% CI: 1.22-15.01) achieved statistical significance among pregnant women. This study revealed an overall high prevalence of HBsAg among HIV-infected pregnant and post-partum women in Kinshasa with the latter showing the highest HBsAg prevalence. Among pregnant women, intimate partner violence was independently and statistically associated with HBsAg positivity, requiring further investigation.


Facile fabrication of complex networks of memristive devices.
We describe the memristive properties of cluster-assembled gold films. We show that resistive switching is observed in pure metallic nanostructured films at room temperature and atmospheric pressure, in response to applied voltage inputs. In particular, we observe resistance changes up to 400% and archetypal switching events that have remarkable symmetry with the applied voltage. We associated this symmetry with 'potentiation' and 'anti-potentiation' processes involving the activation of synapses and of pathways comprising multiple synapses. The stability and reproducibility of the resistance switching, which lasted over many hours, make these devices ideal test-beds for exploration of the basic mechanisms of the switching processes, and allow convenient fabrication of devices that may have neuromorphic properties.


The HIV-1 subtype C epidemic in South America is linked to the United Kingdom.
The global spread of HIV-1 has been accompanied by the emergence of genetically distinct viral strains. Over the past two decades subtype C viruses, which predominate in Southern and Eastern Africa, have spread rapidly throughout parts of South America. Phylogenetic studies indicate that subtype C viruses were introduced to South America through a single founder event that occurred in Southern Brazil. However, the external route via which subtype C viruses spread to the South American continent has remained unclear. We used automated genotyping to screen 8,309 HIV-1 subtype C pol gene sequences sampled within the UK for isolates genetically linked to the subtype C epidemic in South America. Maximum likelihood and Bayesian approaches were used to explore the phylogenetic relationships between 54 sequences identified in this screen, and a set of globally sampled subtype C reference sequences. Phylogenetic trees disclosed a robustly supported relationship between sequences from Brazil, the UK and East Africa. A monophyletic cluster comprised exclusively of sequences from the UK and Brazil was identified and dated to approximately the early 1980s using a Bayesian coalescent-based method. A sub-cluster of 27 sequences isolated from homosexual men of UK origin was also identified and dated to the early 1990s. Phylogenetic, demographic and temporal data support the conclusion that the UK was a crucial staging post in the spread of subtype C from East Africa to South America. This unexpected finding demonstrates the role of diffuse international networks in the global spread of HIV-1 infection, and the utility of globally sampled viral sequence data in revealing these networks. Additionally, we show that subtype C viruses are spreading within the UK amongst men who have sex with men.


Yogic breathing when compared to attention control reduces the levels of pro-inflammatory biomarkers in saliva: a pilot randomized controlled trial.
Self-report measures indicate that Yoga practices are perceived to reduce stress; however, molecular mechanisms through which YB affects stress are just beginning to be understood. While invasive sampling such as blood has been widely used to measure biological indicators such as pro-inflammatory biomarkers, the use of saliva to measure changes in various biomolecules has been increasingly recognized. As Yoga practice stimulates salivary secretion, and saliva is considered a source of biomarkers, changes in salivary cytokines before and after Yogic breathing exercise as specified in an ancient Tamil script, Thirumanthiram, were examined using a Cytokine Multiplex to compare to Attention Control (AC) group. Twenty healthy volunteers were randomized into two groups stratified by gender (N = 10 per YB and AC groups); The YB group performed two YB exercises, each for ten minutes, for a total of twenty minutes in a single session as directed by a trained Yoga instructor. The AC group read a text of their choice for 20 min. Saliva was collected immediately after YB training at 0, 5, 10, 15 and 20 min and analyzed by Multiplex enzyme linked immunosorbent assay (ELISA). The levels of interleukin (IL)-1β, IL-8, and monocyte chemotactic protein -1 (MCP-1) were significantly reduced in YB group when compared to AC group. The level of reduction of IL-8 was significant at all time points tested, whereas IL-1β showed reduction at 15 and 20 min time points (p < 0.05), and MCP-1 level was marginally different at 5-20 min. There were no significant differences between YB and AC groups in the salivary levels of IL-1RA, IL-6, IL-10, IL-17, IP-10, MIP-1b, and TNF-α. These data are the first to demonstrate the feasibility of detecting salivary cytokines using multiplex assay in response to a Yoga practice. This study was registered in Clinical Trials.gov # NCT02108769.


