Surface chemistry of methanol on different ZnO surfaces studied by vibrational spectroscopy.
The adsorption and reactions of CH3OH on nonpolar mixed-terminated ZnO(101[combining macron]0), polar O-ZnO(0001[combining macron]) and Zn-ZnO(0001) surfaces have been studied systematically using high-resolution electron energy loss spectroscopy (HREELS) in conjunction with temperature programmed desorption (TPD). For all three ZnO surfaces, exposure to methanol at room temperature leads to (partially) dissociative adsorption resulting in the formation of hydroxyl and methoxy species. Upon heating to higher temperatures, the dissociated and intact methanol species on ZnO(101[combining macron]0) predominantly undergo molecular desorption releasing CH3OH at 370 and 440 K. The Zn-O dimer vacancies are responsible for the decomposition of a small fraction of methanol yielding H2, CH2O and CO at 540 and 565 K. The interaction of methanol with polar O-ZnO and Zn-ZnO surfaces is dominated by thermal decomposition of CH3OH to produce CH2O, H2, CO, CO2 and H2O at elevated temperatures. The high chemical reactivity of both polar surfaces is related to the high abundance of different types of surface defects formed via massive restructuring. Importantly, the reconstructed Zn-ZnO surface exhibits high selectivity for hydrogen production at 520 K, which was not observed for the polar O-ZnO surface. The HREELS data revealed that this low-temperature hydrogen evolution on Zn-ZnO results from methoxy oxidation to a formate species occurring at O-terminated step-edge sites.


Mechanisms of ion and acid-base regulation at the gills of freshwater fish.
This review examines the branchial mechanisms utilized by freshwater fish to regulate internal acid-base status and presents a model to explain the underlying basis of the compensatory processes. Rainbow trout, Oncorhynchus mykiss, and brown bullhead, Ictalurus nebulosus, were examined under a variety of experimental treatments which induced respiratory and metabolic acid-base disturbances. Acid-base regulation was achieved by appropriate adjustments of Na+ and Cl- net fluxes across the gills which, in turn, were accomplished by variable contributions of three different branchial mechanisms: 1) differential changes in Na+ and Cl- diffusive effluxes, 2) changes in internal substrate (H+, HCO3-) availability, and 3) morphological adjustments to the gill epithelium. Differential diffusive efflux of Na+ over Cl- was involved only during periods of metabolic alkalosis. The importance of internal substrate availability was demonstrated using a two-substrate model. According to the model, ionic flux rates (J(in)Cl-, J(in)Na+) are determined not only by the concentration of the external ion (Na+, Cl-) but also by the concentration of the internal counterion (H+, HCO3-). This system provides for an "automatic negative feedback" to aid in the compensation of metabolic acid-base disturbances. Morphological alteration of the gill epithelia and the associated regulation of chloride cell (CC) fractional area is an essential third mechanism which is especially important during respiratory acid-base disturbances. Specifically, fish vary the availability of the CC associated Cl-/HCO3- exchange mechanism by physical covering/uncovering of CCs by adjacent pavement cells.


Influence of magnesium and parathyroid hormone on cisplatin-induced nephrotoxicity in esophageal squamous cell carcinoma.
Magnesium (Mg) supplementation has previously been demonstrated to confer protective effects against nephrotoxicity induced by cisplatin. Parathyroid hormone (PTH) regulates Mg homeostasis. The aim of present study was to determine the protective effects of Mg supplementation against cisplatin-induced nephrotoxicity and its association with PTH levels in patients with esophageal squamous cell carcinoma (ESCC). A total of 55 patients with primary ESCC who received chemotherapy with high-dose cisplatin were examined. Mg was administered intravenously, and serum concentrations of PTH, parathyroid hormone-related protein (PTH-rP), creatinine and Mg were prospectively measured. Of the 55 patients, 37 received Mg supplementation. Post-chemotherapeutic creatinine concentrations were significantly increased in patients without Mg supplementation (P=0.01), with grade 1 and 2 increases of 22.2 and 5.6%, respectively, whereas these increases were suppressed by Mg supplementation (change in creatinine, P=0.21), with grade 1 and 2 increases of 8.1 and 0%, respectively. In addition, PTH and PTH-rP concentrations were high in 8 (14.5%) and 6 (10.9%) of all 55 patients, respectively. Alterations in creatinine concentrations (post-/pre-chemotherapy) due to chemotherapy were higher in patients with high levels of PTH regardless of Mg supplementation (P<0.01). Pre-therapeutic creatinine concentrations did not correlate with the alterations in creatinine concentrations due to chemotherapy. Intravenous Mg supplementation therefore conferred protective effects against cisplatin-induced nephrotoxicity in patients with ESCC. Furthermore, increases in PTH or PTH-rP may have influenced the extent of nephrotoxicity.


A boronate affinity sandwich assay: an appealing alternative to immunoassays for the determination of glycoproteins.
Immunoassay has been an essential tool in many areas, including clinical diagnostics. However, it suffers from drawbacks, such as poor availability of high specificity antibodies, limited stability of biological reagents, as well as damage to health and susceptibility of chemical labels to the sample environment. Here we present a new approach, a boronate-affinity sandwich assay (BASA), for the specific and sensitive determination of trace glycoproteins in complex samples. BASA relies on the formation of sandwiches between boronate-affinity molecularly imprinted polymers (MIPs), target glycoproteins, and boronate-affinity surface-enhanced Raman scattering (SERS) probes. The MIP ensures the specificity, while the SERS detection provides the sensitivity. BASA overcomes the drawbacks of traditional immunoassays and offers a great prospect for application.


Virtual lesion of right posterior superior temporal sulcus modulates conscious visual perception of fearful expressions in faces and bodies.
The posterior Superior Temporal Suclus (pSTS) represents a central hub in the complex cerebral network for person perception and emotion recognition as also suggested by its heavy connections with face- and body-specific cortical (e.g., the fusiform face area, FFA and the extrastriate body area, EBA) and subcortical structures (e.g., amygdala). Information on whether pSTS is causatively involved in sustaining conscious visual perception of emotions expressed by faces and bodies is lacking. We explored this issue by combining a binocular rivalry procedure (where emotional and neutral face and body postures rivaled with house images) with off-line, 1-Hz repetitive transcranial magnetic stimulation (rTMS). We found that temporary inhibition of the right pSTS reduced perceptual dominance of fearful faces and increased perceptual dominance of fearful bodies, while leaving unaffected the perception of neutral face and body images. Inhibition of the vertex had no effect on conscious visual perception of neutral or emotional face or body stimuli. Thus, the right pSTS plays a causal role in shortening conscious vision of fearful faces and in prolonging conscious vision of fearful bodies. These results suggest that pSTS selectively modulates the activity of segregated networks involved in the conscious visual perception of emotional faces or bodies. We speculate that the opposite role of the right pSTS for conscious perception of fearful face and body may be explained by the different connections that this region entertains with face- and body-selective visual areas as well as with amygdalae and premotor regions.


Charcot-Marie-Tooth disease subtypes and genetic testing strategies.
Charcot-Marie-Tooth disease (CMT) affects 1 in 2,500 people and is caused by mutations in more than 30 genes. Identifying the genetic cause of CMT is often necessary for family planning, natural history studies, and for entry into clinical trials. However genetic testing can be both expensive and confusing to patients and physicians. We analyzed data from 1,024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. We identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT. Of 1,024 patients evaluated, 787 received CMT diagnoses. A total of 527 patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, hereditary neuropathy with liability to pressure palsies (HNPP), CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had >1 genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we propose a strategy of focused genetic testing for CMT, illustrated in a series of flow diagrams created as testing guides.


5-Azido-2-aminopyridine, a new nitrene/nitrenium ion photoaffinity labeling agent that exhibits reversible intersystem crossing between singlet and triplet nitrenes.
The photochemistry of a new photoaffinity labeling (PAL) agent, 5-azido-2-(N,N-diethylamino)pyridine, was studied in aprotic and protic solvents using femtosecond-to-microsecond transient absorption and product analysis, in conjunction with ab initio multiconfigurational and multireference quantum chemical calculations. The excited singlet S1 state is spectroscopically dark, whereas photoexcitation to higher-lying singlet excited S2 and S3 states drives the photochemical reaction toward a barrierless ultrafast relaxation path via two conical intersections to S1, where N2 elimination leads to the formation of the closed-shell singlet nitrene. The singlet nitrene undergoes intersystem crossing (ISC) to the triplet nitrene in aprotic and protic solvents as well as protonation to form the nitrenium ion. The ISC rate constants in aprotic solvents increase with solvent polarity, displaying a "direct" gap effect, whereas an "inverse" gap effect is observed in protic solvents. Transient absorption actinometry experiments suggest that a solvent-dependent fraction from 20% to 50% of nitrenium ions is generated on a time scale of a few tens of picoseconds. The closed-shell singlet and triplet nitrene are separated by a small energy gap in protic solvents. As a result, the unreactive triplet state nitrene undergoes delayed, thermally activated reverse ISC to reform the reactive closed-shell singlet nitrene, which subsequently protonates, forming the remaining fraction of nitrenium ions. The product studies demonstrate that the resulting nitrenium ion stabilized by the electron-donating 4-amino group yields the final cross-linked product with high, almost quantitative efficiency. The enhanced PAL function of this new azide with respect to the widely applied 4-amino-3-nitrophenyl azide is discussed.


