Alcohol intake and renal cell cancer in a pooled analysis of 12 prospective studies.
The association between alcohol intake and risk of renal cell cancer has been inconsistent in case-control studies. An inverse association between alcohol intake and risk of renal cell cancer has been suggested in a few prospective studies, but each of these studies included a small number of cases. We performed a pooled analysis of 12 prospective studies that included 530,469 women and 229,575 men with maximum follow-up times of 7-20 years. All participants had completed a validated food-frequency questionnaire at baseline. Using the primary data from each study, the study-specific relative risks (RRs) for renal cell cancer were calculated using Cox proportional hazards models and then pooled using a random-effects model. All statistical tests were two-sided. A total of 1430 (711 women and 719 men) cases of incident renal cell cancer were identified. The study-standardized incidence rates of renal cell cancer were 23 per 100,000 person-years among nondrinkers and 15 per 100,000 person-years among those who drank 15 g/day or more of alcohol. Compared with nondrinking, alcohol consumption (> or = 15 g/day, equivalent to slightly more than one alcoholic drink per day) was associated with a decreased risk of renal cell cancer (pooled multivariable RR = 0.72, 95% confidence interval = 0.60 to 0.86; P(trend)<.001); statistically significant inverse trends with increasing intake were seen in both women and men. No difference by sex was observed (P(heterogeneity) = .89). Associations between alcohol intake and renal cell cancer were not statistically different across alcoholic beverage type (beer versus wine versus liquor) (P = .40). Moderate alcohol consumption was associated with a lower risk of renal cell cancer among both women and men in this pooled analysis.


Effect of follicular fluid oxidative stress parameters on intracytoplasmic sperm injection outcome.
The purpose of this study was to evaluate the association between the follicular fluid (FF) reactive oxygen species (ROS) levels, total antioxidant capacity (TAC) and ROS-TAC score and pregnancy after intracytoplasmic sperm injection (ICSI). A total of 138 consecutive women who had ICSI were included in this study. FF ROS and TAC were measured by enhanced chemiluminescence and colorimetric assay, respectively, and then the ROS-TAC score was calculated. Out of the 138 included patients, 42 (30%) achieved pregnancy after ICSI. Log ROS, TAC, and the ROS-TAC score were not significantly different across diagnoses. Pregnant cycles were associated with significantly lower ROS (P < 0.001), higher TAC (P < 0.001) and higher ROS-TAC scores (P < 0.001). After adjusting for age, there was a significant positive correlation between log ROS and the number of follicles on the day of HCG administration (correlation 0.20, 95% CI: 0.02, 0.39) as well as the number of oocytes retrieved (correlation 0.18, 0.001, 0.36) but not with TAC. Interestingly, in women with endometriosis, higher TAC levels and higher ROS-TAC scores were associated with a higher likelihood of finding normal oocytes (P = 0.005 and P = 0.002, respectively). Higher FF TAC, higher FF ROS-TAC scores and lower FF ROS levels are associated with pregnancy after ICSI. Oxidative stress parameters may be markers of metabolic activity within the follicle.


Compliance of nutritional recommendations of Spanish pregnant women according to sociodemographic and lifestyle characteristics: a cohort study.
To assess nutrient intakes and compliance with nutritional recommendations in pregnant women according to selected sociodemographic characteristics and lifestyles. Cross-sectional study based on data from Spanish INMA cohort which recruited 2,585 pregnant women between 2003 and 2008 from four different regions of Spain. Sociodemographic information and anthropometry was collected and dietary intake was assessed through Food Frequency Questionnaires. The adequacy of food group intake was assessed considering current recommendations and from the Spanish Society of Nutrition. Moreover, intake of vitamin A, vitamin C and vitamin E, were compared with the Dietary Reference Intakes of the US Institute of Medicine. Percentage of women that did not fulfil the recommendations for cereals and legumes (3-4 servings/day) was 70.0%, for fruit intake (2-3 servings/day) it was 39.2%, for vegetables (2-4 servings/day) 47.3% and for dairy (3-4 servings/day) it was 51.6%. Intake of fruit and vegetables increased with age, educational degree and with physical activity (p<0.05). Also non-Spanish achieved better the recommendations. Percentage of pregnant women that did not fulfil the requirements (DRI) of vitamins A and C was 13.2 % and 16.2 respectively. More than 65% of the women did not met the recommended diary intake of vitamin E of 19 mg/day during the lactation period. Maternal age, education, having healthy habits, as well as country of origin are factors strongly associated with the composition of the diet. Sedentary women and those with a low education are at risk for low vitamin and antioxidant intake and non-optimal food choices during pregnancy.


Participants' perspectives on mindfulness-based cognitive therapy for inflammatory bowel disease: a qualitative study nested within a pilot randomised controlled trial.
Mindfulness-based interventions have shown to improve depression and anxiety symptoms as well as quality of life in patients with inflammatory bowel disease (IBD). However, little is known about the experiences of this group of patients participating in mindfulness interventions. This paper sets out to explore the perspectives of patients with IBD recruited to a pilot randomised controlled trial (RCT) of mindfulness-based cognitive therapy (MBCT) about the intervention. In a qualitative study nested within a parallel two-arm pilot RCT of mindfulness-based cognitive therapy for patients with IBD, two focus group interviews (using the same schedule) and a free text postal survey were conducted. Data from both were analysed using thematic analysis. Data and investigator triangulation was performed to enhance confidence in the ensuing findings. Forty-four patients with IBD were recruited to the pilot RCT from gastroenterology outpatient clinics from two Scottish NHS boards. Eighteen of these patients (ten from mindfulness intervention and eight from control group) also completed a postal survey and participated in two focus groups after completing post intervention assessments. The major themes that emerged from the data were the following: perceived benefits of MBCT for IBD, barriers to attending MBCT and expectations about MBCT. Participants identified MBCT as a therapeutic, educational and an inclusive process as key benefits of the intervention. Key barriers included time and travel constraints. This qualitative study has demonstrated the acceptability of MBCT in a group of patients with IBD. Participants saw MBCT as a therapeutic and educational initiative that transformed their relationship with the illness. The inclusive process and shared experience of MBCT alleviated the sense of social isolation commonly associated with IBD. However, time commitment and travel were recognised as a barrier to MBCT which could potentially influence the degree of therapeutic gain from MBCT for some participants.


Solar ultraviolet radiation in Africa: a systematic review and critical evaluation of the health risks and use of photoprotection.
Most information on the harmful health effects of solar ultraviolet radiation (UVR) has been obtained in populations in which the majority has fair skin. Here a systematic review of evidence on diseases related to solar UVR in Africa was undertaken, and the appropriateness of effective photoprotection for these people considered. There are few population-based studies on UV-induced skin cancers (melanoma, squamous and basal cell carcinomas) in Africa, although limited reports indicated that they occur, even in people with deeply pigmented skin. The incidence of melanoma is particularly high in the white population living in the Western Cape of South Africa and has increased significantly in recent years. Cataract is extremely common in people of all skin colours and is a frequent cause of blindness, particularly in the elderly. For both skin cancer and cataract, the proportion of the disease risk that is attributable to exposure to solar UVR in African populations, and therefore the health burden caused by UV irradiation is unclear. There was little published information on the use of sun protection in Africa. The potential disease burden attributable to solar UVR exposure of Africans is high, although accurate data to quantify this are sparse. Information is required on the incidence, prevalence and mortality for the range of UV-related diseases in different populations living throughout Africa. Photoprotection is clearly required, at least for those subpopulations at particularly high risk, but may be limited by cost and cultural acceptability.


Cortically-controlled population stochastic facilitation as a plausible substrate for guiding sensory transfer across the thalamic gateway.
The thalamus is the primary gateway that relays sensory information to the cerebral cortex. While a single recipient cortical cell receives the convergence of many principal relay cells of the thalamus, each thalamic cell in turn integrates a dense and distributed synaptic feedback from the cortex. During sensory processing, the influence of this functional loop remains largely ignored. Using dynamic-clamp techniques in thalamic slices in vitro, we combined theoretical and experimental approaches to implement a realistic hybrid retino-thalamo-cortical pathway mixing biological cells and simulated circuits. The synaptic bombardment of cortical origin was mimicked through the injection of a stochastic mixture of excitatory and inhibitory conductances, resulting in a gradable correlation level of afferent activity shared by thalamic cells. The study of the impact of the simulated cortical input on the global retinocortical signal transfer efficiency revealed a novel control mechanism resulting from the collective resonance of all thalamic relay neurons. We show here that the transfer efficiency of sensory input transmission depends on three key features: i) the number of thalamocortical cells involved in the many-to-one convergence from thalamus to cortex, ii) the statistics of the corticothalamic synaptic bombardment and iii) the level of correlation imposed between converging thalamic relay cells. In particular, our results demonstrate counterintuitively that the retinocortical signal transfer efficiency increases when the level of correlation across thalamic cells decreases. This suggests that the transfer efficiency of relay cells could be selectively amplified when they become simultaneously desynchronized by the cortical feedback. When applied to the intact brain, this network regulation mechanism could direct an attentional focus to specific thalamic subassemblies and select the appropriate input lines to the cortex according to the descending influence of cortically-defined "priors".