Evaluation of vaginoscopy for the diagnosis of clinical endometritis in dairy cows.
The objective of the study was to evaluate the visual assessment of vaginal discharge by vaginoscopy for the diagnosis of clinical endometritis (CE) in dairy cows. In an in vivo trial, inter- and intraobserver repeatability of vaginoscopic examination (VE) was determined and the effect of transrectal palpation and experience of the investigator evaluated. Holstein-Friesian cows (n=380) were examined by vaginoscopy between 21 and 27 d in milk by 3 investigators twice. Vaginal discharge was categorized on a 4-point classification system (0=clear mucus, 1=mucus containing flecks of pus, 2=discharge containing less than 50% pus, 3=discharge containing more than 50% pus). Cows with a vaginal discharge score (VDS) of 0 were classified as healthy, whereas cows with a VDS of 1 to 3 were classified as having CE. Vaginal discharge score on a scale from 0 to 3 has moderate intra- (Cohen's kappa coefficient, κ=0.55-0.60) and interobserver (κ=0.44) repeatability. The prevalence of CE was comparable between the 3 investigators (first VE: 42.6, 34.8, and 38.7; second VE 46.8, 36.9, and 43.7%). Transrectal palpation (relative risk=0.96-1.03) or experience of the investigator (relative risk=0.9-1.1) did not affect results of VE. In an in vitro trial, sensitivity and specificity of visual assessment were determined utilizing 33 images showing yellow and pink areas in certain percentages as a reference standard. Pus was represented by yellow areas and the mucosa, including clear mucus, by pink areas. These images were visually assessed by 30 investigators via PowerPoint presentation (experiment 1) and by 23 investigators via a simulated vaginal examination (experiment 2) utilizing the same 4-point classification system. Sensitivity was 99.6 and 96.3% and specificity was 96.7 and 90.1% in experiments 1 and 2, respectively. The results provide evidence that a visual assessment conducted by vaginoscopic examination is not perfect but can be considered a reasonable measurement of vaginal discharge and is a practical tool to distinguish healthy from diseased cows.


Preschoolers' Thoughts on the Concept of Time.
This study aimed to examine preschool children's epistemological views in the context of the concept of time via their drawings of the time machine. The study was conducted with 30 five-year-old children (17 girls and 13 boys) attending state and private preschools in the academic year 2018/2019. The data collection tools used in the study were the Test for Creative Thinking - Drawing Production TCT-DP, Children's Thoughts on Time Questionnaire (CTTQ) and Children's Epistemological Views Questionnaire (CEVQ). Of the mixed methods typologies, the fully mixed sequential dominant status-qualitative design was employed. The results obtained from the study indicated that the time machine drawings of almost half the participating children included creative elements and logical thinking products. In addition, 40% of the children's responses reflected sophisticated epistemological views such as scientific, imaginative/science fiction-based, divergent and eccentric approaches and non-authority figures regarding the concept of time. In conclusion: contrary to Piegatian interpretation, our results show that five-year old children can demonstrate abstract scientific understanding regarding the concept of time and preschoolers' epistemic approach has a critical role in determining their development of abstract cognitive concepts.


Protective effects of a Modified Vaccinia Ankara-based vaccine candidate against Crimean-Congo Haemorrhagic Fever virus require both cellular and humoral responses.
Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. There is no approved vaccine currently available against CCHF. The most promising candidate, which has previously been shown to confer protection in the small animal model, is a modified Vaccinia Ankara virus vector expressing the CCHF viral glycoprotein (MVA-GP). It has been shown that MVA-GP induces both humoral and cellular immunogenicity. In the present study, sera and T-lymphocytes were passively and adoptively transferred into recipient mice prior to challenge with CCHF virus. Results demonstrated that mediators from both arms of the immune system were required to demonstrate protective effects against lethal challenge.


The Rey Dot Counting Test as a Tool for Detecting Suboptimal Performance in Athlete Baseline Testing.
The limitations of Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT)'s embedded validity measures (EVMs) are well-documented, as estimates suggest up to 35% of invalid baseline performances go undetected. Few studies have examined standalone performance validity tests (PVT) as a supplement to ImPACT's EVMs. College athletes (n = 1,213) were administered a preseason baseline assessment that included ImPACT and the Rey Dot Counting Test (DCT), a standalone PVT, among other measures. Sixty-nine athletes (5.69%) met criteria for suboptimal effort on either ImPACT or the DCT. The DCT detected more cases of suboptimal effort (n = 50) than ImPACT (n = 21). A χ2 test of independence detected significant disagreement between the two measures, as only two individuals produced suboptimal effort on both (χ2(2) = 1.568, p = .210). Despite this disagreement, there were significant differences between the suboptimal effort DCT group and the adequate effort DCT group across all four ImPACT neurocognitive domains (U = 19,225.000, p < .001; U = 17,859.000, p < .001; U = 13,854.000, p < .001; U = 17,850.500, p < .001). The DCT appears to detect suboptimal effort otherwise undetected by ImPACT's EVMs.


Gene regulation in adult neural stem cells. Current challenges and possible applications.
Adult neural stem and progenitor cells (NSPCs) offer a unique opportunity for neural regeneration and niche modification in physiopathological conditions, harnessing the capability to modify from neuronal circuits to glial scar. Findings exposing the vast plasticity and potential of NSPCs have accumulated over the past years and we currently know that adult NSPCs can naturally give rise not only to neurons but also to astrocytes and reactive astrocytes, and eventually to oligodendrocytes through genetic manipulation. We can consider NSPCs as endogenous flexible tools to fight against neurodegenerative and neurological disorders and aging. In addition, NSPCs can be considered as active agents contributing to chronic brain alterations and as relevant cell populations to be preserved, so that their main function, neurogenesis, is not lost in damage or disease. Altogether we believe that learning to manipulate NSPC is essential to prevent, ameliorate or restore some of the cognitive deficits associated with brain disease and injury, and therefore should be considered as target for future therapeutic strategies. The first step to accomplish this goal is to target them specifically, by unveiling and understanding their unique markers and signaling pathways.