4D-PET reconstruction using a spline-residue model with spatial and temporal roughness penalties.
4D reconstruction of dynamic positron emission tomography (dPET) data can improve the signal-to-noise ratio in reconstructed image sequences by fitting smooth temporal functions to the voxel time-activity-curves (TACs) during the reconstruction, though the optimal choice of function remains an open question. We propose a spline-residue model, which describes TACs as weighted sums of convolutions of the arterial input function with cubic B-spline basis functions. Convolution with the input function constrains the spline-residue model at early time-points, potentially enhancing noise suppression in early time-frames, while still allowing a wide range of TAC descriptions over the entire imaged time-course, thus limiting bias. Spline-residue based 4D-reconstruction is compared to that of a conventional (non-4D) maximum a posteriori (MAP) algorithm, and to 4D-reconstructions based on adaptive-knot cubic B-splines, the spectral model and an irreversible two-tissue compartment ('2C3K') model. 4D reconstructions were carried out using a nested-MAP algorithm including spatial and temporal roughness penalties. The algorithms were tested using Monte-Carlo simulated scanner data, generated for a digital thoracic phantom with uptake kinetics based on a dynamic [18F]-Fluromisonidazole scan of a non-small cell lung cancer patient. For every algorithm, parametric maps were calculated by fitting each voxel TAC within a sub-region of the reconstructed images with the 2C3K model. Compared to conventional MAP reconstruction, spline-residue-based 4D reconstruction achieved >50% improvements for five of the eight combinations of the four kinetics parameters for which parametric maps were created with the bias and noise measures used to analyse them, and produced better results for 5/8 combinations than any of the other reconstruction algorithms studied, while spectral model-based 4D reconstruction produced the best results for 2/8. 2C3K model-based 4D reconstruction generated the most biased parametric maps. Inclusion of a temporal roughness penalty function improved the performance of 4D reconstruction based on the cubic B-spline, spectral and spline-residue models.


LCC-09, a Novel Salicylanilide Derivative, Exerts Anti-Inflammatory Effect in Vascular Endothelial Cells.
Endothelial cell (EC) activation facilitates leukocyte adhesion to vascular walls, which is implicated in a variety of cardiovascular diseases and is a target for prevention and treatment. Despite the development of anti-inflammatory medications, cost-effective therapies with significant anti-inflammatory effects and lower organ toxicity remain elusive. The goal of this study is to identify novel synthetic compounds that inhibit EC inflammatory response with minimal organ toxicity. In this study, we discovered LCC-09, a salicylanilide derivative consisting of the functional fragment of magnolol, 2,4-difluorophenyl, and paeonol moiety of salicylate, as a novel anti-inflammatory compound in cultured ECs and zebrafish model. LCC-09 was shown to inhibit pro-inflammatory cytokine tumor necrosis factor-α (TNFα)-induced expression of adhesion molecules and inflammatory cytokines, leading to reduced leukocyte adhesion to ECs. Mechanistically, LCC-09 inhibits the phosphorylation of signal transducer and activator of transcription 1 (STAT1), TNFα-induced degradation of NF-κ-B Inhibitor-α (IκBα) and phosphorylation of NFκB p65, resulting in reduced NFκB transactivation activity and binding to E-selectin promoter. Additionally, LCC-09 attenuated TNFα-induced generation of reactive oxygen species in ECs. Molecular docking models suggest the binding of LCC-09 to NFκB essential modulator (NEMO) and Janus tyrosine kinase (JAK) may lead to dual inhibition of NFκB and STAT1. Furthermore, the anti-inflammatory effect of LCC-09 was validated in the lipopolysaccharides (LPS)-induced inflammation model in zebrafish. Our results demonstrated that LCC-09 significantly reduced the LPS-induced leukocyte recruitment and mortality of zebrafish embryos. Finally, LCC-09 was administered to cultured ECs and zebrafish embryos and showed minimal toxicities. Our results support that LCC-09 inhibits EC inflammatory response but does not elicit significant toxicity.


Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes.
It is well established that NADH/NAD+ redox balance is heavily perturbed in diabetes, and the NADH/NAD+ redox imbalance is a major source of oxidative stress in diabetic tissues. In mitochondria, complex I is the only site for NADH oxidation and NAD+ regeneration and is also a major site for production of mitochondrial reactive oxygen species (ROS). Yet how complex I responds to the NADH/NAD+ redox imbalance and any potential consequences of such response in diabetic pancreas have not been investigated. We report here that pancreatic mitochondrial complex I showed aberrant hyperactivity in either type 1 or type 2 diabetes. Further studies focusing on streptozotocin (STZ)-induced diabetes indicate that complex I hyperactivity could be attenuated by metformin. Moreover, complex I hyperactivity was accompanied by increased activities of complexes II to IV, but not complex V, suggesting that overflow of NADH via complex I in diabetes could be diverted to ROS production. Indeed in diabetic pancreas, ROS production and oxidative stress increased and mitochondrial ATP production decreased, which can be attributed to impaired pancreatic mitochondrial membrane potential that is responsible for increased cell death. Additionally, cellular defense systems such as glucose 6-phosphate dehydrogenase, sirtuin 3, and NQO1 were found to be compromised in diabetic pancreas. Our findings point to the direction that complex I aberrant hyperactivity in pancreas could be a major source of oxidative stress and β cell failure in diabetes. Therefore, inhibiting pancreatic complex I hyperactivity and attenuating its ROS production by various means in diabetes might serve as a promising approach for anti-diabetic therapies.


Childhood language skills and adult literacy: a 29-year follow-up study.
Our aim was to assess the longitudinal trajectory of childhood receptive language skills and early influences on the course of language development. Drawing on data collected for a nationally representative British birth cohort, the 1970 British Cohort Study, we examined the relationship between directly assessed early receptive language ability, family background, housing conditions, early literacy environment, and adult literacy skills. A sample of 11349 cohort members who completed the English Picture Vocabulary Test at 5 years of age were studied again at 34 years of age, when they completed a direct assessment of their basic literacy skills. We contrasted experiences of individuals with language problems at age 5 against the experiences of those with normal language skills at that age, assessing the role of socioeconomic family background and early literacy environment in influencing the longitudinal course of developmental language problems. Statistical comparisons of rates with chi(2) tests at P values of .001, .01, and .05 were made, as well as multivariate logistic regressions. Cohort members with receptive language problems at age 5 had a relatively disadvantaged home life in childhood, both in terms of socioeconomic resources and the education level of their parents, but also regarding their exposure to a stimulating early literacy environment. Although there is significant risk for poor adult literacy among children with early language problems, the majority of these children develop competent functional literacy levels by the age of 34. Factors that reduce the risk for persistent language problems include the child being born into a working family, parental education beyond minimum school-leaving age, advantageous housing conditions, and preschool attendance. Effective literacy-promoting interventions provided by pediatric primary care providers should target both children and parents.


Detection of Naegleria species in environmental samples from Peninsular Malaysia.
In Malaysia, researchers and medical practitioners are unfamiliar with Naegleria infections. Thus little is known about the existence of pathogenic Naegleria fowleri, and the resultant primary amoebic meningoencephalitis (PAM) is seldom included in the differential diagnosis of central nervous system infections. This study was conducted to detect the presence of Naegleria species in various environmental samples. A total of 41 Naegleria-like isolates were isolated from water and dust samples. All these isolates were subjected to PCR using two primer sets designed from the ITS1-ITS2 regions. The N. fowleri species-specific primer set failed to produce the expected amplicon. The Naegleria genus-specific primers produced amplicons of 408 bp (35), 450 bp (2), 457 bp (2) or 381 bp (2) from all 41 isolates isolated from aquatic (33) and dust (8) samples. Analysis of the sequences from 10 representative isolates revealed that amplicons with fragments 408, 450 and 457 bp showed homology with non-pathogenic Naegleria species, and 381 bp showed homology with Vahlkampfia species. These results concurred with the morphological observation that all 39 isolates which exhibited flagella were Naegleria, while 2 isolates (AC7, JN034055 and AC8, JN034056) that did not exhibit flagella were Vahlkampfia species. To date, pathogenic species of N. fowleri have not been isolated from Malaysia. All 39 isolates that produced amplicons (408, 450 and 457 bp) from the genus-specific primers were identified as being similar to nonpathogenic Naegleria. Amplicon 408 bp from 5 representative isolates showed 100% and 99.7% identity to Naegleria philippinensis isolate RJTM (AM167890) and is thus believed to be the most common species in our environment. Amplicons 450 bp and 457 bp were respectively believed to be from 2 new species of Naegleria, since representative isolates showed lower homology and had a longer base pair length when compared to the reference species in the Genbank, Naegleria schusteri (AJ566626) and Naegleria laresi (AJ566630), respectively.


Papillomavirus-like particles are an effective platform for amyloid-beta immunization in rabbits and transgenic mice.
Immunization with amyloid-beta (Abeta) prevents the deposition of Abeta in the brain and memory deficits in transgenic mouse models of Alzheimer's disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Abeta vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Abeta vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1-9 aa of Abeta protein repetitively on the viral capsid surface (Abeta-VLP). This Abeta peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Abeta-VLP were well tolerated and induced high-titer autoAb against Abeta, that inhibited effectively assembly of Abeta(1-42) peptides into neurotoxic fibrils in vitro. Following Abeta-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Abeta deposits in the brain and increased numbers of activated microglia. Furthermore, Abeta-VLP vaccinated mice also showed increased levels of Abeta in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Abeta-VLP vaccine induces an effective humoral immune response to Abeta and may thus form a basis to develop a safe and efficient immunotherapy for human AD.