Health-Care Workers' Perspectives on Ebola Virus Vaccine: A Focus Group and In-Depth Interview Interventional Study.
Health-care workers (HCWs) will require Ebola virus vaccine (EVV) when it is introduced because of the high risk of exposure to the disease. Evaluations of factors that facilitate or limit vaccine uptake are critical for a successful vaccine program. Nigerian HCWs were interviewed to evaluate their knowledge, levels of acceptance, determinants of acceptance, and willingness to pay for EVV. The significance level was set at P ≤ 0.05. None of the 193 participating HCWs had correct knowledge of EVV; 34.7% (67/193) of workers thought that EVV was an extract of the serum of Ebola virus patients. About 77.3% (51/66) of workers in a region that reported Ebola cases (Lagos) were willing to be vaccinated, compared with 4.7% (3/61) in Enugu and 13.6% (9/66) in Abia (P = 0.0001). After health education, the proportion of HCWs willing to receive EVV increased (P = 0.006) except for doctors (P < 0.1). The percentage of HCWs willing to pay for EVV was 86.4%, 72.1%, and 59% in Lagos, Enugu, and Abia, respectively. The workers had fears about EVV based on nonfactual assumptions. Therefore, the EVV introduction strategy should include a strong awareness campaign with adequate explanation about the content of EVV.


Explaining household socio-economic related child health inequalities using multiple methods in three diverse settings in South Africa.
Despite free healthcare to pregnant women and children under the age of six, access to healthcare has failed to secure better child health outcomes amongst all children of the country. There is growing evidence of socioeconomic gradient on child health outcomes The objectives of this study were to measure inequalities in child mortality, HIV transmission and vaccination coverage within a cohort of infants in South Africa. We also used the decomposition technique to identify the factors that contribute to the inequalities in these three child health outcomes. We used data from a prospective cohort study of mother-child pairs in three sites in South African. A relative index of household socio-economic status was developed using principal component analysis. This paper uses the concentration index to summarise inequalities in child mortality, HIV transmission and vaccination coverage. We observed disparities in the availability of infrastructure between least poor and most poor families, and inequalities in all measured child health outcomes. Overall, 75 (8.5%) infants died between birth and 36 weeks. Infant mortality and HIV transmission was higher among the poorest families within the sample. Immunisation coverage was higher among the least poor. The inequalities were mainly due to the area of residence and socio-economic position. This study provides evidence that socio-economic inequalities are highly prevalent within the relatively poor black population. Poor socio-economic position exposes infants to ill health. In addition, the use of immunisation services was lower in the poor households. These inequalities need to be explicitly addressed in future programme planning to improve child health for all South Africans.


Deep learning-based pseudo-mass spectrometry imaging analysis for precision medicine.
Liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics provides systematic profiling of metabolic. Yet, its applications in precision medicine (disease diagnosis) have been limited by several challenges, including metabolite identification, information loss and low reproducibility. Here, we present the deep-learning-based Pseudo-Mass Spectrometry Imaging (deepPseudoMSI) project (https://www.deeppseudomsi.org/), which converts LC-MS raw data to pseudo-MS images and then processes them by deep learning for precision medicine, such as disease diagnosis. Extensive tests based on real data demonstrated the superiority of deepPseudoMSI over traditional approaches and the capacity of our method to achieve an accurate individualized diagnosis. Our framework lays the foundation for future metabolic-based precision medicine.


Expression of complexin I and II mRNAs and their regulation by antipsychotic drugs in the rat forebrain.
Complexin (cx) I and II are homologous synaptic protein genes which are differentially expressed in mouse and human brain and differentially affected in schizophrenia. We characterized the distribution of cx I and II mRNAs in rat forebrain and examined whether their abundance, or the transcript of the synaptic marker synaptophysin, is affected by 14 days' administration of antipsychotic drugs (haloperidol, chlorpromazine, risperidone, olanzapine, or clozapine). Cx I mRNA predominated in medial habenula, medial septum-diagonal band complex, and thalamus, whereas cx II mRNA was more abundant in most other regions, including isocortex and hippocampus. Within the hippocampus, cx I mRNA was primarily expressed by interneurons and cx II mRNA by granule cells and pyramidal neurons. Localized cx II mRNA signal was seen in the dentate gyrus molecular layer, suggestive of its transport into granule cell dendrites. Antipsychotic treatment produced selective, modest effects on cx mRNA expression. Cx I mRNA was elevated by olanzapine in dorsolateral striatum and frontoparietal cortex, while the abundance of cx II mRNA relative to cx I mRNA was decreased in both areas by olanzapine and haloperidol. Chlorpromazine increased cx II mRNA in frontoparietal cortex and synaptophysin mRNA in dorsolateral striatum. In summary, the data have implications both for understanding the effects of antipsychotic medication on synaptic organization, and for synaptic protein expression studies in patients treated with the drugs.


Influence of pretreatment polarographically measured oxygenation levels in spontaneous canine tumors treated with radiation therapy.
The level of hypoxia in primary tumors has been described to influence response to treatment. The aim of the present study was to investigate the impact of pretreatment oxygen level measurements in spontaneous canine tumors on treatment outcome. Data of pretreatment tumor oxygenation status and local tumor response after primary radiation therapy in a group of spontaneously occurring tumors in dogs (n=52) was collected. Radiation therapy was given with curative (14-17x3-3.5 Gy) or palliative intent (3x8 Gy or 4-5x6 Gy). Progression-free interval and overall survival were correlated to polarographically measured tumor oxygenation status. In the curatively irradiated group, tumors with median pO2 values<or=10 mmHg tended to have shorter median progression- free interval compared to better oxygenated tumors (246 vs. 739 days). The same trend could be shown for overall survival (330 vs. 745 days), indicating a cutoff value in this region. In the group treated with lower doses of radiation, the level of oxygen was no longer found to be of prognostic value; however, in this group hemoglobin had a significant impact on outcome. In curatively irradiated spontaneous canine tumors, tumor hypoxia was found to be a prognostic indicator, independent of tumor histologies and volume.


Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats.
We determined that treatment of immature rats with allopurinol at 15 min after cerebral hypoxia-ischemia reduces brain damage. Seven-d postnatal rats were subjected to right common carotid artery ligation followed by 2.25 h of hypoxia (8% O2). At 15 min of recovery in room air, the rat pups received either allopurinol (135 mg/kg s.c.) or saline. Some of the rats (n = 65) were killed at 42 h of recovery for measurement of cerebral hemispheric water content. Other animals (n = 63) were killed at 30 d for morphologic assessment of the severity of damage. In separate rats, we measured the levels of allopurinol and its metabolites in serum and in the brain around the time of peak serum levels. We also determined the effect of allopurinol on rat pup body temperature. Allopurinol reduced the increase in right hemisphere water content and markedly reduced atrophy. No cavitary lesions were seen in the 31 allopurinol-treated rats, whereas 15 of 32 saline-treated rats had cavitary cerebral lesions. Histologic examination confirmed that the allopurinol-treated rats had less brain injury. Serum allopurinol and oxypurinol peaked between 0.5 and 1 h after allopurinol injection. Their peak serum concentrations at 0.75 h postinjection combined was between 360 and 510 microM. Allopurinol did not lower rectal temperature more than 0.04 degrees C. In conclusion, high-dose allopurinol administered at 15 min of recovery from cerebral hypoxia-ischemia markedly reduces both acute brain edema and long-term cerebral injury in immature rats.


Mechanisms of estrogens' dose-dependent neuroprotective and neurodamaging effects in experimental models of cerebral ischemia.
Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens' actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings.


Anthropometric profiling of elite junior and senior Australian football players.
Body structure and physical development must be addressed when preparing junior athletes for their first season in a senior competition. The aim of this preliminary study was to measure the extent of the assumption that final year junior Australian Football (AF) athletes are at a physical mismatch to their senior counterparts. Twenty-one male participants (17.71 ± 0.27 y) were recruited from one state based elite junior AF competition and forty-one male participants (22.80 ± 4.24 y) were recruited from one club competing in the senior elite Australian Football League (AFL), who were subsequently divided into two groups; professional rookies aged 18-20 y (19.44 ± 0.70 y; n = 18) and professional seniors aged 21+ y (25.43 ± 3.98 y; n = 23). Dual energy X-ray absorptiometry (DEXA) scans of all participants were completed. Despite being an average 6.0% and 6.1% lighter in total weight and lean mass respectively, no significant difference was found between the elite junior athletes and their professional AFL rookie counterparts. However, significant differences were demonstrated in comparison with the professional AFL senior athletes (P < .01). Both professional AFL groups demonstrated greater than 0.3 kg total bone mineral content (BMC) than the elite junior athletes (P < .01) and significantly greater segmental BMC and bone mineral density (BMD) results (P < .05). While the results identify the differences in body composition of the elite junior athletes, development in a linear fashion is noted, providing useful information for the creation of age appropriate expectations and training programs.


Challenges in the diagnosis and treatment of pulmonary arterial hypertension.
Advances in the diagnosis and management of pulmonary arterial hypertension (PAH) have resulted in significant improvements in outcomes for patients with this devastating and progressive disease. However, because of the non-specific nature of its symptoms, and the low level of suspicion among clinicians, prompt and accurate diagnosis of PAH as a rare disease remains a challenge. This article explains some of the issues that need to be addressed when faced with a patient with suspected PAH and describes how noninvasive and invasive techniques can be used effectively to ensure an accurate diagnosis. The availability of PAH-specific therapy means that once diagnosed, patients have a much greater chance of survival than they would have had in the past. However, despite improved survival, mortality is still high and, therefore, there is still room for improvement. It is currently recommended that patients with an inadequate clinical response to treatment receive sequential combination therapy; however, supportive data are still scarce. Although there is no clear explanation, these findings may be explained by the design and end-points chosen in clinical trials, the changing population of PAH and a need to improve the management strategy in this disease. Indeed, there is a clear need for randomised controlled studies that investigate whether adopting individualised treatment strategies, including upfront combination therapy, could help to optimise long-term management of patients with PAH.