Association of serum hemolytic complement levels with the major histocompatibility complex in chickens.
The total hemolytic complement (C) levels in inbred line 7 chicks and adults were lower than C levels in inbred lines 2 and 3 and in outbred chickens of the same age. In all birds, adult levels of C were obtained in 5- to 6-wk-old chickens. Analysis of F1 and F3 generations clearly showed that the C level in chickens was determined by a dominant gene(s) associated with the major histocompatibility complex. Finding this association in a nonmammal strengthens the importance of the relationship between closely linked genes controlling histocompatibility, immune responsiveness, mixed leukocyte reaction, and C activity.


Laparoscopic radical nephrectomy vs laparoscopic or open partial nephrectomy for T1 renal cell carcinoma: comparison of complication rates in elderly patients during the initial phase of adoption.
To assess postoperative complication profiles and 30-day mortality (30 dM) in older patients undergoing either laparoscopic radical nephrectomy (LRN) compared with open partial nephrectomy (OPN) or laparoscopic partial nephrectomy (LPN) for early stage renal cell carcinoma. Using the Surveillance, Epidemiology, and End Results-Medicare linked database, 2277 patients aged>65 years with T1 renal cell carcinoma, who underwent LRN, OPN, or LPN were identified (1992-2005). Surgical and medical complications and 30 dM after nephrectomy were abstracted. Bivariate and multivariate logistic regression analyses were performed. Relative to LRN, the rate of surgical complications was higher for OPN (28% vs 20%; P<.001) and LPN (29% vs 20%; P=.01). These differences persisted after multivariate adjustment for patient and tumor characteristics (OPN: odds ratio, 1.6; 95% confidence interval, 1.28-1.91; P<.001; LPN: odds ratio, 1.6; 95% confidence interval, 1.13-2.39; P=.01). Specifically, relative to LRN, OPN was associated with a 7% higher rate of genitourinary complications (13% vs 20%; P<.001). Similarly, relative to LRN, LPN was associated with a 7% higher rate of genitourinary complications (13% vs 20%; P=.001) and with a 4% higher rate of hemorrhagic complications (8% vs 4%; P=.02). No statistically significant differences were recorded for all other surgical and/or medical complication types and 30 dM (all P≥.2). The complication and 30-dM rates were not different between LRN, OPN, and LPN groups. Exceptions include genitourinary complications that favor LRN relative to OPN and LPN and hemorrhagic complications that favor LRN relative to LPN. It is doubtful that these results should discourage the use of partial nephrectomy relative to LRN in older patients.


Cold-induced sweating syndrome with neonatal features of Crisponi syndrome: longitudinal observation of a patient homozygous for a CRLF1 mutation.
Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder caused by mutations in CRLF1 (cytokine receptor-like factor 1), characterized by profuse sweating in cold environmental temperature and craniofacial and skeletal features. Mutations in CRLF1 also cause Crisponi syndrome (CS), characterized by neonatal-onset paroxysmal muscular contractions as well as craniofacial and skeletal manifestations and abnormal functions of the autonomic nerve system. To date, it is an unresolved problem whether the two conditions are distinct clinical entities or a single clinical entity with variable expressions or with different presentations depending on the patients' age at diagnosis. We report on a 30-year-old Japanese woman with CISS and homozygous out-of-frame 23-base deletion of CRLF1. In infancy, she did not show paroxysmal muscular contractions, but showed feeding difficulty, hyperthermia, and facial characteristics including thick and arched eyebrows, a short nose with anteverted nostrils, full cheeks, an inverted upper lip, and a small mouth, resembling those observed in CS. Profuse sweating was noticed at 3 years of age. Cold-induced sweating was recognized in her elementary school days. In adolescence to adulthood, she showed a Marfanoid habitus with progressive kyphoscoliosis and craniofacial characteristics including dolichocephaly, a slender face with poor expression, a distinctive nose with hypoplastic nares, malar hypoplasia, prognathism, and a small mouth. This is the first report of detailed longitudinal observation of a patient with CRLF1 abnormalities, compatible with the notion that CISS and CS may be a single clinical entity.


Exploring Heat Stress Relief Measures among the Australian Labour Force.
Australia experiences frequent heat waves and generally high average temperatures throughout the continent with substantial impacts on human health and the economy. People adapt to heat by adopting various relief measures in their daily lives including changing their behaviour. Many labour intensive outdoor industries implement standards for heat stress management for their workforce. However, little is known about how people cope with heat at their workplaces apart from studies targeting some specific industries where labourers are exposed to extreme heat. Here, we analysed responses from 1719 people in the Australian labour force to self-reported heat stress and associated coping mechanisms. Three quarters of respondents experienced heat stress at their workplace with fatigue and headache being the two most frequently stated symptoms. Almost all of those who were affected by heat would hydrate (88%), 67% would cool, and 44% would rest as a strategy for coping with heat. About 10% intended to change their jobs because of heat stress in the workplace. We found differences in heat relief measures across gender, education, health, level of physical intensity of job, and time spent working outside. People working in jobs that were not very demanding physically were more likely to choose cooling down as a relief measure, while those in labour intensive jobs and jobs that required considerable time outside were more likely to rest. This has potential consequences for their productivity and work schedules. Heat affects work in Australia in many types of industry with impact dependent on workforce acclimatisation, yet public awareness and work relief plans are often limited to outdoor and labour intensive industries. Industries and various levels of government in all sectors need to implement standards for heat management specific to climate zones to help people cope better with high temperatures as well as plan strategies in anticipation of projected temperature increases.