Diagnostic delay in breast cancer: correlation with disease stage and prognosis.
Diagnostic delay in a group of 189 women with breast cancer was studied and correlated with first symptom, stage of disease, histologic grade and prognosis. Diagnostic delay was divided into patient delay (time from the patient's discovery of a symptom to the first medical consultation) and system delay (time from medical diagnosis to treatment). Patients were divided into five groups by patient-delay time: 0 to 30 days; 31 to 90 days; 91 to 180 days; 181 to 365 days; and greater than 365 days. The median diagnostic delay was 60 days (range, 4-980) and was not influenced by patient age, marital status or nature of first symptom. A consistent and direct relationship was found between delay and tumor size, nodal involvement, presence of metastases, and histologic grade of disease at diagnosis. No correlation was found between diagnostic delay and histologic type distribution. The three-year survival rate after treatment was significantly lower for patients with a longer delay. Our data indicate that diagnostic delay appears to be an important determinant of stage at diagnosis in women with breast cancer and that it has an important influence on survival. In most cases, delay was mainly patient dependent (60 days); the median system-dependent delay was 15 days (range, 4-47). Since early treatment is generally accepted to be one of the most important determinants of prognosis in breast cancer patients, a reduction in diagnostic delay may lengthen survival time.


Association of endometriosis and breast cancer: mini review of the literature.
Endometriosis is a common, estrogen-dependent, gynecological disease, which is defined as the presence of endometrial tissue outside the uterine cavity. Current data have associated endometriosis with specific malignancies, including ovarian and breast cancer. The purpose of our study is to summarize and present published literature providing evidence regarding the possible relationship between endometriosis and breast cancer. Pubmed and Scopus databases were searched systematically for studies that sought to identify a potential association of endometriosis and breast cancer. 15 relevant articles were retrieved and included in the present review. A small number of observational studies have shown a correlation of endometriosis and breast cancer. Other studies found that the risk of breast cancer increases with age. The scenario of an early interruption of the inflammatory process, derived from endometriosis, by oophorectomy and a possible consequent decrease in the risk of breast cancer has also been proposed. The hypothesis that both conditions could be related through common mutations on BRAC1 and BRAC2 genes has also been investigated. The available published evidence is inconclusive. Further studies are needed to evaluate the association of endometriosis and breast cancer and the possible pathogenetic pathways that relate the two disorders.


A novel approach to postmastectomy radiation therapy using scanned proton beams.
Postmastectomy radiation therapy (PMRT), currently offered at Massachusetts General Hospital, uses proton pencil beam scanning (PBS) with intensity modulation, achieving complete target coverage of the chest wall and all nodal regions and reduced dose to the cardiac structures. This work presents the current methodology for such treatment and the ongoing effort for its improvements. A single PBS field is optimized to ensure appropriate target coverage and heart/lung sparing, using an in-house-developed proton planning system with the capability of multicriteria optimization. The dose to the chest wall skin is controlled as a separate objective in the optimization. Surface imaging is used for setup because it is a suitable surrogate for superficial target volumes. In order to minimize the effect of beam range uncertainties, the relative proton stopping power ratio of the material in breast implants was determined through separate measurements. Phantom measurements were also made to validate the accuracy of skin dose calculation in the treatment planning system. Additionally, the treatment planning robustness was evaluated relative to setup perturbations and patient breathing motion. PBS PMRT planning resulted in appropriate target coverage and organ sparing, comparable to treatments by passive scattering (PS) beams but much improved in nodal coverage and cardiac sparing compared to conventional treatments by photon/electron beams. The overall treatment time was much shorter than PS and also shorter than conventional photon/electron treatment. The accuracy of the skin dose calculation by the planning system was within ±2%. The treatment was shown to be adequately robust relative to both setup uncertainties and patient breathing motion, resulting in clinically satisfying dose distributions. More than 25 PMRT patients have been successfully treated at Massachusetts General Hospital by using single-PBS fields. The methodology and robustness of both the setup and the treatment have been discussed.


HIV infection of primate lymphocytes and conservation of the CD4 receptor.
The CD4 T-lymphocyte differentiation antigen is an essential component of the cell surface receptor for human immunodeficiency viruses (HIVs) causing AIDS (acquired immune deficiency syndrome) (refs 1-3). Peripheral blood lymphocytes of apes, New World and Old World monkeys express cell surface antigens homologous to CD4 of human T-helper lymphocytes. The cells of several of these species can be infected in short term culture with diverse strains of the type-1 or type-2 human immunodeficiency viruses (HIV-1 and HIV-2). HIV-1 is the prototype AIDS virus, and HIV-2 is the second type of AIDS virus, prevalent in West Africa. Infection of the primate cells correlates with evolutionary conservation on CD4 of one particular epitope cluster, and is inhibited by treatment of the cells with monoclonal antibodies to this epitope. The capacity of HIV to replicate in simian cells may provide a means for evaluating antiviral drugs and vaccines.


Use of electric blankets and association with prevalence of endometrial cancer.
The objective of this study was to assess the relationship between electric blanket use and prevalence of endometrial cancer for women. Information relating to women enrolled in the Women's Health Initiative Observational Data Set (n=93 676) used to test the relationship factors associated with endometrial cancer included older age at screening, younger age at last menstrual period, region of domicile (highest prevalence in the South), less than a high school education, lower income, body mass index >25 kg/m, low parity, unopposed use of estrogen, never use of estrogen plus progesterone, past alcohol use, higher percentage of daily calories from fat and any electric blanket use. Following a univariate identification of factors significantly related to endometrial cancer, stepwise logistic regression analysis was performed for those factors with P values of less than 0.001 in the univariate analysis. Using electric blankets was associated with a 15% higher prevalence of endometrial cancer than never having used electric blankets (odds ratio=1.15, 95% confidence interval: 1.03-1.27). After controlling for variables significantly associated with endometrial cancer, use of electric blankets for 20 years or more was associated with 36% higher prevalence of endometrial cancer (odds ratio=1.36, 95% confidence interval: 1.16-1.59). Although we were unable to determine the duration of electric blanket use before diagnosis of endometrial cancer, we found that women using electric blankets for 20 years or more had a significantly higher prevalence.


Responsive and Equitable Health Systems-Partnership on Non-Communicable Diseases (RESPOND) study: a mixed-methods, longitudinal, observational study on treatment seeking for hypertension in Malaysia and the Philippines.
Hypertension is a leading contributor to the global burden of disease. While safe and effective treatment exists, blood pressure control is poor in many countries, often reflecting barriers at the levels of health systems and services as well as at the broader level of patients' sociocultural contexts. This study examines how these interact to facilitate or hinder hypertension control, taking into account characteristics of service provision components and social contexts. The study, set in Malaysia and the Philippines, builds on two systematic reviews of barriers to effective hypertension management. People with hypertension (pre-existing and newly diagnosed) will be identified in poor households in 24-30 communities per country. Quantitative and qualitative methods will be used to examine their experiences of and pathways into seeking and obtaining care. These include two waves of household surveys of 20-25 participants per community 12-18 months apart, microcosting exercises to assess the cost of illness (including costs due to health seeking activities and inability to work (5 per community)), preliminary and follow-up in-depth interviews and digital diaries with hypertensive adults over the course of a year (40 per country, employing an innovative mobile phone technology), focus group discussions with study participants and structured assessments of health facilities (including formal and informal providers). Ethical approval has been granted by the Observational Research Ethics Committee at the London School of Hygiene and Tropical Medicine and the Research Ethics Boards at the Universiti Putra Malaysia and the University of the Philippines Manila. The project team will disseminate findings and engage with a wide range of stakeholders to promote uptake and impact. Alongside publications in high-impact journals, dissemination activities include a comprehensive stakeholder analysis, engagement with traditional and social media and 'digital stories' coproduced with research participants.


Effects of corticosterone on corticotrophin-releasing hormone and gastrin-releasing peptide release in response to an aversive stimulus in two regions of the forebrain (central nucleus of the amygdala and prefrontal cortex).
Previous research has shown that chronic corticosterone treatment increases the expression of corticotrophin-releasing hormone (CRH) mRNA at the central nucleus of the amygdala (CeA). Like CRH, gastrin-releasing peptide (GRP) appears to be involved in mediation of the stress response and is released at the CeA during exposure to an acute stressor. Using in-vivo microdialysis, this study examined the effects of corticosterone treatment on the release of CRH and GRP in response to an airpuff challenge at two forebrain regions, the CeA and medial prefrontal cortex. Adrenally intact rats were treated with corticosterone by systemic implants over a 14-day period prior to microdialysis probe insertion. We found that, at both regions, the airpuff-induced CRH and GRP release were enhanced in the corticosterone pellet-implanted rats as compared with the release observed in the vehicle-implanted control rats. These findings suggest that chronic corticosterone exposure potentiates the stressor-elicited release of CRH and GRP. As cortisol dysregulation has frequently been reported in people with psychiatric conditions, such as anxiety disorders or depression, a better understanding of the glucocorticoid-mediating regulation of CRH and GRP may provide insight into the underlying neurochemical mechanisms involved in both adaptive fear-type responses and maladaptive responses leading to pathology.


Low-dose apatinib monotherapy in advanced chemotherapy-refractory small cell lung cancer: a case series and literature review.
The therapeutic regimen for small cell lung cancer (SCLC) has changed little in the past several decades. Apatinib is a small molecule inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase. Apatinib has demonstrated efficacy against advanced gastric cancer and breast cancer, and recent studies have also reported its successful use in non-SCLC; however, its efficacy in SCLC remains unclear. In this study, we used apatinib as salvage therapy for chemotherapy-refractory SCLC. Five male patients with advanced SCLC were administered oral apatinib (250 mg/day) as 2nd- to 4th-line treatment. One patient showed a partial response to apatinib, one showed stable disease, and three patients showed progressive disease. The progression-free survival durations in the patients with stable disease and partial response were 1.5 and 3 months, respectively. Only three patients showed adverse effects, including mild hypertension, vomiting, and hand-foot syndrome, respectively, all of which were manageable. Apatinib might thus be a salvage option in patients with advanced SCLC after chemotherapy.


mRNA quality control goes transcriptional.
Eukaryotic mRNAs are extensively processed to generate functional transcripts, which are 5' capped, spliced and 3' polyadenylated. Accumulation of unprocessed (aberrant) mRNAs can be deleterious for the cell, hence processing fidelity is closely monitored by QC (quality control) mechanisms that identify erroneous transcripts and initiate their selective removal. Nucleases including Xrn2/Rat1 and the nuclear exosome have been shown to play an important role in the turnover of aberrant mRNAs. Recently, with the growing appreciation that mRNA processing occurs concomitantly with polII (RNA polymerase II) transcription, it has become evident that QC acts at the transcriptional level in addition to degrading aberrant RNAs. In the present review, we discuss mechanisms that allow cells to co-transcriptionally initiate the removal of RNAs as well as down-regulate transcription of transcripts where processing repeatedly fails.