Sustained attention is not necessary for velocity adaptation.
Prolonged adaptation to a stimulus, such as a drifting grating, lowers sensitivity for detecting similar stimuli, and changes their appearance, for example, making gratings of the same orientation appear of lower contrast and move more slowly. It has been suggested that adaptation is increased by sustained attention to the adapting stimulus and is decreased by distracting attention with a competing task. This paper describes a novel 2AFC (spatial) measure of adaptation in which adaptation and bias are carefully distinguished by the random interleaving of different test conditions. The experiment revealed significant adaptation of perceived velocity, but no effect of attentional distraction.


A comparison of hospital-based and private outpatient physical therapy practices.
A paucity of data exists about the delivery of contemporary adult outpatient physical therapy services in the United States. Although many debates about this issue have taken place within the physical therapy profession, assumptions about practice patterns have generally not been studied. This article reports some of the first-year findings from a 3-year survey research effort begun in September 1988 by Mathematica Policy Research Inc for the American Physical Therapy Association. Analyses are based on survey data from national probability samples of physical therapy facilities and discharged patients from 155 hospital-based and 166 private outpatient practices. The primary goal was to compare outpatient physical therapy practice patterns in the hospital-based and private practice settings. Findings reveal considerable homogeneity in private and hospital-based outpatient physical therapy practices. Hospital-based and private practices serve predominantly young, white adults who have private health insurance and a prevalence of orthopedic impairments. In both settings, direct access to outpatient physical therapy services was the exception and not the rule. Even in states in which direct access without a physician's referral was permitted by law, the majority of outpatient physical therapy was provided with a physician's referral. Most respondents in direct-access states indicated that reimbursement requirements were the major reason for needing a physician's referral to provide outpatient physical therapy.


An Epigenetic Mechanism Underlying Chromosome 17p Deletion-Driven Tumorigenesis.
Chromosome copy-number variations are a hallmark of cancer. Among them, the prevalent chromosome 17p deletions are associated with poor prognosis and can promote tumorigenesis more than TP53 loss. Here, we use multiple functional genetic strategies and identify a new 17p tumor suppressor gene (TSG), plant homeodomain finger protein 23 (PHF23). Its deficiency impairs B-cell differentiation and promotes immature B-lymphoblastic malignancy. Mechanistically, we demonstrate that PHF23, an H3K4me3 reader, directly binds the SIN3-HDAC complex through its N-terminus and represses its deacetylation activity on H3K27ac. Thus, the PHF23-SIN3-HDAC (PSH) complex coordinates these two major active histone markers for the activation of downstream TSGs and differentiation-related genes. Furthermore, dysregulation of the PSH complex is essential for the development and maintenance of PHF23-deficient and 17p-deleted tumors. Hence, our study reveals a novel epigenetic regulatory mechanism that contributes to the pathology of 17p-deleted cancers and suggests a susceptibility in this disease. SIGNIFICANCE: We identify PHF23, encoding an H3K4me3 reader, as a new TSG on chromosome 17p, which is frequently deleted in human cancers. Mechanistically, PHF23 forms a previously unreported histone-modifying complex, the PSH complex, which regulates gene activation through a synergistic link between H3K4me3 and H3K27ac.This article is highlighted in the In This Issue feature, p. 1.


Respiratory syncytial virus induces selective production of the chemokine RANTES by upper airway epithelial cells.
The presence of histamine and eosinophil cationic protein in nasopharyngeal secretions of infants with respiratory syncytial virus (RSV)-induced bronchiolitis implies the activation of basophil and eosinophil leukocytes, but the specific mechanism of their recruitment has not been elucidated. Chemokines are potent and selective leukocyte chemotactic molecules that are also expressed by airway epithelial cells. Therefore, the pattern of chemokines produced in response to RSV infection was investigated in primary cultures of human nose- and adenoid-derived epithelial cells. Interleukin-8, growth-related peptide-alpha, and monocyte chemotactic protein-1 were constitutively released by uninfected epithelial cells and were not further enhanced by infection with RSV. RANTES (regulated upon activation, normal T cell-expressed and -secreted), which was present in negligible concentrations in uninfected cultures, was strongly induced by RSV infection, in a dose- and time-dependent manner. Through the release of RANTES, epithelial cells may control the selective concentration and activation of basophils and eosinophils in RSV-infected airway mucosa.


Dynamics of self-sustained asynchronous-irregular activity in random networks of spiking neurons with strong synapses.
Random networks of integrate-and-fire neurons with strong current-based synapses can, unlike previously believed, assume stable states of sustained asynchronous and irregular firing, even without external random background or pacemaker neurons. We analyze the mechanisms underlying the emergence, lifetime and irregularity of such self-sustained activity states. We first demonstrate how the competition between the mean and the variance of the synaptic input leads to a non-monotonic firing-rate transfer in the network. Thus, by increasing the synaptic coupling strength, the system can become bistable: In addition to the quiescent state, a second stable fixed-point at moderate firing rates can emerge by a saddle-node bifurcation. Inherently generated fluctuations of the population firing rate around this non-trivial fixed-point can trigger transitions into the quiescent state. Hence, the trade-off between the magnitude of the population-rate fluctuations and the size of the basin of attraction of the non-trivial rate fixed-point determines the onset and the lifetime of self-sustained activity states. During self-sustained activity, individual neuronal activity is moreover highly irregular, switching between long periods of low firing rate to short burst-like states. We show that this is an effect of the strong synaptic weights and the finite time constant of synaptic and neuronal integration, and can actually serve to stabilize the self-sustained state.


Identification of Protor as a novel Rictor-binding component of mTOR complex-2.
The mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth. Two complexes of mTOR have been identified: complex 1, consisting of mTOR-Raptor (regulatory associated protein of mTOR)-mLST8 (termed mTORC1), and complex 2, comprising mTOR-Rictor (rapamycininsensitive companion of mTOR)-mLST8-Sin1 (termed mTORC2). mTORC1 phosphorylates the p70 ribosomal S6K (S6 kinase) at its hydrophobic motif (Thr389), whereas mTORC2 phosphorylates PKB (protein kinase B) at its hydrophobic motif (Ser473). In the present study, we report that widely expressed isoforms of unstudied proteins termed Protor-1 (protein observed with Rictor-1) and Protor-2 interact with Rictor and are components of mTORC2. We demonstrate that immunoprecipitation of Protor-1 or Protor-2 results in the co-immunoprecipitation of other mTORC2 subunits, but not Raptor, a specific component of mTORC1. We show that detergents such as Triton X-100 or n-octylglucoside dissociate mTOR and mLST8 from a complex of Protor-1, Sin1 and Rictor. We also provide evidence that Rictor regulates the expression of Protor-1, and that Protor-1 is not required for the assembly of other mTORC2 subunits into a complex. Protor-1 is a novel Rictor-binding subunit of mTORC2, but further work is required to establish its role.


Controlling near-field polarization distribution of a plasmonic prolate nanospheroid by its aspect ratio and polarization of the incident electromagnetic field.
Near-field polarization distribution of a plasmonic prolate nanospheroid in an incident electromagnetic field versus its polarization and the spheroid's aspect ratio is studied in detail. Polarization of the near-field is described with the help of the 3D generalized Stokes parameters, allowing simple visualization. It is shown that this distribution has a complex structure, which drastically depends on the incident field polarization and parameters of the plasmon resonance of the nanoparticle. Received analytical solutions cover the whole set of particles with shape varying from spherical to the nanoneedles and nanorods by changing the aspect ratio of the spheroid. An experiment for visualization of the vectorial near-field around a plasmonic nanoparticle is proposed.


Invasive lobular carcinoma of the breast: mammographic and sonographic evaluation.
To evaluate the efficacy of mammography and sonography together in the assessment of patients with pure invasive lobular carcinomas (ILCs) of the breast. We retrospectively reviewed 38 cases of pure invasive lobular carcinomas of the breast. The tumors were evaluated both mammographically and sonographically. The mammographic images were reviewed by two experienced mammographers. All patients underwent surgical management. Histopathologic assessments were made by experienced breast pathologists. On physical examination, six tumors (15.7%) showed no clinical findings. The most common mammographic result was a spiculated mass or architectural distortion (42%). Eleven lesions (29%) were mammographically negative. Five cases (13%) showed pleomorphic or heterogeneous calcifications that were compatible with Breast Imaging Reporting and Data System (BI-RADS) 4 or 5. The most common sonographic result was a hypoechoic mass with or without shadowing (60.5%). Four tumors (10.5%) were sonographically invisible. Two cases (5%) were negative, and 25 cases (65.8%) were positive in both modalities. The overall sensitivity was 71.05% for mammography and 89.47% for sonography. The number of tumors detected by either of these two modalities was 36, and the overall sensitivity was 94.73%. Mammography and ultrasonography are useful imaging methods in the evaluation of invasive lobular carcinoma. Because of the low rate of suspicious calcifications and low density of lesions, the false-negative rate tends to be high for these tumors. With the use of sonography and mammography together, invasive lobular carcinomas can be detected with a sensitivity of 94.73%. We recommend additional sonographic evaluations for all patients, especially those with dense breast tissue with or without positive mammographic findings.