Treatment options in idiopathic subglottic stenosis: protocol for a prospective international multicentre pragmatic trial.
Idiopathic subglottic stenosis (iSGS) is an unexplained progressive obstruction of the upper airway that occurs almost exclusively in adult, Caucasian women. The disease is characterised by mucosal inflammation and localised fibrosis resulting in life-threatening blockage of the upper airway. Because of high recurrence rates, patients with iSGS will frequently require multiple procedures following their initial diagnosis. Both the disease and its therapies profoundly affect patients' ability to breathe, communicate and swallow. A variety of treatments have been advanced to manage this condition. However, comparative data on effectiveness and side effects of the unique approaches have never been systematically evaluated. This study will create an international, multi-institutional prospective cohort of patients with iSGS. It will compare three surgical approaches to determine how well the most commonly used treatments in iSGS 'work' and what quality of life (QOL) trade-offs are associated with each approach. A prospective pragmatic trial comparing the 'Standard of Care' for iSGS at multiple international institutions. Patients with a diagnosis of iSGS without clinical or laboratory evidence of vasculitis or a history of endotracheal intubation 2 years prior to symptom onset will be included in the study. Prospective evaluation of disease recurrence requiring operative intervention, validated patient-reported outcome (PRO) measures as well as patient-generated health data (mobile peak flow recordings and daily steps taken) will be longitudinally tracked for 36 months. The primary endpoint is treatment effectiveness defined as time to recurrent operative procedure. Secondary endpoints relate to treatment side effects and include PRO measures in voice, swallowing, breathing and global QOL as well as patient-generated health data. This protocol was approved by the local IRB Committee of the Vanderbilt University Medical Center in July 2015. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and directly to patient with iSGS via social media-based support groups. NCT02481817.


Antimycobacterial activity of Citrullus colocynthis (L.) Schrad. against drug sensitive and drug resistant Mycobacterium tuberculosis and MOTT clinical isolates.
Citrullus colocynthis (Cucurbitaceae), a folk herbal medicine and traditionally used natural remedy for tuberculosis in India has been studied to validate its antitubercular activity against drug sensitive and drug resistant (including multidrug resistant) Mycobacterium tuberculosis and Mycobacterium other than tuberculosis (MOTT) bacilli. Inhibitory and bactericidal activities of crude extracts, fractions and compounds of Citrullus colocynthis plant, consisting of aerial parts and ripe deseeded fruits were performed against the drug sensitive standard strain of Mycobacterium tuberculosis H37Rv (ATCC 27294), 16 drug resistant strains of Mycobacterium tuberculosis and two MOTT strains, using radiometric BACTEC 460TB system. Methanolic extract of ripe deseeded fruit of Citrullus colocynthis has shown good activity (MIC ≤ 62.5 µg/ml), whereas among the bioactive fractions, FC IX demonstrated the best activity (MIC 31.2 µg/ml) against Mycobacterium tuberculosis H37Rv. Bioactive FC III, IX and X also inhibited 16 clinical isolates of Mycobacterium tuberculosis consisting of seven non-multidrug resistants, eight multidrug resistants, one extensively drug resistant and two of MOTTs with MICs in the range of 50-125, 31.2-125 and 62.5-125 µg/ml, respectively. Ursolic acid and cucurbitacin E 2-0-β-d-glucopyranoside were identified as the main biomarkers active against Mycobacterium tuberculosis H37Rv (MICs 50 and 25 µg/ml respectively), as well as against the 18 clinical isolates. FC III and FC IX showed better inhibition of drug resistant and MOTT clinical isolates. Minimal bactericidal concentrations of extracts, fractions and compound C-2 were ≥ two-fold MIC values. The study provides a scientific rationale for the traditional use of Citrullus colocynthis fruit in the treatment of tuberculosis. In addition, the study elucidates a broad spectrum antimycobacterial action of Citrullus colocynthis fruit, which can contribute to the development of improved preparation of an antitubercular natural drug for the treatment of drug resistant tuberculosis and MOTT infection as well.