Association between Chronic Kidney Disease and Risk of Cataract: A Nationwide Retrospective Cohort Study.
Previous studies have established a relationship between chronic kidney disease (CKD) and cataract, but the relationship between the severity of renal impairment and risk of cataract is uncertain. This study investigates the relationship between the severity of renal disease and cataract in a nationwide sample from Taiwan. The cohort from 1-million National Health Insurance beneficiaries from Taiwan was retrospectively analyzed. All adult beneficiaries were followed from January 1, 2005 until December 31, 2013, to identify patients who underwent cataract surgeries. On the basis of the ambulatory care records, those diagnosed with CKD (ICD-9-CM code: 585) during the follow-up period were enrolled as CKD patients after careful evaluation. Each patient with CKD was age- and gender-matched with 4 individuals who did not have CKD. Cox regression models were applied to compare the hazard of cataract surgery in individuals with and without CKD. Subgroup analysis was used to compare patients with end-stage renal disease (ESRD) with age- and gender-matched non-CKD individuals. ESRD was defined by CKD patients who need regular renal replacement therapy. The same method was applied to evaluate hazard ratios (HRs). After age and gender matching, there were 11,881 patients in the CKD group and 47,524 in the non-CKD group. After control for possible confounding, the adjusted HR (aHR) of cataract was 1.84 (95% CI 1.73-1.95) for the CKD group. Subgroup analysis of patients with ESRD (n = 3,209) and non-CKD individuals (n = 12,836), with matching done on the basis of age and gender, indicated an aHR of cataract was 2.33 (95% CI 2.10-2.59) for the ESRD group. This study indicates a relationship between CKD and cataract, and suggests that the risk for cataract increases with the severity of renal impairment.


The use of echinocandins in hospitalized children in the United States.
Echinocandins are used for treatment of invasive candidiasis, but data on their use in children are limited. We sought to describe the epidemiology of echinocandin use in hospitalized children in the United States. We performed a retrospective cohort study of children <18 years of age hospitalized between January 2005 and December 2015 and exposed to ≥1 day of a systemic antifungal agent using the Pediatric Health Information System (PHIS) database. Univariate analyses compared recipients of two echinocandin agents, caspofungin and micafungin. Crude prescribing rates of each antifungal group were calculated across hospitals and per year. The rate of antifungal agent prescribing over time was assessed using two-level mixed-effects negative binomial regression, accounting for variability in prescribing by hospital over time. From 2005 to 2015, fluconazole was prescribed most often (n = 148,859, 74.3%), followed by mould-active triazoles (n = 36,131, 18.0%), amphotericin products (n = 29,008, 14.5%), and echinocandins (n = 28,371, 14.2%). The crude rate of systemic antifungal prescribing decreased across all PHIS hospitals from 36.3 to 33.8 per 1000 admissions during the study period, but echinocandin prescribing increased from 2.2 to 7.2 per 1000 admissions. A mixed effects regression model revealed that echinocandin prescribing increased by 15.1% per year (95% CI 11.2-19.2). Echinocandin administration increased from 6.1% to 21.0% of admissions during which a systemic antifungal agent was given. In conclusion, echinocandin use has increased significantly over time, accounting for an increasing proportion of systemic antifungal prescribing in children.


Surgeon radiation dose during complex endovascular procedures.
Surgeon radiation dose during complex fluoroscopically guided interventions (FGIs) has not been well studied. We sought to characterize radiation exposure to surgeons during FGIs based on procedure type, operator position, level of operator training, upper vs lower body exposure, and addition of protective shielding. Optically stimulable, luminescent nanoDot (Landauer, Inc, Glenwood, Ill) detectors were used to measure radiation dose prospectively to surgeons during FGIs. The nanoDot dosimeters were placed outside the lead apron of the primary and assistant operators at the left upper chest and left lower pelvis positions. For each case, the procedure type, the reference air kerma, the kerma-area product, the relative position of the operator, the level of training of the fellow, and the presence or absence of external additional shielding devices were recorded. Three positions were assigned on the right-hand side of the patient in decreasing relative proximity to the flat panel detector (A, B, and C, respectively). Position A (main operator) was closest to the flat panel detector. Position D was on the left side of the patient at the brachial access site. The nanoDots were read using a microSTARii medical dosimetry system (Landauer, Inc) after every procedure. The nanoDot dosimetry system was calibrated for scattered radiation in an endovascular suite with a National Institute of Standards and Technology traceable solid-state radiation detector (Piranha T20; RTI Electronics, Fairfield, NJ). Comparative statistical analysis of nanoDot dose levels between categories was performed by analysis of variance with Tukey pairwise comparisons. Bonferroni correction was used for multiple comparisons. There were 415 nanoDot measurements with the following case distribution: 16 thoracic endovascular aortic repairs/endovascular aneurysm repairs, 18 fenestrated endovascular aneurysm repairs (FEVARs), 13 embolizations, 41 lower extremity interventions, 10 fistulograms, 13 visceral interventions, and 3 cerebrovascular procedures. The mean operator effective dose for FEVARs was higher than for other case types (P < .03), 20 μSv at position A and 9 μSv at position B. For all case types, position A (9.0 μSv) and position D (20 μSv) received statistically higher effective doses than position B (4 μSv) or position C (0.4 μSv) (P < .001). However, the mean operator effective dose for position D was not statistically different from that for position A. The addition of the lead skirt significantly decreased the lower body dose (33 ± 3.4 μSv to 6.3 ± 3.3 μSv) but not the upper body dose (6.5 ± 3.3 μSv to 5.7 ± 2.2 μSv). Neither ceiling-mounted shielding nor level of fellow training affected operator dose. Surgeon radiation dose during FGIs depends on case type, operator position, and table skirt use but not on the level of fellow training. On the basis of these data, the primary operator could perform approximately 12 FEVARs/wk and have an annual dose <10 mSv, which would not exceed lifetime occupational dose limits during a 35-year career. With practical case loads, operator doses are relatively low and unlikely to exceed occupational limits.


A hand and a field effect in on-line motor control in unilateral optic ataxia.
Patients with bilateral optic ataxia fail to show rapid perturbation-induced corrections during manual aiming movements. Based on this, it has been proposed that this pathology results from a disruption of processes of on-line motor control in the posterior parietal cortex (PPC). Here, we show that on-line motor control performance in a patient with unilateral optic ataxia is similar to that of pointing towards stationary targets in peripheral vision, showing the same combination of hand and field effects. We also show that in the patient, manual correction towards his ataxic field was possible only when a preceding saccade (100msec earlier) rapidly provides foveal information about the new target location. In control subjects, manual correction was often, but not necessarily preceded by a saccade. These results allow us to put forward a model of visuo-manual transformation, which involves updating of the reach plan based on the target-eye error, and rely upon two dissociated spatial representations (of the hand and of the target, respectively) within the PPC.


Macromolecular and elemental composition analysis and extracellular metabolite balances of Pichia pastoris growing at different oxygen levels.
Analysis of the cell operation at the metabolic level requires collecting data of different types and to determine their confidence level. In addition, the acquired information has to be combined in order to obtain a consistent operational view. In the case of Pichia pastoris, information of its biomass composition at macromolecular and elemental level is scarce particularly when different environmental conditions, such as oxygen availability or, genetic backgrounds (e.g. recombinant protein production vs. non production conditions) are compared. P. pastoris cells growing in carbon-limited chemostat cultures under different oxygenation conditions (% O2 in the bioreactor inlet gas: 21%, 11% and 8%, corresponding to normoxic, oxygen-limiting and hypoxic conditions, respectively), as well as under recombinant protein (antibody fragment, Fab) producing and non-producing conditions, were analyzed from different points of view. On the one hand, the macromolecular and elemental composition of the biomass was measured using different techniques at the different experimental conditions and proper reconciliation techniques were applied for gross error detection of the measured substrates and products conversion rates. On the other hand, fermentation data was analyzed applying elemental mass balances. This allowed detecting a previously missed by-product secreted under hypoxic conditions, identified as arabinitol (aka. arabitol). After identification of this C5 sugar alcohol as a fermentation by-product, the mass balances of the fermentation experiments were validated. After application of a range of analytical and statistical techniques, a consistent view of growth parameters and compositional data of P. pastoris cells growing under different oxygenation conditions was obtained. The obtained data provides a first view of the effects of oxygen limitation on the physiology of this microorganism, while recombinant Fab production seems to have little or no impact at this level of analysis. Furthermore, the results will be highly useful in other complementary quantitative studies of P. pastoris physiology, such as metabolic flux analysis.