[Intracranial hemorrhage from an arteriovenous malformation (AVM) in a tuberous sclerosis patient].
We describe a previously diagnosed tuberous sclerosis patient that arrived to the hospital with an intracerebral hemorrhage whose origin was an arteriovenous malformation (AVM). A craniectomy was performed and the hematoma was evacuated with the alleviation of the patient. Although the association between tuberous sclerosis and intracerebral hemorrhage is known in the literature it has never been described associated with an AVM.


Binge-eating and self-induced vomiting in the community. A preliminary study.
This study examined by questionnaire the prevalence of binge-eating and self-induced vomiting among a sample of 369 consecutive attenders at a family planning clinic. 20.9 per cent reported current episodes of uncontrollable and excessive eating ('binges'), 2.9 per cent currently induced vomiting as a means of weight control; and 4.9 per cent reported using laxatives. Binge-eating and self-induced vomiting were strongly associated with disturbed attitudes to food, eating, body weight and shape; and with psychiatric disturbance. Menstrual dysfunction was not associated with either body weight or binge-eating; it was however associated with psychiatric state. Applying conservative rules, 1.9 per cent appeared to fulfil diagnostic criteria for the recently described syndrome bulimia nervosa.


Operator volume is not associated with mortality following percutaneous coronary intervention: insights from the British Cardiovascular Intervention Society registry.
The relationship between operator volume and outcomes for percutaneous coronary intervention (PCI) has been studied in the past, but recent analyses of national data covering the modern radial, acute coronary syndrome-dominant era are limited. Changing in case-mix, practice, and service provision mean that previously described volume-outcome relationships may no longer be relevant, and a reassessment in contemporary practice is needed. We aim to assess whether operator volume is associated with independently reported 30-day mortality in a contemporary PCI cohort. This observational cohort study analysed procedures recorded in the British Cardiovascular Intervention Society PCI database from 2013 to 2014 in England and Wales. Mixed effects multiple logistic regression modelling was used to account for operator and centre level effects and to adjust for potential confounders. Volume is defined as the total number of procedures the operator was responsible for in the previous 12 months. A total of 133 970 procedures were analysed. Median volume across all procedures was 178 per year (interquartile range 128-239). The 30-day mortality rate was 2.6%. After adjustment for case-mix, the association between volume and mortality was negligible (odds ratio per 100 procedures 0.99, 95% confidence interval 0.93-1.05; P = 0.725). Sensitivity analyses showed similar results amongst high-risk PCI subsets and in-hospital outcomes. There is no evidence that mortality differs by operator volume in the UK. Volume-outcome relationships in PCI should be carefully monitored in response to future changes in practice.


Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study.
Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.


Effects of fish oil and spirulina on oxidative stress and inflammation in hypercholesterolemic hamsters.
Altered plasma lipids, oxidative stress, and inflammation have been involved in the pathogenesis of cardiovascular disease. Fish oil has shown inconclusive effects on plasma lipids and oxidative stress. Spirulina has both cholesterol lowering and antioxidant properties. However, the effect of fish oil and spirulina on hypercholesterolemia has not been studied. We investigated the effects of fish oil, spirulina, and their combination on hypercholesterolemia. The hamsters were divided into 7 groups: control, high cholesterol (HF), fish oil (post FO), spirulina (post SP), and a combination of fish oil and spirulina (post SF, pre-SF, and HF + SF) groups. The HF and HF + SF groups were given a high cholesterol diet for 8 weeks. The post FO, post SP, and post SF groups were given a high cholesterol diet for 4 weeks and then the treatment for 4 weeks. The pre-SF group was given the combined treatment for 4 weeks and then a high cholesterol diet for 4 weeks. The HF and HF + SF groups altered plasma lipids, increased oxidative stress, inhibited antioxidants, and increased inflammation. While the post FO group increased plasma lipids and was more atherogenic. The vice versa was observed in spirulina-treated group. Both the post SP and post SF groups inhibited oxidative stress and increased antioxidant status, and post FO and post SP diets regulated pro-inflammatory cytokines to near the control levels. Both single treatment of fish oil or spirulina inhibit oxidative stress and inflammation. Treatment with a combination of fish oil and spirulina (post SF) may be beneficial for diet-induced hypercholesterolemic hamsters.


Diaphragm training in amyotrophic lateral sclerosis.
There is a continued need for therapies to improve respiratory function and quality of life in patients with amyotrophic lateral sclerosis. In this pilot trial, we studied 8 subjects with amyotrophic lateral sclerosis and respiratory involvement. We measured respiratory function and quality of life at baseline. We then taught subjects diaphragm training, a method of breath control designed to improve respiratory muscle strength and efficiency. We repeated measures of respiratory function and quality of life 6 and 12 weeks later. There was no significant improvement in any outcome measure after instituting diaphragm training. There was a nonsignificant trend toward a slower rate of decline in respiratory function in those subjects who mastered the technique; however, only half the subjects were able to successfully change their pattern of breathing. A larger study of this technique is warranted; however, in determining the sample size for a larger study, the difficulty for patients in mastering the technique must be taken into consideration.


Variant-dependent heterogeneity in amyloid β burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study.
Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP. We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40). Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses. Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes. National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development.


Sex peptide causes mating costs in female Drosophila melanogaster.
Conflicts between females and males over reproductive decisions are common . In Drosophila, as in many other organisms, there is often a conflict over how often to mate. The mating frequency that maximizes male reproductive success is higher than that which maximizes female reproductive success . In addition, frequent mating reduces female lifespan and reproductive success , a cost that is mediated by male ejaculate accessory gland proteins (Acps) . We demonstrate here that a single Acp, the sex peptide (SP or Acp70A), which decreases female receptivity and stimulates egg production in the first matings of virgin females , is a major contributor to Acp-mediated mating costs in females. Females continuously exposed to SP-deficient males (which produce no detectable SP ) had significantly higher fitness and higher lifetime reproductive success than control females. Hence, rather than benefiting both sexes, receipt of SP decreases female fitness, making SP the first identified gene that is likely to play a central role in sexual conflict.


Bond strength of composite luting cement to zirconia ceramic surfaces.
To evaluate the bond strength of dental resin agent to zirconia ceramic after surface pre-treatment with different techniques. Specimens of hot isostatic pressed yttrium-oxide-partially-stabilized zirconia blocks (ZF) were fabricated (Procera Zircon, Nobel Biocare, Sweden) and compared to glossy dense zirconia blocks (ZG). Four groups of specimens with different surface treatment were prepared. Group I: ZF (n = 5) and ZG (n = 5) without any pre-treatment, Group II: ZF-s (n = 5) and ZG-s (n = 5) treated with silane solution, Group III: ZF-P (n = 10) and ZG-P (n = 10) treated with RF plasma spraying (hexamethyldisiloxane) using a reactor (Plasma Electronic, Germany), Group IV: ZF-p (n = 10) and ZG-p (n = 10) treated with micro pearls of low fusing porcelain (720 degrees C) on the surfaces. Composite cylinders (Charisma, Hereus Kulzer, Dormagen, Germany) were luted with Variolink II (Ivoclar-Vivadent, Schaan, Liechtenstein) to the test specimens. The specimens were then stored in air for 1 h before shear loading in a universal testing machine (LRX, Lloyd Instruments, Farnham, England) until failure. No statistical difference was found between the untreated ZF and ZG specimens (Group I) neither between the specimens treated with silane (Group II). Plasma spraying treatment improved bond strength by a factor of three (p < 0.001). Treatment with low fusing porcelain micro pearls increased the bond strength by a factor of 10 compared to untreated surfaces (p < 0.001). No significant difference was seen between the surfaces treated ZF-p and ZG-p specimens. The thickness of the glass pearls layer did not exceed 5 microm. SEM showed dense grain borders of ZF and a flat glossy texture of ZG. Treatment of zirconia ceramic surfaces with plasma spraying or a low fusing porcelain pearl layer significantly increased the bond strength of resin cement to the ceramic surface.


Lessons Learned in Evaluating a Multisite, Comprehensive Teen Dating Violence Prevention Strategy: Design and Challenges of the Evaluation of Dating Matters: Strategies to Promote Healthy Teen Relationships.
This paper describes the multisite, longitudinal cluster randomized controlled trial (RCT) design of the evaluation of the Dating Matters: Strategies to Promote Healthy Relationships initiative, and discusses challenges faced in conducting this evaluation. Health departments in 4 communities are partnering with middle schools in high-risk, urban communities to implement 2 models of teen dating violence (TDV) prevention over 4 years. Schools were randomized to receive either the Dating Matters comprehensive strategy or the "standard of care" strategy (an existing, evidence-based TDV prevention curriculum). Our design permits comparison of the relative effectiveness of the comprehensive and standard of care strategies. Multiple cohorts of students from 46 middle schools are surveyed in middle school and high school, and parents and educators from participating schools are also surveyed. Challenges discussed in conducting a multisite RCT include site variability, separation of implementation and evaluation responsibilities, school retention, parent engagement in research activities, and working within the context of high-risk urban schools and communities. We discuss the strengths and weaknesses of our approaches to these challenges in the hopes of informing future research. Despite multiple challenges, the design of the Dating Matters evaluation remains strong. We hope this paper provides researchers who are conducting complex evaluations of behavioral interventions with thoughtful discussion of the challenges we have faced and potential solutions to such challenges.