Effects of flood irrigation on the risk of selected zoonotic pathogens in an arid and semi-arid area in the eastern Kenya.
To investigate the effects of irrigation on land cover changes and the risk of selected zoonotic pathogens, we carried out a study in irrigated, pastoral and riverine areas in the eastern Kenya. Activities implemented included secondary data analyses to determine land use and land cover (LULC) changes as well as human, livestock and wildlife population trends; entomological surveys to characterize mosquitoes population densities and species distribution by habitat and season; and serological surveys in people to determine the risk of Rift Valley fever virus (RVFV), West Nile fever virus (WNV), dengue fever virus (DFV), Leptospira spp. and Brucella spp. Results demonstrate a drastic decline in vegetation cover over ≈25 years particularly in the irrigated areas where cropland increased by about 1,400% and non-farm land (under closed trees, open to closed herbaceous vegetation, bushlands and open trees) reduced by 30-100%. The irrigated areas had high densities of Aedes mcintoshi, Culex spp. and Mansonia spp. (important vectors for multiple arboviruses) during the wet and dry season while pastoral areas had high densities of Ae. tricholabis specifically in the wet season. The seroprevalences of RVFV, WNV and DFV were higher in the irrigated compared to the pastoral areas while those for Leptospira spp and Brucella spp. were higher in the pastoral compared to the irrigated areas. It is likely that people in the pastoral areas get exposed to Leptospira spp by using water fetched from reservoirs that are shared with livestock and wildlife, and to Brucella spp. by consuming raw or partially cooked animal-source foods such as milk and meat. This study suggests that irrigation increases the risk of mosquito-borne infections while at the same time providing a protective effect against zoonotic pathogens that thrive in areas with high livestock population densities.


Long-term outcomes after staged-volume stereotactic radiosurgery for large arteriovenous malformations.
Stereotactic radiosurgery is an effective treatment modality for small arteriovenous malformations (AVMs) of the brain. For larger AVMs, the treatment dose is often lowered to reduce potential complications, but this decreases the likelihood of cure. One strategy is to divide large AVMs into smaller anatomic volumes and treat each volume separately. To prospectively assess the long-term efficacy and complications associated with staged-volume radiosurgical treatment of large, symptomatic AVMs. Eighteen patients with AVMs larger than 15 mL underwent prospective staged-volume radiosurgery over a 13-year period. The median AVM volume was 22.9 mL (range, 15.7-50 mL). Separate anatomic volumes were irradiated at 3- to 9-month intervals (median volume, 10.9 mL; range, 5.3-13.4 mL; median marginal dose, 15 Gy; range, 15-17 Gy). The AVM was divided into 2 volumes in 10 patients, 3 volumes in 5 patients, and 4 volumes in 3 patients. Seven patients underwent retreatment for residual disease. Actuarial rates of complete angiographic occlusion were 29% and 89% at 5 and 10 years. Five patients (27.8%) had a hemorrhage after radiosurgery. Kaplan-Meier analysis of cumulative hemorrhage rates after treatment were 12%, 18%, 31%, and 31% at 2, 3, 5, and 10 years, respectively. One patient died after a hemorrhage (5.6%). Staged-volume radiosurgery for AVMs larger than 15 mL is a viable treatment strategy. The long-term occlusion rate is high, whereas the radiation-related complication rate is low. Hemorrhage during the lag period remains the greatest source of morbidity and mortality.


Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum.
Dysfunction of the hypocretin/orexin (Hcrt/Orx) peptide system is closely linked to the sleep disorder narcolepsy, suggesting that it is also central to the normal regulation of sleep and wakefulness. Indeed, Hcrt/Orx peptides produce long-lasting excitation of arousal-related neurons, including those in the laterodorsal tegmentum (LDT) and the dorsal raphe (DR), although the mechanisms underlying these actions are not understood. Since Hcrt/Orx mobilizes intracellular calcium ([Ca(2+)](i)) in cells transfected with orexin receptors and since receptor-mediated Ca(2+) transients are ubiquitous signaling mechanisms, we investigated whether Hcrt/Orx regulates [Ca(2+)](i) in the LDT and DR. Changes in [Ca(2+)](i) were monitored by fluorescence changes of fura-2 AM loaded cells in young mouse brain slices. We found Hcrt/Orx (Orexin-A, 30-1,000 nM) evoked long-lasting increases in [Ca(2+)](i) with differing temporal profiles ranging from spiking to smooth plateaus. A fragment of Hcrt/Orx (16-33) failed to evoke changes in [Ca(2+)](i) and changes were not blocked by TTX or ionotropic glutamate receptor antagonists, suggesting they resulted from specific activation of postsynaptic orexin receptors. Unlike orexin receptor-transfected cells, Hcrt/Orx-responses were not attenuated by depletion of Ca(2+) stores with cyclopiazonic acid (CPA; 3-30 microM), thapsigargin (3 microM), or ryanodine (20 microM), although store-depletion by either CPA or ryanodine blocked Ca(2+) mobilization by the metabotropic glutamate receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 30 microM). In contrast, Hcrt/Orx responses were strongly attenuated by lowering extracellular Ca(2+) ( approximately 20 microM) but were not inhibited by concentrations of KB-R7943 (10 microM) selective for blockade of sodium/calcium exchange. Nifedipine (10 microM), inhibited Hcrt/Orx responses but was more effective at abolishing spiking than plateau responses. Bay K 8644 (5-10 microM), an L-type calcium channel agonist, potentiated responses. Finally, responses were attenuated by inhibitors of protein kinase C (PKC) but not by inhibitors of adenylyl cyclase. Collectively, our findings indicate that Hcrt/Orx signaling in the reticular activating system involves elevation of [Ca(2+)](i) by a PKC-involved influx of Ca(2+) across the plasma membrane, in part, via L-type calcium channels. Thus the physiological release of Hcrt/Orx may help regulate Ca(2+)-dependent processes such as gene expression and NO production in the LDT and DR in relation with behavioral state. Accordingly, the loss of Hcrt/Orx signaling in narcolepsy would be expected to disrupt calcium-dependent processes in these and other target structures.