Vascular age to determine cardiovascular disease risk: A systematic review of its concepts, definitions, and clinical applications.
Vascular age is an alternate means of representing an individual's cardiovascular risk. Little consensus exists on what vascular age represents and its clinical utility has not been determined. We systematically reviewed the literature to provide a comprehensive overview of different methods that have been used to define vascular age, and to examine its potential clinical value in patient communication and risk prediction. This was a systematic review with data sources of PubMed and Embase. We identified 39 articles on vascular age, 20 proposed to use vascular age as a communication tool and 19 proposed to use vascular age as a means to improve cardiovascular risk prediction. Eight papers were methodological and 31 papers reported on vascular age in study populations. Of these 31 papers, vascular age was a direct translation of the absolute risk estimated by existing cardiovascular risk prediction models in 15 papers, 12 derived vascular age from the reference values of an additional test, and in three papers vascular age was defined as the age at which the estimated cardiovascular risk equals the risk from non-invasive imaging observed degree of atherosclerosis. One trial found a small effect on risk factor levels when vascular age was communicated instead of cardiovascular risk. Despite sharing a common name, various studies have proposed distinct ways to define and measure vascular age. Studies into the effects of vascular age as a tool to improve cardiovascular risk prediction or patient communication are scarce but will be required before its clinical use can be justified.


Tunnel field-effect transistors as energy-efficient electronic switches.
Power dissipation is a fundamental problem for nanoelectronic circuits. Scaling the supply voltage reduces the energy needed for switching, but the field-effect transistors (FETs) in today's integrated circuits require at least 60 mV of gate voltage to increase the current by one order of magnitude at room temperature. Tunnel FETs avoid this limit by using quantum-mechanical band-to-band tunnelling, rather than thermal injection, to inject charge carriers into the device channel. Tunnel FETs based on ultrathin semiconducting films or nanowires could achieve a 100-fold power reduction over complementary metal-oxide-semiconductor (CMOS) transistors, so integrating tunnel FETs with CMOS technology could improve low-power integrated circuits.


Updated antibiotic resistance and clinical spectrum of infections caused by Streptococcus pneumoniae in Taiwan: Emphasis on risk factors for penicillin nonsusceptibilities.
Streptococcus pneumoniae is one of the leading pathogens causing community-acquired infection with high mortality rates in elderly patients. Emerging antibiotic resistance was found in past decades. Continuous surveillance to monitor changes in antibiotic resistance of S. pneumoniae and associated risk factors are important clinical issues. Isolates of S. pneumoniae collected from six hospitals participating in the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program III (2002) - VI (2008) were enrolled in this study. Bacterial susceptibilities were determined by minimum inhibitory concentration. The clinical data of source patients were collected retrospectively. A total of 330 nonduplicate S. pneumoniae isolates were enrolled in this study. Sputum was the most common specimen source, followed by pus. The mean age of the source patients was 38 years among these 330 patients, and 247 had various infections caused by S. pneumoniae. The overall in-hospital mortality rate was 6% and most (60%)of the mortality occurred in patients older than 65 years. The mortality rates among the patients age 65 years and older and those age 5 years and younger were 12.9% (9 of 70) and 2.4% (2 of 83), respectively. The rates of nonsusceptibility to penicillin by the meningitis criteria (PNSP-M) were 69.0% in 2002, 81.0% in 2004, 73.7% in 2006, and 74.5% in 2008. Resistance to erythromycin and trimethoprim/sulfamethoxazole remained high. Using multivariate analysis, patients with PNSP isolates were more likely to have a history of antibiotic exposure within the previous 15 days compared with patients with penicillin-susceptible (PSSP) isolates (nonmeningitis criteria: 29.70% vs. 18.34%, p = 0.0288; meningitis criteria: 25.30% vs. 9.88%, p = 0.006). Shock at presentation was the risk factor for in-hospital mortality. Our study demonstrated that the rates of penicillin nonsusceptibility among S. pneumoniae remained high in Taiwan during the study period. Previous antibiotic exposure was the only risk factor for subsequent acquisition of penicillin- nonsusceptible S. pneumoniae compared with penicillin-susceptible S. pneumoniae. Judicious antibiotic use is important to control the spread of drug nonsusceptible S. pneumoniae.


Pack-years of tobacco cigarette smoking as a predictor of spontaneous pain reporting and experimental pain reactivity.
The pack-years formula is a widely used estimate of lifetime tobacco smoking exposure, and greater pack-years have been associated with greater risk of chronic pain development and poorer pain-related outcomes among smokers with chronic pain. The pathophysiology underlying these associations is poorly understood. Regular tobacco smoking exposure may dysregulate homeostatic pain processes, producing an allostatic state of pain facilitation. Maladaptive pain mechanisms, such as central and peripheral sensitization, are chronic pain risk factors. Yet no published research has examined the relation between lifetime-smoking exposure and dysregulated pain processing. The current study used hierarchical linear regression analyses to test pack-years of tobacco smoking as a predictor of (a) pain reporting (current pain severity, pain frequency in the last 180 days) among a sample of 228 daily smokers without chronic pain, and (b) experimental capsaicin-induced pain reactivity (pain intensity, area of flare, mechanical pain sensitivity, and area of mechanical hyperalgesia) among 101 daily smokers without chronic pain. As hypothesized, results indicated that pack-years smoking was positively and significantly associated with current pain severity, past 180-day pain frequency, experimental pain intensity, mechanical pain sensitivity ratings, and area of mechanical hyperalgesia. Pack-years smoking was not significantly associated with neurogenic flare. These findings implicate central sensitization as a factor that may underlie the association between chronic tobacco smoking and increased risk for persistent pain. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Cancer in Patients Referred Abroad For Health Care and Related Foreign Currency Expenses.
There is limited access to health services in Burundi, as most of the services such as cancer care are unavailable. Burundian citizen who can afford the costs involved in seeking treatment elsewhere are referred abroad. The purpose of this study was to assess the proportion of patients suffering from cancer among patients referred abroad for healthcare and to evaluate the costs incurred by those patients in relation to what the country would save by establishing cancer healthcare facilities. The study was performed retrospectively from January 2016 to December 2018. With approval of Ministry of Public Health and AIDS control, the data was collected from medical reports at the general management of health facilities and AIDS control office. All patients with medical reports containing the reason for referral were included in the study. Medical reports assessing occupational disability were excluded. Data analysis was performed using Statistical Package for the Social Sciences (SPSS). Male, female and unclear was 45.3%, 39.9% and 14.8% respectively. Average age was 31,82. The main reason for referral was MRI (21.7%). Cancer patients represented 18% of all patients referred abroad for healthcare and the most common type of cancer found was breast (26.5%), genitourinary (15.7%) and digestive (14,2%). If all patients from 2016-2018 were referred to Kenya, Uganda, Rwanda, India or Europe for 30 years, the country would spend in foreign currency US$3,858,229; US$638,342.80; US$21,288,592; US$10,410,192.90; US$54,718,329.70 respectively. Also, if all patients estimated by Globocan in 2018 were to be referred to these countries, the cost of foreign currencies would be US$52,455,122.60; US$38,264,740.88; US$129,272,590.40; US$81,330,325.94; US$276,601,008.02 respectively. There is a good number of cancer patients among patients referred abroad for health care. The estimated costs incurred by patients referred abroad for cancer care are far greater than funds needed to setup modern cancer care centres in Burundi.


A Systematic Review of the Inclusion (or Exclusion) of Women in HIV Research: From Clinical Studies of Antiretrovirals and Vaccines to Cure Strategies.
The effect of clinical interventions can differ because of sex/gender. Studies have shown that women are often under-represented in medical research. The aim of this systematic literature review was to characterize women's participation in HIV clinical studies of antiretroviral drugs (ARV), prophylactic vaccines (VAX), and curative strategies (CURE). Systematic PubMed searches were conducted to identify ARV, VAX, and CURE studies. Data were extracted on the number of women, date of publication, sources of funding, country of study, and trial phase. Correlates of female participation were assessed. Women represented a median of 19.2% participants in ARV studies (387), 38.1% in VAX studies (53), and 11.1% in CURE studies (104). Funding source was not correlated with the proportion of female participants in VAX and CURE studies but was for ARV studies (P = 0.03). ARV trials funded by private noncommercial sources had the highest proportion of women, whereas publicly funded trials had the lowest female participation (median 16.7%). The median proportion of women in ARV trials that were fully or partially funded by the National Institutes of Health was significantly lower than the median in trials funded by other sources (19.6% vs. 22.3%, P = 0.001). Although women comprise nearly half of people living with HIV, they continue to be under-represented in clinical studies. Despite federal policies that have been established to address this, our study shows that publicly funded ARV trials recruit even fewer women than other trials. There is an urgent need to ensure that HIV clinical studies consider sex/gender dimensions.


Management Approaches to Hepatitis B Virus Vaccination Nonresponse.
Background: Despite the availability of hepatitis B virus (HBV) vaccination, HBV remains a cause of significant morbidity and mortality around the world. Immunologic response and the development of immunity to the HBV vaccine vary significantly among patients. Multiple studies have looked at patients who are at risk of nonresponse and have offered their own approaches to patients who do not respond. This article reviews the best approaches to HBV vaccine nonresponse. Methods: We searched the PubMed database for all articles on HBV vaccination response from 1981 to January 2018. Recommended and tested approaches to nonresponse were identified. Results: A total of 71 adequate-quality studies with 2354 patients were identified. Repeat vaccination with the same dose increased immunologic seroconversion in 85.7% of patients who previously reported nonresponse and in over 80% of patients with end-stage renal disease, HIV infection, hepatitis C virus (HCV) infection, advanced age, hypoalbuminemia, liver cirrhosis, and hemodialysis (HD) dependence. Patients with inflammatory bowel disease, celiac disease, and diabetes had a milder response (67.5%). Increasing the vaccination dose to 40 µg improved seroconversion in HIV-infected, HCV-infected, and HD patients of initial nonresponse. The use of a subcutaneous injection route increased response by 12% in patients infected with HIV. Conclusion: Patients not responding to an initial vaccine series and not actively infected with HBV benefited from reimmunization by repeating the vaccine series or receiving a single-dose vaccine booster. Although the overall response rate was approximately 90% of previous nonresponders, the rate varied among the populations studied.