Intravesical Ty21a treatment of non-muscle invasive bladder cancer induces immune responses that correlate with safety and may be associated to therapy potential.
Standard of care treatment of non-muscle invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette Guérin (BCG) is associated with side effects, disease recurrence/progression and supply shortages. We recently showed in a phase I trial (NCT03421236) that intravesical instillation in patients with NMIBC with the maximal tolerated dose of Ty21a/Vivotif, the oral vaccine against typhoid fever, might have a better safety profile. In the present report, we assessed the immunogenicity of intravesical Ty21a in patients of the clinical trial that had received the maximal tolerated dose and compared it with data obtained in patients that had received standard BCG. Urinary cytokines and immune cells of patients with NMIBC treated with intravesical instillations of Ty21a (n=13, groups A and F in NCT03421236) or with standard BCG in a concomitant observational study (n=12, UROV1) were determined by Luminex and flow cytometry, respectively. Serum anti-lipopolysaccharide Typhi antibodies and circulating Ty21a-specific T-cell responses were also determined in the Ty21a patients. Multiple comparisons of different paired variables were performed with a mixed-effect analysis, followed by Sidak post-test. Single comparisons were performed with a paired or an unpaired Student's t-test. As compared with BCG, Ty21a induced lower levels of inflammatory urinary cytokines, which correlated to the milder adverse events (AEs) observed in Ty21a patients. However, both Ty21a and BCG induced a Th1 tumor environment. Peripheral Ty21a-specific T-cell responses and/or antibodies were observed in most Ty21a patients, pointing the bladder as an efficient local immune inductive site. Besides, Ty21a-mediated stimulation of unconventional Vδ2 T cells was also observed, which turned out more efficient than BCG. Finally, few Ty21a instillations were sufficient for increasing urinary infiltration of dendritic cells and T cells, which were previously associated with therapeutic efficacy in the orthotopic mouse model of NMIBC. Ty21a immunotherapy of patient with NMIBC is promising with fewer inflammatory cytokines and mild AE, but induction of immune responses with possible antitumor potentials. Future phase II clinical trials are necessary to explore possible efficacy of intravesical Ty21a.


Gallic acid protects particulate matter (PM10) triggers cardiac oxidative stress and inflammation causing heart adverse events in rats.
Previous studies have shown that exposure to particulate matter (PM) increased variety of health problems, particularly cardiovascular diseases leading to premature mortality. The cardiac effects of particulate matter containing PM10 include increased infarct size, decreased heart function, and increased arrhythmias in experimental ischemia-reperfusion models in rats. The aim of this study was to evaluate the effects of particles with an aerodynamic diameter smaller than 10 μm (PM10) on isolated-rat heart and also to determine the efficacy of gallic acid (GA) as a preventive agent in oxidative damage. The healthy rats were divided into 8 equal groups which served as, control, GA, PM10 (0.5, 2.5, and 5 mg/kg), and PM10+GA groups. PM10 administered into the lungs via the trachea in two stages with 48-h interval. After all experiments, the electrocardiogram was recorded. Then, the hemodynamic parameters and ventricular arrhythmias in rat isolated-hearts were assessed using Langendorff apparatus and according to the Lambeth conventions. In addition, the inflammation and oxidative stress factors in cardiac tissues were evaluated in all groups. The obtained results showed that the exposure to PM caused to decrease in cardiac hemodynamic and electrocardiogram parameters. Also, in PM10 rat groups, the IL-6, TNF-α, and oxidative stress parameters were increased. Gallic acid preserved the value of cardiac parameters and inflammation in rat hearts. In summary, we added a novel therapeutic effect of gallic acid for cardiac dysfunction induced by particulate matter. These findings could be related to antioxidant and antiinflammation properties and the obtained results suggest that natural antioxidant like gallic acid could be a therapeutic agent in prevention and management of health issues in the polluted areas of the world.


Hearing of a presence.
Here we describe a patient with epilepsy (secondary to left parieto-temporal brain damage) suffering from the paroxysmal unilateral experience of hearing a person in her near extrapersonal space. The paroxysmal auditory experience was associated with a deficit in spatial auditory perception and other paroxysmal disorders of somatognosia. Based on these findings, it is suggested that the paroxysmal hearing of a person nearby corresponds to an auditory disorder of somatognosia.


A phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin.
Camptothecins are the only available antitumor agents which target the nuclear enzyme topoisomerase I. 9-Aminocamptothecin (9-AC) is a water-insoluble derivative of camptothecin which has demonstrated impressive antitumor activity in preclinical models. While two other water-soluble derivatives, CPT-11 and topotecan, have successfully completed Phase I and Phase II testing, biochemical and tissue culture studies suggest that camptothecin analogues differ in characteristics which may be important in determining antitumor activity. We performed a Phase I trial of 9-AC to determine the pharmacokinetics, dose-limiting toxicity, and maximum tolerated dose of this agent when administered as a 72-h continuous i.v. infusion. Thirty-one patients with resistant solid cancers received 5-60 microgram/m2/h 9-AC for 72 h, repeated at 3-week intervals. The drug was administered in a vehicle containing dimethylacetamide, polyethylene glycol, and phosphoric acid. Blood samples were collected and the lactone (closed ring) form of 9-AC was quantitated. The maximum tolerated dose of 9-AC was determined to be 45 microgram/m2/h. Dose-limiting toxicity consisted of neutropenia. Thrombocytopenia was also prominent. There were no significant nonhematological toxicities. Minimal responses were seen in patients with gastric, colon, and non-small cell lung cancer. Although significant interpatient variation in plasma 9-AC lactone levels was observed, pooled data were fit to a two-compartment model, with a terminal half-life of 36 h. Analyses of topoisomerase protein levels in peripheral blood cells indicated decreases in topoisomerase I accompanied by increases in topoisomerase II in two of three patients. 9-AC is an active antitumor agent and may be administered safely as a 72-h infusion in patients with cancer. Although Phase II trials with a 72-h infusion of 9-AC are warranted, alternate schedules should be evaluated given the dramatic preclinical activity seen with more prolonged administrations.


Should we hold the obese responsible? - some key issues.
It is a common belief that obesity is wholly or partially a question of personal choice and personal responsibility. It is also widely assumed that when individuals are responsible for some unfortunate state of affairs, society bears no burden to compensate them. This article focuses on two conceptualizations of responsibility: backward-looking and forward-looking conceptualizations. When ascertaining responsibility in a backward-looking sense, one has to determine how that state of affairs came into being or where the agent stood in relation to it. In contrast, a forward-looking conceptualization of responsibility puts aside questions of the past and holds a person responsible by reference to some desirable future state of affairs and will typically mean that he or she is subjected to criticism, censure, or other negative appraisals or that he or she is held cost-responsible in some form, for example, in terms of demanded compensation, loss of privileges, or similar. One example of this view is the debate as to whether the obese should be denied, wholly or partially, free and equal access to healthcare, not because they are somehow personally responsible in the backward-looking sense but simply because holding the obese responsible will have positive consequences. Taking these two conceptions of responsibility into account, the authors turn their analysis toward examining the relevant moral considerations to be taken into account when public policies regarding obesity rely on such a conception of responsibility.


Vitamin D supplementation reduces insulin resistance in Japanese adults: a secondary analysis of a double-blind, randomized, placebo-controlled trial.
Higher circulating 25-hydroxyvitamin D (25[OH]D) concentration has been linked to a lower prevalence of insulin resistance and type 2 diabetes mellitus. However, randomized controlled trials have not clarified the effect of vitamin D supplementation on insulin resistance in healthy adults. The objective of this study was to assess the effect of vitamin D supplementation for 1 year on insulin resistance; the study was a secondary analysis of a clinical trial. We hypothesized that increased 25(OH)D concentration after vitamin D supplementation for 1 year would significantly improve insulin resistance. Ninety-six healthy adults participated in this study, of whom 81 completed the study. The participants randomly received daily either 420 IU vitamin D3 or placebo in a double-blind manner for 1 year. The levels of fasting insulin, glucose, and other parameters were assessed at baseline and after 1 year of intervention. Homeostasis model assessment of insulin resistance index was calculated from insulin and glucose levels. Visceral fat area and physical activity were also investigated. Serum 25(OH)D and 1,25-dihydroxyvitamin D concentrations were significantly increased by approximately 29.5 nmol/L and 7.0 pg/mL, respectively, after 1-year vitamin D supplementation. After vitamin D supplementation, fasting glucose levels and values of homeostasis model assessment of insulin resistance index significantly decreased from 88.3 to 85.3 mg/dL (P < .01) and 1.17 to 0.84 (P < .01), respectively, and the results were independent of physical activity and visceral fat accumulation. In conclusion, the present study showed that vitamin D supplementation for 1 year effectively improves fasting glucose level and insulin resistance in healthy Japanese adults.