Biological activities of a human pluripotent hemopoietic colony stimulating factor on normal and leukemic cells.
We studied the biological effects of pluripoietin, a human pluripotent hemopoietic colony-stimulating factor (CSF) purified from the 5637 bladder carcinoma cell line. We found that this human CSF appears to be a unique hemopoietic growth factor, differing from interleukin 3 (IL-3) by virtue of its leukemia differentiating activity in mouse and man, and from mouse granulocyte CSF, which does have differentiation-inducing activity, but lacks pluripoietic activity. In addition, differences from IL-3 were observed in cross-species activity on normal and leukemic cells.


Emphasizing the experiences of researchers after RCR instructions: Introduction to Responsible Conduct of Research (RCR) in Malaysia.
The purpose of this study is to highlight the experiences of individuals who participate in the Responsible Conduct of Research (RCR) training program held at various universities in Malaysia. In response to a mailing request sent to 40 individuals who had undertaken a RCR training program, 15 participants agreed to be interviewed. The results of the study showed that the three main reasons for participating in the training were as follows: anticipation for knowledge gained; personal experience with research misconduct; and establishing a new network of researchers. In terms of the positive effects gained from undertaking the training, the participants highlighted an increased awareness of the issues and problems related to research misconduct; the need to promote integrity in research conduct; a change in the way they conduct their research; and a change in the way they confront and address misconduct. The findings of this study should be valuable for policy makers and those involved in the management of research programs and ethics, as it demonstrated the importance of RCR training in equipping researchers with the necessary knowledge to conduct research responsibly, and to avoid research misconduct.


Empirically Supported Treatments for Students with Autism: General Education Teacher Knowledge, Use, and Social Validity Ratings.
Objective: To examine teachers' knowledge and use of empirically supported treatments (ESTs) for children with autism spectrum disorder (ASD), and the extent to which they deem them socially valid in general education settings. Method: Totally, 155 general education teachers completed an online survey examining knowledge, use, and perceived social validity of ESTs targeting school readiness skills. Sources of information accessed and the relationship of knowledge, use, and social validity with demographic variables were investigated. Results: Teachers reported knowledge of, and were using, all ESTs. ESTs were used more frequently than non-ESTs. Knowledge, use, and social validity of ESTs were strongly associated. Teachers reported accessing a range of sources of information, with varying degrees of trust placed in these sources. Conclusion: Teachers' knowledge of available ESTs for children with ASD is linked to their use. Increasing awareness of social validity of ESTs, and how they can be successfully translated into classroom settings will influence uptake.


Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting.
Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8(+) T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors.


Plant Growth-Promoting Rhizobacteria Inoculation to Enhance Vegetative Growth, Nitrogen Fixation and Nitrogen Remobilisation of Maize under Greenhouse Conditions.
Plant growth-promoting rhizobacteria (PGPR) may provide a biological alternative to fix atmospheric N2 and delay N remobilisation in maize plant to increase crop yield, based on an understanding that plant-N remobilisation is directly correlated to its plant senescence. Thus, four PGPR strains were selected from a series of bacterial strains isolated from maize roots at two locations in Malaysia. The PGPR strains were screened in vitro for their biochemical plant growth-promoting (PGP) abilities and plant growth promotion assays. These strains were identified as Klebsiella sp. Br1, Klebsiella pneumoniae Fr1, Bacillus pumilus S1r1 and Acinetobacter sp. S3r2 and a reference strain used was Bacillus subtilis UPMB10. All the PGPR strains were tested positive for N2 fixation, phosphate solubilisation and auxin production by in vitro tests. In a greenhouse experiment with reduced fertiliser-N input (a third of recommended fertiliser-N rate), the N2 fixation abilities of PGPR in association with maize were determined by 15N isotope dilution technique at two harvests, namely, prior to anthesis (D50) and ear harvest (D65). The results indicated that dry biomass of top, root and ear, total N content and bacterial colonisations in non-rhizosphere, rhizosphere and endosphere of maize roots were influenced by PGPR inoculation. In particular, the plants inoculated with B. pumilus S1r1 generally outperformed those with the other treatments. They produced the highest N2 fixing capacity of 30.5% (262 mg N2 fixed plant-1) and 25.5% (304 mg N2 fixed plant-1) of the total N requirement of maize top at D50 and D65, respectively. N remobilisation and plant senescence in maize were delayed by PGPR inoculation, which is an indicative of greater grain production. This is indicated by significant interactions between PGPR strains and time of harvests for parameters on N uptake and at. % 15Ne of tassel. The phenomenon is also supported by the lower N content in tassels of maize treated with PGPR, namely, B. pumilus S1r1, K. pneumoniae Fr1, B. subtilis UPMB10 and Acinetobacter sp. S3r2 at D65 harvest. This study provides evidence that PGPR inoculation, namely, B. pumilus S1r1 can biologically fix atmospheric N2 and provide an alternative technique, besides plant breeding, to delay N remobilisation in maize plant for higher ear yield (up to 30.9%) with reduced fertiliser-N input.