Opposing effects of D-aspartic acid and nitric oxide on tuning of testosterone production in mallard testis during the reproductive cycle.
D-Aspartic acid (D-Asp) and nitric oxide (NO) play an important role in tuning testosterone production in the gonads of male vertebrates. In particular, D-Asp promotes either the synthesis or the release of testosterone, whereas NO inhibits it. In this study, we have investigated for the first time in birds the putative effects of D-Asp and NO on testicular testosterone production in relation to two phases of the reproductive cycle of the adult captive wild-strain mallard (Anas platyrhynchos) drake. It is a typical seasonal breeder and its cycle consists of a short reproductive period (RP) in the spring (April-May) and a non reproductive period (NRP) in the summer (July), a time when the gonads are quiescent. The presence and the localization of D-Asp and NO in the testis and the trends of D-Asp, NO and testosterone levels were assessed during the main phases of the bird's reproductive cycle. Furthermore, in vitro experiments revealed the direct effect of exogenously administered D-Asp and NO on testosterone steroidogenesis. By using immunohistochemical (IHC) techniques, we studied the presence and the distributional pattern of D-Asp and NO in the testes of RP and NRP drakes. D-Asp levels were evaluated by an enzymatic method, whereas NO content, via nitrite, was assessed using biochemical measurements. Finally, immunoenzymatic techniques determined testicular testosterone levels. IHC analyses revealed the presence of D-Asp and NO in Leydig cells. The distributional pattern of both molecules was in some way correlated to the steroidogenic pathway, which is involved in autocrine testosterone production. Indeed, whereas NO was present only during the NRP, D-Asp was almost exclusively present during the RP. Consistently, the high testosterone testicular content occurring during RP was coupled to a high D-Asp level and a low NO content in the gonad. By contrast, in sexually inactive drakes (NRP), the low testosterone content in the gonad was coupled to a low D-Asp content and to a relatively high NO level. Consequently, to determine the exogenous effects of the two amino acids on testosterone synthesis, we carried out in vitro experiments using testis sections deriving from both the RP and NRP. When testis slices were incubated for 60 or 120 min with D-Asp, testosterone was enhanced, whereas in the presence of L-Arg, a precursor of NO, it was inhibited. Our results provide new insights into the involvement of D-Asp and NO in testicular testosterone production in the adult captive wild-strain mallard drake. The localization of these two molecules in the Leydig cells in different periods of the reproductive cycle demonstrates that they play a potential role in regulating local testosterone production.


Volumetric two-photon imaging of neurons using stereoscopy (vTwINS).
Two-photon laser scanning microscopy of calcium dynamics using fluorescent indicators is a widely used imaging method for large-scale recording of neural activity in vivo. Here, we introduce volumetric two-photon imaging of neurons using stereoscopy (vTwINS), a volumetric calcium imaging method that uses an elongated, V-shaped point spread function to image a 3D brain volume. Single neurons project to spatially displaced 'image pairs' in the resulting 2D image, and the separation distance between projections is proportional to depth in the volume. To demix the fluorescence time series of individual neurons, we introduce a modified orthogonal matching pursuit algorithm that also infers source locations within the 3D volume. We illustrated vTwINS by imaging neural population activity in the mouse primary visual cortex and hippocampus. Our results demonstrated that vTwINS provides an effective method for volumetric two-photon calcium imaging that increases the number of neurons recorded while maintaining a high frame rate.


Male infants with hypospadias and/or cryptorchidism show a lower 2D/4D digit ratio than normal boys.
In humans the ratio of the index finger to the ring finger is sexually dimorphic, with the mean ratio being larger in women than in men. It has been suggested that this difference is related to prenatal androgen exposure. This has been further demonstrated in children with congenital adrenal hyperplasia. Normal development of the male external genitalia is linked to androgen-mediated events during gestation. We therefore wanted to determine if the 2D:4D digit ratio was normal in boys with cryptorchidism or hypospadias. We prospectively enrolled all prepubertal patients seen in the outpatient clinic for cryptorchidism or hypospadias between September and December 2012. We then compared their 2D:4D digit ratio with two control groups made up of normal boys and normal girls. Interobserver and intraobserver variability was evaluated. We included 57 boys with hypospadias and/or cryptorchidism, 79 boys without genital abnormalities and 25 girls without genital abnormalities. The mean 2D:4D ratio for both hands was significantly different between the three groups, with the digit ratio for boys with genital anomalies being lower than for normal boys and normal girls (p<0.0001). It appears that boys with genital abnormalities (cryptorchidism and/or hypospadias) have a lower 2D:4D digit ratio than boys without genital anomalies.


The Effects of Supplementation with a Vitamin and Mineral Complex with Guaraná Prior to Fasted Exercise on Affect, Exertion, Cognitive Performance, and Substrate Metabolism: A Randomized Controlled Trial.
Exercise undertaken in a fasted state can lead to higher post-exercise mental fatigue. The administration of a vitamin and mineral complex with guaraná (MVM + G) has been shown to attenuate mental fatigue and improve performance during cognitively demanding tasks. This placebo-controlled, double-blind, randomized, balanced cross-over study examined the effect of MVM + G consumed prior to morning exercise on cognitive performance, affect, exertion, and substrate metabolism. Forty active males (age 21.4 ± 3.0 year; body mass index (BMI) 24.0 ± 2.4 kg/m2; maximal oxygen consumption (V̇O2max) 57.6 ± 7.3 mL/min/kg) completed two main trials, consuming either MVM + G or placebo prior to a 30-min run at 60% V̇O2max. Supplementation prior to exercise led to a small but significant reduction in Rating of Perceived Exertion (RPE) during exercise compared to the placebo. The MVM + G combination also led to significantly increased accuracy of numeric working memory and increased speed of picture recognition, compared to the placebo. There were no significant effects of supplementation on any other cognitive or mood measures or on substrate metabolism during exercise. These findings demonstrate that consuming a vitamin and mineral complex containing guaraná, prior to exercise, can positively impact subsequent memory performance and reduce perceived exertion during a moderate-intensity run in active males.


Blockade of 4-1BB and 4-1BBL interaction reduces obesity-induced skeletal muscle inflammation.
Obesity-induced skeletal muscle inflammation is characterized by increased macrophage infiltration and inflammatory cytokine production. In this study, we investigated whether 4-1BB, a member of the TNF receptor superfamily (TNFRSF9) that provides inflammatory signals, participates in obesity-induced skeletal muscle inflammation. Expression of the 4-1BB gene, accompanied by increased levels of inflammatory cytokines, was markedly upregulated in the skeletal muscle of obese mice fed a high-fat diet, in muscle cells treated with obesity factors, and in cocultured muscle cells/macrophages. In vitro stimulation of 4-1BB with agonistic antibody increased inflammatory cytokine levels in TNFα-pretreated muscle cells, and this effect was absent in cells derived from 4-1BB-deficient mice. Conversely, disruption of the interaction between 4-1BB and its ligand (4-1BBL) with blocking antibody decreased the release of inflammatory cytokines from cocultured muscle cells/macrophages. Moreover, deficiency of 4-1BB markedly reduced macrophage infiltration and inflammatory cytokine production in the skeletal muscle of mice fed a high-fat diet. These findings indicate that 4-1BB mediates the inflammatory responses in obese skeletal muscle by interacting with its ligand 4-1BBL on macrophages. Therefore, 4-1BB and 4-1BBL may be useful targets for prevention of obesity-induced inflammation in skeletal muscle.


Survival of children with trisomy 13 and trisomy 18: A multi-state population-based study.
Trisomy 13 (T13) and trisomy 18 (T18) are among the most prevalent autosomal trisomies. Both are associated with a very high risk of mortality. Numerous instances, however, of long-term survival of children with T13 or T18 have prompted some clinicians to pursue aggressive treatment instead of the traditional approach of palliative care. The purpose of this study is to assess current mortality data for these conditions. This multi-state, population-based study examined data obtained from birth defect surveillance programs in nine states on live-born infants delivered during 1999-2007 with T13 or T18. Information on children's vital status and selected maternal and infant risk factors were obtained using matched birth and death certificates and other data sources. The Kaplan-Meier method and Cox proportional hazards models were used to estimate age-specific survival probabilities and predictors of survival up to age five. There were 693 children with T13 and 1,113 children with T18 identified from the participating states. Among children with T13, 5-year survival was 9.7%; among children with T18, it was 12.3%. For both trisomies, gestational age was the strongest predictor of mortality. Females and children of non-Hispanic black mothers had the lowest mortality. Omphalocele and congenital heart defects were associated with an increased risk of death for children with T18 but not T13. This study found survival among children with T13 and T18 to be somewhat higher than those previously reported in the literature, consistent with recent studies reporting improved survival following more aggressive medical intervention for these children. © 2015 Wiley Periodicals, Inc.


Microcystin elimination during sediment contact.
Microcystins (MCYSTs) are a group of structurally similar toxic peptides produced by cyanobacteria ("blue-green algae") which occur frequently in surface waters worldwide. Reliable elimination is necessary when using these waters as drinking water sources. Bank filtration and artificial groundwater recharge utilize adsorption and degradation processes in the subsurface, commonly through sand and gravel aquifers, for the elimination of a wide range of substances during drinking water (pre-) treatment. To obtain parameters for estimating whether MCYST breakthrough is likely in field settings, we tested MCYST elimination in laboratory experiments (batch experiments, column experiments) under a range of conditions. Adsorption coefficients (k(d)-values) obtained from batch studies ranged from 0.2 mL/g for filter sand to 11.6 mL/g for fine grained aquifer materials with 2% fine grains (<63 microm) and 0.8% organic matter. First order degradation rates in column studies reached 1.87 d(-1) under aerobic conditions and showed high variations under anoxic conditions (<0.01-1.35 d(-1)). These results show that, next to sediment texture, redox conditions play an important role for MCYST elimination during sediment passage. Biodegradation was identified as the dominating process for MCYST elimination in sandy aquifer material.