Overexpression of the adiponectin gene mimics the metabolic and stress resistance effects of calorie restriction, but not the anti-tumor effect.
Adiponectin (Adipoq), a peptide hormone secreted from the white adipose tissue, may play a role in the anti-aging and/or anti-tumor effects of calorie restriction (CR). We analyzed metabolic traits in Adipoq gene-overexpressing mice fed ad libitum with a regular diet (RD) or a high-fat diet (HFD), or fed 30% CR of RD initiated at 12 weeks of age. Adipoq-RD and -HFD mice at 6 months of age showed reduced blood glucose and insulin concentrations, and thus increased insulin sensitivity, compared with WT mice fed a RD or a HFD. In the epididymal white adipose tissue in Adipoq mice, senescence-like changes such as upregulation of p53 protein and of biomarkers of inflammation, Cd68 and Ccl2 mRNA, were ameliorated compared with WT-RD and WT-HFD mouse tissues. Resistance to stress induced by lipopolysaccharide was also strengthened in Adipoq mice compared with WT mice. These metabolic changes and stress resistance were also noted in the WT-CR mice, suggesting that Adipoq plays a part in the effect of CR. In contrast, in an allograft tumor growth model, tumor growth was not inhibited in Adipoq mice. The present findings suggest that Adipoq plays a part in the anti-aging, but not in the anti-tumor, effects of CR.


SIRE1, an endogenous retrovirus family from Glycine max, is highly homogeneous and evolutionarily young.
SIRE1 is unusual among Ty1-copia retrotransposons in that it has an additional open reading frame with structural features similar to retroviral envelope proteins between pol and the 3' LTR. Here we report the characterization and comparison of eight different SIRE1 elements derived from a soybean genomic library, as well as SIRE1 reverse transcriptases from Glycine soja. The DNA sequences of the eight SIRE1 elements are highly homogeneous and share greater than 95% nucleotide identity. Partial sequences obtained from BAC ends are similarly conserved. Phylogenetic analyses resolve two closely related SIRE1 lineages, and nucleotide changes within and between SIRE1 lineages have occurred to preserve function. Both the gag and the env-like genes are evolving under similar levels of functional constraint. Considerable sequence heterogeneity in the form of short duplications was found within the LTRs and in the region between the envelope-like ORF and the 3' LTR. These duplications are suggestive of slippage by reverse transcriptase during replication. Sequence identity between LTRs of individual insertions suggests that they transposed within the past 70,000 years. Two of 10 SIRE1 insertions examined abut Ty3-gypsy retroelements. Since the soybean genome harbors more than 1,000 SIRE1 insertions, the collective data suggest that SIRE1 has undergone a very recent and robust amplification in soybean.


Reaction coordinates for the flipping of genetic switches.
We present a detailed analysis, based on the forward flux sampling simulation method, of the switching dynamics and stability of two models of genetic toggle switches, consisting of two mutually repressing genes encoding transcription factors (TFs); in one model (the exclusive switch), the two transcription factors mutually exclude each other's binding, while in the other model (general switch), the two TFs can bind simultaneously to the shared operator region. We assess the role of two pairs of reactions that influence the stability of these switches: TF-TF homodimerization and TF-DNA association/dissociation. In both cases, the switch flipping rate increases with the rate of TF dimerization, while it decreases with the rate of TF-operator binding. We factorize the flipping rate k into the product of the probability rho(q*) of finding the system at the dividing surface (separatrix) between the two stable states, and a kinetic prefactor R. In the case of the exclusive switch, the rate of TF-operator binding affects both rho(q*) and R, while the rate of TF dimerization affects only R. The general switch displays a higher flipping rate than the exclusive switch, and both TF-operator binding and TF dimerization affect k, R, and rho(q*). To elucidate this, we analyze the transition state ensemble. For the exclusive switch, the transition state ensemble is strongly affected by the rate of TF-operator binding, but unaffected by varying the rate of TF-TF binding. Thus, varying the rate of TF-operator binding can drastically change the pathway of switching, while changing the rate of dimerization changes the switching rate without altering the mechanism. The switching pathways of the general switch are highly robust to changes in the rate constants of both TF-operator and TF-TF binding, even though these rate constants do affect the flipping rate; this feature is unique for nonequilibrium systems.


Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus.
Systemic delivery of adenoviral vectors is a major goal in cancer gene therapy, but is currently prohibited by rapid hepatic uptake of virus following intravenous injection with levels of viable virus in the murine plasma typically falling to less than 0.1% after 30 min. We have used a surface-masking technique based on multivalent copolymers of poly(N-(2-hydroxypropyl)methacrylamide) to ablate all pathways of receptor-mediated infection, combined with dose modulation to achieve partial saturation of nonspecific uptake pathways. Polymer coating gave at least 100-fold decreased hepatic transgene expression at all doses and even high doses of coated virus (pc-virus) showed no weight loss or stimulation of serum transaminases. Low doses of virus and pc-virus (10(9) viral particles (vp)/mouse) were mainly captured by the liver (assessed by quantitative PCR), although higher doses led to greater fractional persistence in the plasma (measured after 30 min). Coated virus at a dose of 6 x 10(11) vp/mouse showed nearly 50% plasma circulation, representing a 3.5-fold greater area under the concentration-time curve (0-30 min) compared to unmodified virus. Such an increase in the bioavailability of adenovirus, coupled with substantial decreases in toxicity and unwanted transgene expression is an important step towards producing systemically available tumour-targeted viruses.


Postdiagnostic intake of one-carbon nutrients and alcohol in relation to colorectal cancer survival.
Observational data have suggested that intakes of nutrients involved in one-carbon metabolism are inversely associated with risk of colorectal carcinoma and adenomas. In contrast, results from some preclinical studies and cardiovascular and chemoprevention trials have raised concerns that high folate intake may promote carcinogenesis by facilitating the progression of established neoplasia. We tested the hypothesis that higher total folate intake (including food folate and folic acid from fortified foods and supplements) or other one-carbon nutrient intakes might be associated with poorer survival after a diagnosis of colorectal cancer. We used rectal and colon cancer cases within the following 2 US prospective cohort studies: the Nurses' Health Study and the Health Professionals Follow-Up Study. Biennial questionnaires were used to gather information on medical history and lifestyle factors, including smoking and alcohol consumption. B-vitamin and methionine intakes were derived from food-frequency questionnaires. Data on tumor molecular characteristics (including microsatellite instability, CpG island methylator phenotype, KRAS, BRAF, and PIK3CA mutations, and long interspersed nucleotide element 1 methylation level) were available for a subset of cases. We assessed colorectal cancer-specific mortality according to postdiagnostic intakes of one-carbon nutrients with the use of multivariable Cox proportional hazards regression models. In 1550 stage I-III colorectal cancer cases with a median follow-up of 14.9 y, we documented 641 deaths including 176 colorectal cancer-specific deaths. No statistically significant associations were observed between postdiagnostic intakes of folate or other one-carbon nutrients and colorectal cancer-specific mortality (multivariate P-trend ≥ 0.21). In an exploratory molecular pathologic epidemiology survival analysis, there was no significant interaction between one-carbon nutrients or alcohol and any of the tumor molecular biomarkers examined. Higher postdiagnostic intakes of one-carbon nutrients are not associated with the prognosis in stage I-III colorectal cancer. Our findings do not support the hypothesis that higher folate intake after colorectal cancer diagnosis might increase risk of cancer-related death.


Peripheral nerve pathology in rats with streptozotocin-induced insulinoma.
Peripheral nerve structure was systematically examined in rats with insulinoma induced by streptozotocin (STZ). Normal Wistar rats, aged 3 months (n = 10), were treated with intravenous injections of STZ (20 mg/kg) and housed in plastic cages with free access to water and chow until 24 months of age. Three rats with insulinoma survived and were examined pathologically. Age-matched normal Wistar rats (n = 6) were used for comparison. The insulinoma-bearing rats showed a marked increase in body weight and decrease in blood glucose. In a teased nerve fiber study of the sciatic nerve, the percentage of abnormal fibers undergoing axonal degeneration and de- and remyelination in age-matched normal control rats was 3.9 +/- 2.5% (means +/- SD), whereas in the three insulinoma-bearing rats 49%, 50%, and 24%, respectively, of the fibers showed such changes. Regenerating fibers were also numerous in each insulinoma-bearing rat (36%, 42% and 27%, respectively). Morphometric analysis revealed smaller mean myelinated fiber and axonal areas in all the nerves examined (sciatic, tibial and sural) in insulinoma-bearing rats as compared to those in age-matched normal rats. Fiber area frequency histograms showed a decrease in large myelinated fibers and an increase in small regenerated fibers in insulinoma-bearing rats. Ultrastructurally, endoneurial microvessels exhibited a narrowed vascular lumen with swollen endothelial cells and vacuolar degeneration of pericytes, suggesting an involvement of vascular changes in the neuropathic development. The present study demonstrated marked structural changes in both motor and sensory peripheral nerves of rats bearing experimentally induced insulinoma. We consider that axonal degeneration, regeneration and demyelination constitute the main pathology in the peripheral nerves of insulinoma-bearing rats, although no particular difference in severity of the lesions between sensory and motor and between proximal and distal nerves was apparent.


Sarcocystis calchasi Outbreak in Feral Rock Pigeons ( Columba livia) in California.
Twenty-two feral rock pigeons ( Columba livia) from 10 counties in California with ataxia, torticollis, and difficulty standing and flying were admitted to rehabilitation centers in late winter and spring of 2017 and died or were euthanized. Common necropsy findings included thin body condition, generalized deep red discoloration of organs, and hemorrhagic subcutaneous neck tissues. Meningoencephalitis was observed microscopically in 16 pigeons, and 3 also had protozoal schizonts in the brain. The most consistently affected regions of the brain were cerebellum and brainstem. Skeletal muscles, and less frequently the heart, contained large intrasarcoplasmic bradyzoites typically without inflammation. Fifteen of the 22 birds tested positive using pan- Sarcocystis polymerase chain reaction. The sequence of the amplicon was most closely related to S. calchasi, and the 8 subtyped sequences had 100% homology with S. calchasi. This investigation demonstrated the transcontinental and North American spread of S. calchasi causing a disease outbreak in free-ranging rock pigeons, thus warranting increased surveillance in susceptible native columbids.