Fundamentals of nutrigenetics and nutrigenomics.
This volume of Progress in Molecular Biology and Translational Science is devoted to the exciting and promising field of nutrigenetics and nutrigenomics. The introductory chapter defines the basic concepts necessary for the interpretation of the material covered in the remainder of the volume. Emphasis is on the concept of personalized nutrition and its likely role in public health and disease prevention, as well as in therapeutics. Nutrigenetics refers to the role of DNA sequence variation in the responses to nutrients, whereas nutrigenomics is the study of the role of nutrients in gene expression. This research is predicated on the assumption that there are individual differences in responsiveness to acute or repeated exposures to a given nutrient or combination of nutrients. Throughout human history, diet has affected the expression of genes, resulting in phenotypes that are able to successfully respond to environmental challenges and that allow better exploitation of food resources. These adaptations have been key to human growth and development. Technological advances have made it possible to investigate not only specific genes but also to explore in unbiased designs the whole genome-wide complement of DNA sequence variants or transcriptome. These advances provide an opportunity to establish the foundation for incorporating biological individuality into dietary recommendations, with significant therapeutic potential.


Health related quality of life after gastric bypass or intensive lifestyle intervention: a controlled clinical study.
There is little robust evidence relating to changes in health related quality of life (HRQL) in morbidly obese patients following a multidisciplinary non-surgical weight loss program or laparoscopic Roux-en-Y Gastric Bypass (RYGB). The aim of the present study was to describe and compare changes in five dimensions of HRQL in morbidly obese subjects. In addition, we wanted to assess the clinical relevance of the changes in HRQL between and within these two groups after one year. We hypothesized that RYGB would be associated with larger improvements in HRQL than a part residential intensive lifestyle-intervention program (ILI) with morbidly obese subjects. A total of 139 morbidly obese patients chose treatment with RYGB (n=76) or ILI (n=63). The ILI comprised four stays (seven weeks) at a specialized rehabilitation center over one year. The daily schedule was divided between physical activity, psychosocially-oriented interventions, and motivational approaches. No special diet or weight-loss drugs were prescribed. The participants completed three HRQL-questionnaires before treatment and 1 year thereafter. Both linear regression and ANCOVA were used to analyze differences between weight loss and treatment for five dimensions of HRQL (physical, mental, emotional, symptoms and symptom distress) controlling for baseline HRQL, age, age of onset of obesity, BMI, and physical activity. Clinical relevance was assessed by effect size (ES) where ES<.49 was considered small, between .50-.79 as moderate, and ES>.80 as large. The adjusted between group mean difference (95% CI) was 8.6 (4.6,12.6) points (ES=.83) for the physical dimension, 5.4 (1.5-9.3) points (ES=.50) for the mental dimension, 25.2 (15.0-35.4) points (ES=1.06) for the emotional dimension, 8.7 (1.8-15.4) points (ES=.37) for the measured symptom distress, and 2.5 for (.6,4.5) fewer symptoms (ES=.56), all in favor of RYGB. Within-group changes in HRQOL in the RYGB group were large for all dimensions of HRQL. Within the ILI group, changes in the emotional dimension, symptom reduction and symptom distress were moderate. Linear regression analyses of weight loss on HRQL change showed a standardized beta-coefficient of -.430 (p<.001) on the physical dimension, -.288 (p=.004) on the mental dimension, -.432 (p<.001) on the emotional dimension, .287 (p=.008) on number of symptoms, and .274 (p=.009) on reduction of symptom pressure. Morbidly obese participants undergoing RYGB and ILI had improved HRQL after 1 year. The weaker response of ILI on HRQL, compared to RYGB, may be explained by the difference in weight loss following the two treatments. Clinical Trials.gov number NCT00273104.


Piezo2 integrates mechanical and thermal cues in vertebrate mechanoreceptors.
Tactile information is detected by thermoreceptors and mechanoreceptors in the skin and integrated by the central nervous system to produce the perception of somatosensation. Here we investigate the mechanism by which thermal and mechanical stimuli begin to interact and report that it is achieved by the mechanotransduction apparatus in cutaneous mechanoreceptors. We show that moderate cold potentiates the conversion of mechanical force into excitatory current in all types of mechanoreceptors from mice and tactile-specialist birds. This effect is observed at the level of mechanosensitive Piezo2 channels and can be replicated in heterologous systems using Piezo2 orthologs from different species. The cold sensitivity of Piezo2 is dependent on its blade domains, which render the channel resistant to cold-induced perturbations of the physical properties of the plasma membrane and give rise to a different mechanism of mechanical activation than that of Piezo1. Our data reveal that Piezo2 is an evolutionarily conserved mediator of thermal-tactile integration in cutaneous mechanoreceptors.