Malaria in pregnancy and the endemicity spectrum: what can we learn?
The increased susceptibility of pregnant women to malaria infection has long been recognized, but the magnitude of the disease burden in this particular group, together with the pathophysiology of maternal malaria and the specific difficulties in treatment, have only recently been the focus of research. Most research on maternal malaria has derived from sub-Saharan Africa where transmission is high, whereas most of the studies on the treatment of malaria and the effect of non-falciparum species has been conducted in low-transmission areas of Asia. In this paper, we attempt to improve our understanding of the disease and its mechanisms from observed differences and similarities between contrasting areas of transmission, and to identify priorities for future research.


Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer.
Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n=58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (P<0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P=0.0002, P=0.0003, P=0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P=0.003) and Ki67 (P=0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67(LI)-geminin(LI); (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2(LI)-Ki67(LI); (P=0.01)) and accelerated cell cycle progression (geminin(LI)/Ki67(LI); (P= 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication.


Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo.
The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Commun.2014, 450, 1063). Herein, we establish structure-activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL. However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo.


Addressing the inverse care law: the role of community paediatric services.
Children's health suffers disproportionately from the effects of poverty. The inverse care law states that those who need care the most are the least likely to receive it. Community paediatricians are well placed to address health inequalities in children. To explore, using routinely collected data, whether we address health inequalities and the inverse care law, particularly for certain conditions targeted by our specialty. Five years of data were analysed, during which health equity audits have led to service changes in order to tackle inequities. The data include postcodes, allowing each child to be assigned to a deprivation quintile, and a range of diagnoses, including five sentinel conditions: attention deficit hyperactivity disorder (ADHD) on medication, autistic spectrum disorder (ASD), epilepsy, cerebral palsy and Down's syndrome. This allowed analysis of the caseload by deprivation index for these conditions, comparison with the background population and exploration of time trends. The number of children on the caseload and their distribution across the quintiles remained stable. The proportion of deprived children (i.e. in the lowest two quintiles) on the caseload over the last five years taken together is 56%, compared to 44% in the background population. The numbers of children with ADHD on medication has almost quadrupled in deprived quintiles and doubled in the least deprived quintile, while the numbers of children with this diagnosis in the most deprived is four times that in the least deprived. Numbers of children with ASD have also increased in each quintile. In contrast, the number of children with epilepsy and cerebral palsy did not show much variation, but those from deprived quintiles made up a greater proportion of the caseload. Routine data collection demonstrates that inequalities are addressed using all four quality domains of service provision and sentinel conditions more likely to affect deprived children are targeted. We believe it is possible for all services to collect and analyse data thus with minimal effort, thereby providing a foundation from which to address the inverse care law.


Subpopulations of hyphae secrete proteins or resist heat stress in Aspergillus oryzae colonies.
Hyphae at the outer part of colonies of Aspergillus niger and Aspergillus oryzae are heterogeneous with respect to transcriptional and translational activity. This heterogeneity is maintained by Woronin body mediated closure of septal pores that block interhyphal mixing of cytoplasm. Indeed, heterogeneity between hyphae is abolished in ΔhexA strains that lack Woronin bodies. The subpopulation of hyphae with high transcriptional and translational activity secretes enzymes that degrade the substrate resulting in breakdown products that serve as nutrients. The role of hyphae with low transcriptional and translational activity was not yet known. Here, we show that this subpopulation is more resistant to environmental stress in A. oryzae, in particular to temperature stress, when compared to hyphae with high transcriptional and translational activity. Notably, all hyphae of the ΔhexA strain of A. oryzae were sensitive to heat stress explained by the reduced heterogeneity in this strain. Together, we show that different subpopulations of hypha secrete proteins and resist heat stress showing the complexity of a fungal mycelium.


The effect of an ossicle of the lateral malleolus on ligament reconstruction of chronic lateral ankle instability.
Ossicles at the tip of the lateral malleolus are frequently found in patients with chronic lateral ankle instability (CLAI). However, the relationship between the presence or the size of an ossicle and the outcome of ligament reconstruction is poorly understood. Therefore, this study aimed to evaluate the effect of an ossicle at the tip of the lateral malleolus on ligament reconstruction in CLAI. Seventy-four ankles with chronic lateral instability that received lateral ligament reconstruction using a modified Broström technique between January 2001 and March 2007 were included. The mean followup was 47 (range, 25 to 89) months. Ankles were divided into 2 groups: the ossicle group (26 ankles, 35.1%) and the non-ossicle group (48 ankles, 64.9%). Then, depending on the size, the ossicle group was subdivided into small (less than 10 mm, 14 ankles) and large ossicles (greater than 10 mm, 12 ankles). Pre- and postoperative Karlsson-Peterson ankle scores and findings on stress radiographs were compared between the groups. Both the ossicle and non-ossicle groups improved significantly on stress radiographs without difference between the groups. Karlsson-Peterson ankle scores showed functional improvement in each group, however, the mean score at last followup was significantly lower in the ossicle group (p=0.01). The prevalence of an osteochondral lesion of the talus was significantly higher in the ossicle group (p=0.046). In ankles with large ossicles, varus stability was achieved but anterior displacement of the talus was not improved after ligament reconstruction. The surgeon should be aware of the inferior functional outcome in ankles with ossicles. Also, when the ossicle is large, excision and modified Broström technique may not be suitable to achieve mechanical anteroposterior stability. Therefore, fusing the ossicle to the fibular tip or using other methods of ligament reconstruction can be considered when performing ligament reconstruction in CLAI with associated large ossicles.


TRESK is a key regulator of nocturnal suprachiasmatic nucleus dynamics and light adaptive responses.
The suprachiasmatic nucleus (SCN) is a complex structure dependent upon multiple mechanisms to ensure rhythmic electrical activity that varies between day and night, to determine circadian adaptation and behaviours. SCN neurons are exposed to glutamate from multiple sources including from the retino-hypothalamic tract and from astrocytes. However, the mechanism preventing inappropriate post-synaptic glutamatergic effects is unexplored and unknown. Unexpectedly we discovered that TRESK, a calcium regulated two-pore potassium channel, plays a crucial role in this system. We propose that glutamate activates TRESK through NMDA and AMPA mediated calcium influx and calcineurin activation to then oppose further membrane depolarisation and rising intracellular calcium. Hence, in the absence of TRESK, glutamatergic activity is unregulated leading to membrane depolarisation, increased nocturnal SCN firing, inverted basal calcium levels and impaired sensitivity in light induced phase delays. Our data reveals TRESK plays an essential part in SCN regulatory mechanisms and light induced adaptive behaviours.


The Role of Elders in the Wellbeing of a Contemporary Australian Indigenous Community.
Traditional Elders are integral to the social structure of Australian Indigenous communities. Due to progressive loss of traditional way of life, however, the role of Elders has been eroding. This study aims to develop a conceptual model of the role of Elders in an Australian Indigenous community, with the goal of attaining strategies to strengthen the role of Elders. The study, conducted in a regional Indigenous community in Australia, adopted a community-based participatory approach. Design and focus of the project were informed by a community forum (Yarning Circle). One-on-one semistructured interviews and focus groups with community members were conducted by Indigenous researchers. Group concept mapping (GCM) was applied to elicit major themes in qualitative data, from the point of view of community members, and to derive a conceptual model of the role of Elders. Fifty members of the Indigenous community took part in interviews and focus groups. The participants' median age was 45 years (range 18-76 years); 31 (62%) were female. An additional 24 Indigenous community members took part in the data sorting task of GCM. GCM identified seven major aspects of the role of Elders, including Community relations, Passing down the knowledge, Dealing with racism and oppression, Building a better resourced community, Intergenerational connectedness, Safeguarding our identity, and Caring for our youth. Elders fulfill many important roles in contemporary Indigenous communities. Our results can be used to assist the community to codesign a program to increase community wellbeing.


Are reproductive skew models evolutionarily stable?
Reproductive skew theory has become a popular way to phrase problems and test hypotheses of social evolution. The diversity of reproductive skew models probably stems from the ease of generating new variations. However, I show that the logical basis of skew models, that is, the way in which group formation is modelled, makes use of hidden assumptions that may be problematical as they are unlikely to be fulfilled in all social systems. I illustrate these problems by re-analysing the basic concessive skew model with staying incentives. First, the model assumes that dispersal is an all-or-nothing response: all subordinates disperse as soon as concessions drop below a certain value. This leads to a discontinuous 'cliff-edge' shape of dominant fitness, and it is not clear that selection will balance a population at such an edge. Second, it is assumed that subordinates have perfect knowledge of their benefits if they stay in the group. I examine the effects of relaxing these two assumptions. Relaxing the first one strengthens reproductive skew theory, but relaxing the latter makes evolutionary stability disappear. In cases where subordinates cannot accurately measure benefits provided by the individual dominant with which they live, so that their behaviour instead evolves as a response to population-wide average benefits, the logic of reproductive skew models does not apply. This warns against too indiscriminate an application of reproductive skew theory to problems in social evolution: for example, transactional models of extra-pair paternity assume perfect knowledge of paternity, which is unlikely to hold true in nature. It is recommended that models specify the mechanisms by which individuals can adjust their behaviour to that of others, and pay attention to changes that occur in evolutionary versus behavioural time.


Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin.
Muscle glycogen stores are depleted during exercise and are rapidly repleted during the recovery period. To investigate the mechanism for this phenomenon, untrained male rats were run for 45 min on a motor-driven treadmill and the ability of their muscles to utilize glucose was then assessed during perfusion of their isolated hindquarters. Glucose utilization by the hindquarter was the same in exercised and control rats perfused in the absence of added insulin; however, when insulin (30-40,000 muU/ml) was added to the perfusate, glucose utilization was greater after exercise. Prior exercise lowered both, the concentration of insulin that half-maximally stimulated glucose utilization (exercise, 150 muU/ml; control, 480 muU/ml) and modestly increased its maximum effect. The increase in insulin sensitivity persisted for 4 h following exercise, but was not present after 24 h. The rate-limiting step in glucose utilization enhanced by prior exercise appeared to be glucose transport across the cell membrane, as in neither control nor exercised rats did free glucose accumulate in the muscle cell. Following exercise, the ability of insulin to stimulate the release of lactate into the perfusate was unaltered; however its ability to stimulate the incorporation of [(14)C]glucose into glycogen in certain muscles was enhanced. Thus at a concentration of 75 muU/ml insulin stimulated glycogen synthesis eightfold more in the fast-twitch red fibers of the red gastrocnemius than it did in the same muscle of nonexercised rats. In contrast, insulin only minimally increased glycogen synthesis in the fast-twitch white fibers of the gastrocnemius, which were not glycogen-depleted. The uptake of 2-deoxyglucose by these muscles followed a similar pattern suggesting that glucose transport was also differentially enhanced. Prior exercise did not enhance the ability of insulin to convert glycogen synthase from its glucose-6-phosphate-dependent (D) to its glucose-6-phosphate-independent (1) form. On the other hand, following exercise, insulin prevented a marked decrease in muscle glucose-6-phosphate, which could have diminished synthase activity in situ. The possibility that exercise enhanced the ability of insulin to convert glycogen synthase D to an intermediate form of the enzyme, more sensitive to glucose-6-phosphate, remains to be explored. These results suggest that following exercise, glucose transport and glycogen synthesis in skeletal muscle are enhanced due at least in part to an increase in insulin sensitivity. They also suggest that this increase in insulin sensitivity occurs predominantly in muscle fibers that are deglycogenated during exercise.


Wavelength conversion of 28 GBaud 16-QAM signals based on four-wave mixing in a silicon nanowire.
We demonstrate error-free wavelength conversion of 28 GBaud 16-QAM single polarization (112 Gb/s) signals based on four-wave mixing in a dispersion engineered silicon nanowire (SNW). Wavelength conversion covering the entire C-band is achieved using a single pump. We characterize the performance of the wavelength converter subsystem through the electrical signal to noise ratio penalty as well as the bit error rate of the converted signal as a function of input signal power. Moreover, we evaluate the degradation of the optical signal to noise ratio due to wavelength conversion in the SNW.


In Vitro evaluation of thymoquinone on apoptosis and oxidative DNA damage in high glucose condition.
The study was planned to investigate the effects of thymoquinone (TQ), which is a compound in N. sativa, on caspase dependent apoptosis and oxidative DNA damage in high glucose treated PC12 cells. PC12 cells were treated with high glucose (G1-150 mM, G2-250 mM, G3-350 mM), TQ (20 µM), and their combinations. Oxidative DNA damage (8-OHdG (8-Oxo-2'-deoxyguanosine)), and apoptosis (caspase 3, caspase 8, caspase 9 enzymes and M30 protein) parameters were analyzed with ELISA. The 8-OHdG levels decreased in all combination groups compared to the control (p≤0.001). There was no statistically significant difference between caspase 3 and 9. Caspase 8 in TQ, G3, TQG1, TQG2 groups were higher than the control (p≤0.002). Low M30 levels were observed in TQG1 group (p≤0.002). In conclusion, it was observed that in PC12 cell line treated with the high glucose concentrations, TQ administration had a statistically significant effect on oxidative DNA damage and some apoptotic parameters (caspase 8 and M30 protein).


Axotomized motoneurons can be rescued from cell death by peripheral nerve grafts: the effect of donor age.
Injury to neonatal nerves, unlike adult nerves, results in poor regeneration and extensive motoneuron death. We examined whether exposure to a more mature nerve environment could rescue axotomized motoneurons following neonatal injury. The sciatic nerve in 1 hindlimb of 3-day-old (P3) rats was transected and the cut end sutured to a nerve graft taken from donor rats, which ranged between P3 and P21. The extent of motoneuron survival and axon regeneration was established 7 days later. Since integrins play an important role in regeneration, we also examined the effect of manipulating integrin binding in nerve grafts. Following axotomy at P3 and implantation of nerve grafts from 3-day-old rats, approximately 38% of motoneurons survived. In contrast, grafts from rats aged 5 days and older resulted in an improvement in regeneration, and over 70% of motoneurons survived. This survival-promoting effect of P5 grafts was prevented by blocking beta1-integrins. In contrast, increasing beta1-integrin levels in grafts from P3 rats dramatically increased motoneuron survival. Thus, following neonatal nerve injury, exposure to a more mature nerve environment significantly increases motoneuron survival, an effect that is dependent upon beta1-integrin signaling. Therefore, pharmacological upregulation of beta1-integrins may significantly improve the outcome of neonatal nerve injuries.


Genetic basis in motor skill and hand preference for tool use in chimpanzees (Pan troglodytes).
Chimpanzees are well known for their tool using abilities. Numerous studies have documented variability in tool use among chimpanzees and the role that social learning and other factors play in their development. There are also findings on hand use in both captive and wild chimpanzees; however, less understood are the potential roles of genetic and non-genetic mechanisms in determining individual differences in tool use skill and laterality. Here, we examined heritability in tool use skill and handedness for a probing task in a sample of 243 captive chimpanzees. Quantitative genetic analysis, based on the extant pedigrees, showed that overall both tool use skill and handedness were significantly heritable. Significant heritability in motor skill was evident in two genetically distinct populations of apes, and between two cohorts that received different early social rearing experiences. We further found that motor skill decreased with age and that males were more commonly left-handed than females. Collectively, these data suggest that though non-genetic factors do influence tool use performance and handedness in chimpanzees, genetic factors also play a significant role, as has been reported in humans.


An evaluation of mindfulness-based childbirth and parenting courses for pregnant women and prospective fathers/partners within the UK NHS (MBCP-4-NHS).
An evaluation of mindfulness-based childbirth and parenting courses for pregnant women and prospective fathers/partners within the UK NHS (MBCP-4-NHS). To explore the usefulness within the National Health Service (NHS) of a brief (four week, ten hour) course based upon the Mindfulness Based Childbirth and Parenting (MBCP) programme (Duncan and Bardacke, 2010) described here as MBCP-4-NHS. The National Maternity Review (2016) and report of The Independent Mental Health Taskforce to the NHS (2016a, 2016b) in England highlight the need for significant investment into perinatal mental health services, with the Government pledging funding to improve such services through a range of measures. Whilst the field of mindfulness during the perinatal period is in need of well controlled trials and studies exploring the mechanisms of action (Hall et al., 2016) the limited research to date supports the potential for mindfulness based interventions in pregnancy and the need for further scientific study in this area (Dhillon et al., 2017; Shi and Macbeth, 2017). Particularly because it may broaden women's repertoire of coping strategies with the potential to improve the developmental trajectory of both parents and infants (Dunn et al., 2012; Duncan and Bardacke, 2010; Vieten and Astin, 2008). However, most of the studies to date have involved lengthy courses of around 8-9 weeks (24 h) duration, which may not be feasible or economical within a UK NHS setting and therefore, would be unlikely to be adopted as routine practice. An initial pilot study to discover if MBCP-4-NHS is acceptable and feasible within NHS maternity services, comparing maternal and paternal pre and post intervention self-report measures of mental health to begin to explore the effectiveness of this intervention. NHS antenatal education classes held in children's centres for expectant parents across Oxfordshire. All expectant parents receiving Oxfordshire maternity services between October 2014 and January 2015 were invited to self-refer into the intervention, of which 155 individuals (86 women and 69 men) took part. 'MBCP-4-NHS' - A brief (four week, ten hour) course developed from the nine week Mindfulness Based Childbirth and Parenting (MBCP) intervention. Self-report measures of mental health including low mood/depression, mindfulness, stress, anxiety, pregnancy related distress and experiences. The results showed a significant increase in both maternal and paternal mental health with women demonstrating a significant improvement in symptoms of stress, anxiety, depression, pregnancy-related distress, labour worry and positive and negative pregnancy experiences; and men improving significantly in symptoms of anxiety, depression and showing a trend for improvement in self-reported symptoms of perceived stress. This is a promising antenatal intervention that can be feasibly implemented within NHS which might have the potential to impact upon parental mental health and, therefore, possibly also the health of next generation. However, caution is needed interpreting these findings given that this study did not include an active control group. This research provides a clear rationale and justification for a large randomised control trial of this intervention within the NHS, which should include a more diverse population, across multiple centres and should explore both the potential health benefits for parents and infants/children as well as potential economic costs/benefits.


Ca2+-activated K channel of the BK-type in the inner mitochondrial membrane of a human glioma cell line.
A single channel current was recorded from mitoplasts (i.e., inner mitochondrial membrane) of the human glioma cell line LN229 using patch-clamp techniques in the mitoplast-attached mode. We frequently found a 295 +/- 18 pS channel that showed a straight i-E relation in the range +/-60 mV in 150 mM KCl solutions on either side of the mitoplast. If KCl in the bath was exchanged against NaCl, outward currents were undetectable, indicating potassium selectivity. Channel activity determined as open probability increased with increasing Ca2+ concentrations (EC50 = 0.9 microM at 60 mV). Open probability was voltage dependent. An e-fold increase of time spent in the open state was induced by a depolarization of 10.5 mV. Open probability was decreased by charybdotoxin concentration and voltage dependently (EC50 = 1.4 nM). In conclusion, we show for the first time that the inner mitochondrial membrane in human glioma cells contains a calcium-dependent K channel of the BK-type.