Randomized Trial of Pleural Fluid Drainage Frequency in Patients with Malignant Pleural Effusions. The ASAP Trial.
Patients with malignant pleural effusions have significant dyspnea and shortened life expectancy. Indwelling pleural catheters allow patients to drain pleural fluid at home and can lead to autopleurodesis. The optimal drainage frequency to achieve autopleurodesis and freedom from catheter has not been determined. To determine whether an aggressive daily drainage strategy is superior to the current standard every other day drainage of pleural fluid in achieving autopleurodesis. Patients were randomized to either an aggressive drainage (daily drainage; n = 73) or standard drainage (every other day drainage; n = 76) of pleural fluid via a tunneled pleural catheter. The primary outcome was the incidence of autopleurodesis following the placement of the indwelling pleural catheters. The rate of autopleurodesis, defined as complete or partial response based on symptomatic and radiographic changes, was greater in the aggressive drainage arm than the standard drainage arm (47% vs. 24%, respectively; P = 0.003). Median time to autopleurodesis was shorter in the aggressive arm (54 d; 95% confidence interval, 34-83) as compared with the standard arm (90 d; 95% confidence interval, 70 to nonestimable). Rate of adverse events, quality of life, and patient satisfaction were not significantly different between the two arms. Among patients with malignant pleural effusion, daily drainage of pleural fluid via an indwelling pleural catheter led to a higher rate of autopleurodesis and faster time to liberty from catheter. Clinical trial registered with www.clinicaltrials.gov (NCT 00978939).


Monoclonal anti-TNF antibodies can elevate hemoglobin level in patients with ankylosing spondylitis.
Anemia is one of the extra-articular findings of ankylosing spondylitis (AS), and anti-TNF therapy has been shown benefit in patients with anemia associated AS. In this study, we aimed to evaluate and compare the effects of biological and non-biological agents on hemoglobin levels in AS patients. One hundred consecutive patients who fulfilled ASAS criteria for AS were included in the study. Fifty-four of the patients treated with anti-TNF agents (20 patients treated with infliximab, 20 patients with adalimumab, and 14 patients with etanercept), and 46 patients treated with non-steroidal anti-inflammatory drugs and/or other disease modifying anti-rheumatic drugs. The C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin (HGB), hematocrit (HCT) counts, and BASDAI scores were compared before starting therapy and at 52 weeks. There was no statistically significant difference between patients about demographical data (age, sex) and disease age (p > 0.05 for all). Significant difference was determined between HGB, HCT, CRP, ESR, and BASDAI values before and after therapy (for infliximab p: 0.001; 0.000; 0.000; 0.000; 0.000, respectively, and for adalimumab p: 0.017; 0.03; 0.001; 0.002; 0.000, respectively). In etanercept group, there was no significant difference in HGB values, when compared with before starting therapy and at 52 weeks (p > 0.05). In the group of treated with non-biological agents, ESR values and BASDAİ scores showed distinctive improvement after 52 weeks of therapy, but was not a significant difference in hemoglobin and hematocrit values. Anti-TNF-alpha therapy with monoclonal antibodies (adalimumab and infliximab) did not only suppress disease activity but also provided a significant improvement in HGB levels. In the groups of treated with a TNF-alpha receptor antagonist (ETA) and non-biological agents, disease activity was suppressed, but there was not founded significant improvement in HGB levels after 52 weeks. Different outcomes of anti-TNF agents may be associated with their different effect mechanisms.


Molecular palaeontology illuminates the evolution of ecdysozoan vision.
Colour vision is known to have arisen only twice-once in Vertebrata and once within the Ecdysozoa, in Arthropoda. However, the evolutionary history of ecdysozoan vision is unclear. At the molecular level, visual pigments, composed of a chromophore and a protein belonging to the opsin family, have different spectral sensitivities and these mediate colour vision. At the morphological level, ecdysozoan vision is conveyed by eyes of variable levels of complexity; from the simple ocelli observed in the velvet worms (phylum Onychophora) to the marvellously complex eyes of insects, spiders, and crustaceans. Here, we explore the evolution of ecdysozoan vision at both the molecular and morphological level; combining analysis of a large-scale opsin dataset that includes previously unknown ecdysozoan opsins with morphological analyses of key Cambrian fossils with preserved eye structures. We found that while several non-arthropod ecdysozoan lineages have multiple opsins, arthropod multi-opsin vision evolved through a series of gene duplications that were fixed in a period of 35-71 million years (Ma) along the stem arthropod lineage. Our integrative study of the fossil and molecular record of vision indicates that fossils with more complex eyes were likely to have possessed a larger complement of opsin genes.


Examination of femtosecond laser matter interaction in multipulse regime for surface nanopatterning of vitreous substrates.
The paper presents our results on laser micro- and nanostructuring of sodium aluminosilicate glass for the permanent storage purposes and photonics applications. Surface structuring is realized by fs laser irradiation followed by the subsequent etching in a potassium hydroxide (10M@80 °C) for 1 to 10 minutes. As the energy deposited is lower than the damage and/or ablation threshold, the chemical etching permits to produce small craters in the laser modified region. The laser parameters dependent interaction regimes are revealed by microscopic analysis (SEM and AFM). The influence of etching time on craters formation is investigated under different incident energies, number of pulses and polarization states.


Functional annotation of deubiquitinating enzymes using RNA interference.
Protein ubiquitination is a dynamic process, depending on a tightly regulated balance between the activity of ubiquitin ligases and their antagonists, the ubiquitin-specific proteases or deubiquitinating enzymes. The family of ubiquitin ligases has been studied intensively and it is well established that their deregulation contributes to diverse disease processes, including cancer. Much less is known about the function and regulation of the large group of deubiquitinating enzymes. This chapter describes how RNA interference against deubiquitinating enzymes can be used to elucidate their function. The application of this technology will greatly improve the functional annotation of this family of proteases.


The TLR-4/NF-κB signaling pathway activation in cochlear inflammation of rats with noise-induced hearing loss.
The TLR-4/NF-κB signaling pathway is involved in innate immunity and inflammation induced by trauma. The present study aimed to investigate possible TLR-4/NF-κB signaling pathway activation in the cochlea associated with acoustic trauma that might induce cochlear inflammation. A total of 72 rats were exposed to white noise at 120 dB SPL for 8 h per day repeated over 2 successive days. Auditory brainstem responses (ABR) were measured in animals before noise exposure and 0 d (PE0), 1 d (PE1), 3 d (PE3), 7 d (PE7), and 14 d (PE14) after noise exposure. At each defined time point, animals were sacrificed, and cochleae were collected to evaluate the expression levels of TLR4, MyD88, cytoplasmic NF-κB p65, IκBα, TNF-α, and IL-1β using western blotting and NF-κB p65 transcriptional activity using an NF-κB p65 Transcription Factor Assay Kit. Cochlear localizations of TLR-4, TNF-α and IL-1β were analyzed using immunohistochemistry in paraffin-embedded slices. The nuclear translocation of NF-κB p65 was evaluated using immunofluorescence staining in paraffin-embedded slices. DNA fragmentation was measured with a TUNEL assay in paraffin-embedded slices. We found a stable permanent threshold shift after noise exposure. After noise exposure, expression levels of TLR-4, MyD88, IκBα, TNF-α, and IL-1β were significantly upregulated (PE3); DNA binding activity of NF-κB p65 was also significantly enhanced (PE3), while the cytoplasmic NF-κB p65 levels were unchanged. TLR-4, TNF-α, and IL-1β immunostaining intensities were substantially enhanced in spiral ganglion cells and spiral ligament fibrocytes after noise exposure (PE3). In conclusion, the results of this study indicate that the TLR-4/NF-κB signaling pathway is activated in noise-exposed cochleae and that it participates in noise-induced cochlear inflammation.


Genetic analysis of a pleiotropic deletion mutation (delta igf) in Bacillus subtilis.
A delta igf mutation of Bacillus subtilis (formerly called fdpAl) is a large deletion causing pleiotropic defects. The mapping of the delta igf deletion by phage PBS1 transduction revealed the following map order: sacA, thiC, hsrE, delta igf, ts199, purA. To analyze the pleiotropic nature of the delta igf mutation, mutants affected in each property of the pleiotropic mutation were isolated, and the mutations were mapped. iol and gnt mutants could not grow on inositol and gluconate, respectively, and fdp mutants were affected only in fructose-bisphosphatase. The map order from sacA to purA was as follows: sacA, thiC, hsrE, iol-6, gnt-4, fdp-74, hsrB, ts199, purA. The delta igf deletion covered loci from iol-6 to hsrB.