Size of error affects cerebellar contributions to motor learning.
Small errors may affect the process of learning in a fundamentally different way than large errors. For example, adapting reaching movements in response to a small perturbation produces generalization patterns that are different from large perturbations. Are distinct neural mechanisms engaged in response to large versus small errors? Here, we examined the motor learning process in patients with severe degeneration of the cerebellum. Consistent with earlier reports, we found that the patients were profoundly impaired in adapting their motor commands during reaching movements in response to large, sudden perturbations. However, when the same magnitude perturbation was imposed gradually over many trials, the patients showed marked improvements, uncovering a latent ability to learn from errors. On sudden removal of the perturbation, the patients exhibited aftereffects that persisted much longer than did those in healthy controls. That is, despite cerebellar damage, the brain maintained the ability to learn from small errors and the motor memory that resulted from this learning was strongly resistant to change. Of note was the fact that on completion of learning, the motor output of the cerebellar patients remained distinct from healthy controls in terms of its temporal characteristics. Therefore cerebellar degeneration impaired the ability to learn from large-magnitude errors, but had a lesser impact on learning from small errors. The neural basis of motor learning in response to small and large errors appears to be distinct.


Adalimumab reduces hand bone loss in rheumatoid arthritis independent of clinical response: subanalysis of the PREMIER study.
Anti-TNF therapy has been shown to reduce radiographic joint damage in rheumatoid arthritis (RA) independent of clinical response. This has previously not been examined for periarticular bone loss, the other characteristic feature of bone involvement in RA.The objective of this study was to examine if treatment with the TNF-α inhibitor adalimumab also could reduce periarticular bone loss in RA patients independent of disease activity. RA patients were recruited from the PREMIER study and included 214 patients treated with methotrexate (MTX) plus adalimumab and 188 patients treated with MTX monotherapy. Periarticular bone loss was assessed by digital X-ray radiogrammetry metacarpal cortical index (DXR-MCI). Change in DXR-MCI was evaluated in patients with different levels of clinical response, as assessed by changes in DAS28 score at 52 weeks and in mean C-reactive protein (CRP) levels during follow-up. In the MTX group, there was a greater median DXR-MCI loss among patients with moderate and high disease activity compared to those in remission or with low disease activity (-3.3% vs. -2.2%, p = 0.01). In contrast, periarticular bone loss was independent of disease activity (-1.9% vs. -2.4%, p = 0.99) in the combination group. In the MTX group patients with a mean CRP of ≥ 10 mg/l lost significantly more DXR-MCI than patients with low CRP (-3.1% vs. -1.9%, p <0.01) whereas in the combination group no significant differences between the two CRP groups was seen (-2.4% vs. -2.0%, p = 0.48). Adalimumab in combination with MTX reduces periarticular bone loss independently of clinical response. These results support the hypothesis that TNF-α stimulates the osteoclast not only by the inflammatory pathway but do also have a direct effect on the osteoclast. ClinicalTrials (NCT): NCT001195663.


High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial.
Clinical outcomes are worse in patients with COPD and chronic bronchitis. N-acetylcysteine (NAC) is commonly prescribed for such patients but with uncertain clinical benefits. We postulated that oral NAC, at much larger doses than those ordinarily prescribed, would improve clinical outcomes in a subset of patients with COPD and chronic bronchitis. The aim of this study was to determine whether very high-dose NAC would improve respiratory health status in patients with COPD and chronic bronchitis. Patients with COPD and chronic bronchitis were enrolled in a randomized, controlled, double-blinded trial. Patients received oral NAC (1,800 mg) or matching placebo twice daily for 8 weeks in addition to their usual respiratory medications. The primary outcome, respiratory health status, was assessed by changes in the St George's Respiratory Questionnaire. The effects of NAC on lung function and circulating markers of oxidative stress and inflammation were also evaluated. We terminated the study prematurely because new external information suggested the possibility of a safety issue. Of the planned 130 patients, 51 were randomized and 45 (22 in the placebo arm and 23 in the NAC arm) completed the study. There was no statistically significant difference between changes in the St George's Respiratory Questionnaire total score, comparing NAC to placebo (adjusted mean difference, 0.1 U; 95% CI, -7.8 to 8.18 U; P=0.97). There were also no significant NAC-related improvements in any of the secondary outcomes. In this 8-week trial, we were unable to show any clinical benefit from a very high dose of NAC in patients with COPD and chronic bronchitis.


Ultra long-term cellular tracing by a fluorescent AIE bioconjugate with good water solubility over a wide pH range.
Strongly fluorescent and water soluble bioprobes are in great demand for studying important biological events and processes. The quenching effect of conventional organic dyes caused by aggregation, and the high toxicity of inorganic quantum dots are thorny issues that have constantly obsessed scientists in this area of research. In this work, a large number of tetraphenylethene (TPE) units were successfully attached to N-succinyl-chitosan (NSCS) macromolecular chains to fabricate a novel TPE-NSCS fluorescent bioconjugate, which was strongly emissive in the solid state due to its aggregation-induced emission effect. TPE-NSCS could be solubilized in water over a wide range of pH values. We were pleasantly surprised to see that stained cells still showed a bright fluorescence emission for as many as 30 passages. The water solubility over a wide pH range, ultra long-term retention in cells, and strong fluorescence signals indicate that TPE-NSCS is a promising candidate for various biomedical applications.