Aspartic protease nepenthesin-1 as a tool for digestion in hydrogen/deuterium exchange mass spectrometry.
Hydrogen/deuterium exchange coupled to mass spectrometry (HXMS) utilizes enzymatic digestion of proteins to localize the information about altered exchange patterns in protein structure. The ability of the protease to produce small peptides and overlapping fragments and provide sufficient coverage of the protein sequence is essential for localizing regions of interest. Recently, it was shown that there is an interesting group of proteolytic enzymes from carnivorous pitcher plants of the genus Nepenthes. In this report, we describe successful immobilization and the use of one of these enzymes, nepenthesin-1, in HXMS workflow. In contrast to pepsin, it has different cleavage specificities, and despite its high inherent susceptibility to reducing and denaturing agents, it is very stable upon immobilization and withstands even high concentration of guanidine hydrochloride and reducing agents. We show that denaturing agents can alter digestion by reducing protease activity and/or substrate solubility, and additionally, they influence the trapping of proteolytic peptides onto the reversed phase resin.


Cutaneous melanoma.
In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially-anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs.


The impact of antiretroviral therapy on symptom burden among HIV outpatients with low CD4 count in rural Uganda: nested longitudinal cohort study.
Individuals with HIV have a high prevalence of physical and psychological symptoms throughout their disease course. Despite the clinical and public health implications of unresolved pain and symptoms, little is known about the effect of anti-retroviral therapy (ART) on these outcomes. This study aimed to assess the impact on symptom burden for the year after ART initiation in individuals with a CD4 count <200 cells/uL in Uganda. HIV-infected, ART-naıve adults referred from voluntary testing and counseling services in rural Uganda for enrollment into a randomized controlled trial to test fluconazole as primary prophylaxis against cryptococcal disease were invited to complete the Memorial Symptom Assessment Scale-Short Form (MSAS-SF) prior to commencing ART and at two subsequent follow up visits. This tool measures self-reported 7-day period prevalence and associated burden of physical and psychological symptoms. Changes in the total number of symptoms and distress indices with time on ART and trial arm were investigated through fitting Linear Mixed Models for repeated measures. During the first year of ART initiation the prevalence of most individual symptoms remained constant. The notable exceptions which improved after commencing ART are as follow; prevalence of pain (prevalence changed from 79% to 60%), weight loss (67% to 31%), lack of appetite (46% to 28%), feeling sad (52% to 25%) and difficulty sleeping (35% to 23%). The total number of symptoms and distress indices reduced after treatment commenced. Of concern was that half or more study participants remained with symptoms of pain (60%), itching (57%), skin changes (53%) and numbness in hands and feet (52%) after starting ART. Sixteen symptoms remained with a burden of 25% or more. Despite the beneficial effect of ART on reducing symptoms, some patients continue to experience a high symptom burden. It is essential that HIV services in sub-Saharan Africa integrate management of symptoms into their programmes. CRYPTOPRO [ISRCTN 76481529 ], November 2004.


Evaluating satellite-based evapotranspiration estimates for hydrological applications in data-scarce regions: A case in Ethiopia.
Water resource development opens up opportunities for improving smallholder farmer livelihoods in sub-Saharan Africa; however, implementation of water resource interventions to ensure sustainability hinges on the availability of sufficient quantity and quality data for monitoring, analysis and planning. Such data is often acquired through instrumentation of water resources (e.g. stream flow monitoring) or the use of hydrological models. In sub-Saharan Africa, data scarcity has limited the ability to monitor and make appropriate decisions for water resource allocation and use. Data derived from remote sensing has been considered a viable option to fill this gap; however, there is limited research in the region that evaluate the quality of the remotely sensed based datasets. This study evaluated actual evapotranspiration (AET) estimates derived from Advanced Very High Resolution Radiometer (AVHRR AET) images and Moderate Resolution Imaging Spectrometer (MOD16 AET) images using estimates from a grid-based Soil and Water Assessment Tool (SWAT). The SWAT model was set up for the entire country of Ethiopia, and calibrated and validated using observed streamflow at several meso-scale watersheds in which satisfactory model performance was obtained. AET estimates from the calibrated and validated SWAT model were then used to evaluate remotely sensed based AET for three landscapes. The AVHRR AET better agreed with the SWAT-simulated AET than the MOD16 AET, although the AVHRR AET overestimated the SWAT-simulated AET in all of the landscapes. Both remotely sensed AET products showed better agreement with the SWAT-simulated AET over agriculture dominated landscapes compared to grassland and forest dominated landscapes. The findings of the study suggest that remotely sensed based AET may help to fine-tune hydrological models in agricultural landscapes in data-scarce regions to improve studies on the impacts of water management interventions aiming to ensure environmental sustainability while enhancing agricultural production, and household income and nutrition.


Endoscopic findings around the gastroesophageal junction: an experience from a tertiary hospital in Korea.
Important lesions related to gastroesophageal reflux disease (GERD) are located around the gastroesophageal junction (GEJ). This study examined the distribution of endoscopic findings around the GEJ and elucidated their relationship to each other and esophageal manometric features. Endoscopic data were collected prospectively from 2,450 consecutive diagnostic upper gastrointestinal endoscopies. The presence and degree of hiatal hernia (HH), columnar-lined esophagus (CLE), and reflux esophagitis (RE) were recorded. Esophageal manometric data were collected from 181 patients. The prevalence of HH, CLE, and RE was 9.8, 18.8, and 9.9%, respectively. Of all HH and CLE cases, 62.8 and 98.9%, respectively, were of the short-segment variety. Of all RE cases, 95.0% were mild. Younger age, male gender, the presence of HH, and a higher gastroesophageal flap valve (GEFV) grades were associated with the presence of RE. Increased ZAP grades were associated with increased prevalence and grades of HH, CLE, and RE. Higher GEFV grades were associated with increased prevalence and grades of HH, CLE, and RE. Lower esophageal sphincter pressure (LESP) decreased in patients with HH or RE compared to those without HH or RE. Endoscopic findings around the GEJ revealed that a substantial proportion of our patients showed features potentially related to GERD. In combination with other recent reports, our study implies that Korea is no longer a very-low-prevalence area of GERD, although it may predominate in silent or milder forms.


Multifunctions of dietary polyphenols in the regulation of intestinal inflammation.
Food for specified health use is a type of functional food approved by the Japanese government, with more than 1250 products in 10 health-claim categories being approved as of April 2016. Polyphenols are currently used as functional ingredients in seven of the 10 categories. Although they have not yet been used for the food-for-specified-health-use category of "gut health promotion," polyphenols are expected to contribute to the future development of gut-modulating food. Intestinal functions include digestion/absorption, acting as a barrier, recognition of external factors, and signal transduction. Owing to incessant exposure to external stress factors including food substances, bacteria, and environmental chemicals, intestines are always inflammatory to some extent, which may cause damage to and dysfunction of intestinal tissues depending on the situation. We identified food factors that could suppress immoderate inflammation in the intestines. In addition to certain amino acids and peptides, polyphenols such as chlorogenic acid and isoflavones were found to suppress inflammation in intestinal cells. Intestinal inflammation is caused by various factors in diverse mechanisms. Recent studies revealed that activation of pattern recognition receptors, such as Toll-like receptors and nucleotide-binding oligomerization domain proteins, in epithelial cells triggers intestinal inflammation. Intracellular receptors or signaling molecules controlling the intestinal detoxification system are also involved in the regulation of inflammation. Differentiation of regulatory T cells by activating a transcription factor Foxp-3 is known to suppress intestinal inflammation. A variety of phytochemicals including polyphenols modulate these receptors and signaling molecules, and are thus anti-inflammatory. Polyphenols affect epigenetic changes occurring in intestinal tissues by interacting with the enzymes responsible for DNA methylation and histone acetylation. New types of anti-inflammatory food factors may be discovered by examining dietary substances that interact with the abovementioned target molecules.


Preparation of novel solid lipid microparticles loaded with gentamicin and its evaluation in vitro and in vivo.
To formulate and evaluate solid-reversed-micellar-solution (SRMS)-based solid lipid microparticles (SLMs) for intramuscular administration of gentamicin. SRMS formulated with Phospholipon® 90G and Softisan® 154 were used to prepare gentamicin-loaded SLMs. Characterizations based on size and morphology, stability and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release of gentamicin from the SLMs was performed in phosphate buffer while in vivo release studies were conducted in rats. Maximum EE% of 90.0, 91.6 and 83.0% were obtained for SLMs formed with SRMS 1:1, 1:2 and 2:1, respectively. Stable, spherical and smooth SLMs of size range 9.80 ± 1.46 µm to 33.30 ± 6.42 µm were produced. The release of gentamicin in phosphate buffer varied widely with the lipid contents. Moreover, significant (p < 0.05) amount of gentamicin was released in vivo from the SLMs. SRMS-based SLMs would likely offer a reliable means of delivering gentamicin intramuscularly.


Cervical dentin hypersensitivity. Part III: resolution following occlusal equilibration.
This retrospective study was designed to investigate changes of cervical dentin hypersensitivity (CDH) in response to occlusal equilibration. Written records for 250 active-care patients were randomly selected and analyzed for associations between CDH, and its resolution following occlusal equilibration. Patients in group A (treatment) and B (delayed treatment) received occlusal equilibration following the detection of verified CDH using the air indexing method. Group C patients were not detected with verified CDH during the study period of 17 years. The resolution of CDH was measured by the loss of a positive patient threshold response to air stimulation. Significant associations existed between CDH, hyperfunction, parafunction, and abfractive lesions. Furthermore, it was found that occlusal equilibration resulted in the long-term resolution of CDH. The resolution of CDH by occlusal equilibration, thus negating the null hypothesis, suggests that further studies are indicated to evaluate the impact of these findings upon restoring and maintaining health of the masticatory system.