Exercise, free radicals and oxidative stress.
This article reviews the role of free radicals in causing oxidative stress during exercise. High intensity exercise induces oxidative stress and although there is no evidence that this affects sporting performance in the short term, it may have longer term health consequences. The mechanisms of exercise-induced oxidative stress are not well understood. Mitochondria are sometimes considered to be the main source of free radicals, but in vitro studies suggest they may play a more minor role than was first thought. There is a growing acceptance of the importance of haem proteins in inducing oxidative stress. The release of metmyoglobin from damaged muscle is known to cause renal failure in exercise rhabdomyolysis. Furthermore, levels of methaemoglobin increase during high intensity exercise, while levels of antioxidants, such as reduced glutathione, decrease. We suggest that the free-radical-mediated damage caused by the interaction of metmyoglobin and methaemoglobin with peroxides may be an important source of oxidative stress during exercise.


Coronary artery bypass grafting in South Asian patients: Impact of gender.
Outcomes following Coronary artery bypass grafting (GABG) vary between genders, with females having a higher postoperative mortality than males. Most of the studies are on Caucasian or mixed population and it is postulated that Asian population and in particular women have higher morbidity and mortality. In this study we have compared outcomes of elective CABG in men and women of South Asian origin in terms of morbidity and mortality. From January 2006 to December 2012, 1970 patients underwent isolated elective CABG at the Aga Khan University Hospital, Pakistan were selected. The prospectively collected data was analyzed retrospectively including univariate and multivariate analysis to find the association of morbidity and mortality. Among the study patients 1664 (85%) were male and 306 (15%) female. Hypertension and diabetes were the most common comorbid conditions seen preoperatively in female patients. Atrial fibrillation and sepsis were the most common postop complications seen in females. In hospital mortality was 3.9% in female underwent CABG as against 0.6% in male. Multivariate analysis showed older age, renal failure, dyslipidemia and prolonged cross clamp time as predictors of postoperative morbidity. Multivariate analysis showed female gender, age and renal failure as predictors of in hospital mortality. Female gender is an independent risk factor for postoperative mortality following CABG however, female gender is not found to be independent risk factor for morbidity. The trend of higher mortality in female patients was comparable to most studies done on Caucasian patients.


Human dendritic cells mediate anti-tumor activity against hematopoietic tumor cells without direct contact and Fas/FasL killing pathway.
During maturation, the capacity of dendritic cells (DCs) to uptake and process antigens becomes diminished while the expression of MHC molecules and costimulatory molecules is up-regulated. These phenotypic changes make DCs potent antigen presenting cells with the ability to initiate and modulate immune responses. Recent findings have shown that DCs can mediate direct cytotoxicity toward tumor cells. Here, we investigated the effect of monocyte derived DC (moDC) on hematopoietic tumor cells by assessing the uptake of [methyl-3H]thymidine (3H-TdR), JAM test (radiometric assay for DNA fragmentation) and 51Cr-release assay. We found that moDCs significantly inhibited the growth of 6 tumor cell lines and stimulated another 4 cell lines independently of the expression of Fas protein. MoDCs also inhibited the proliferation of tumor cells in transwell culture, including two cell lines that were driven to proliferate by direct contact with moDCs. Apoptosis, but not cytolysis, was detected in all the cell lines inhibited by moDCs. In contrast, no cytostatic or cytotoxic effect was detected on K562 cells (chronic myeloid leukemia) and BY94 cells (sporadic Burkitt's lymphoma). The inhibitory activity of moDCs on Fas-expressing tumor cells fully persisted after the neutralization of FasL. Accordingly, there was no detection of FasL protein or FasL mRNA expression in moDC. These results suggest that moDCs can mediate a direct anti-tumor activity against hematopoietic tumor cells through cytostasis in absence of contact or through apoptosis without triggering the Fas/FasL pathway.


Assessment of biofertilizer use for sustainable agriculture in the Great Mekong Region.
A growing concern on the deleterious effects of chemical inputs to the environment has been on the rise from the excessive use of chemical inputs leading to soil and water pollution, destruction to fauna and microbial communities, reduced soil fertility and increased crop disease susceptibility. In the Great Mekong Region (GMR), a large majority of the population relies on agriculture and faces severe challenges including decline in soil fertility, increased pests and diseases, leading to lower ecosystem productivity. In this region, over-dependence on chemical fertilizers also continues to impact negatively on soil health and the wider ecosystem. Agroecological practices, and beneficial microorganisms in particular, offer an affordable and sustainable alternative to mineral inputs for improved plant nutrition and soil health for optimal crop performance and sustainable production. Biofertilizers are a key component in integrated nutrient management as well as for increased economic benefits from reduced expenditure on chemical fertilizers, holistically leading to sustainable agriculture. To cope with the need for biofertilizer adoption for sustainable agricultural production, the countries in the GMR are putting efforts in promoting development and use of biofertilizers and making them available to farmers at affordable costs. Despite these efforts, farmers continue to use chemical fertilizers at high rates with the hope of increased yields instead of taking advantage of microbial products capable of providing plant nutrients while restoring or improving soil health. This study explored the current agricultural practices in the six countries in the GMR (China, Vietnam, Myanmar, Thailand, Cambodia and Lao PDR), the critical need for sustainable agroecological practices with a special emphasis on biofertilizers. We highlighted the current status, distribution, adoption and gaps of biofertilizer production in the GMR, in order to obtain an insight on the nature of biofertilizers, efficacy and production standards, adoption or lack of biofertilizers in the GMR.


Using semantic predications to uncover drug-drug interactions in clinical data.
In this study we report on potential drug-drug interactions between drugs occurring in patient clinical data. Results are based on relationships in SemMedDB, a database of structured knowledge extracted from all MEDLINE citations (titles and abstracts) using SemRep. The core of our methodology is to construct two potential drug-drug interaction schemas, based on relationships extracted from SemMedDB. In the first schema, Drug1 and Drug2 interact through Drug1's effect on some gene, which in turn affects Drug2. In the second, Drug1 affects Gene1, while Drug2 affects Gene2. Gene1 and Gene2, together, then have an effect on some biological function. After checking each drug pair from the medication lists of each of 22 patients, we found 19 known and 62 unknown drug-drug interactions using both schemas. For example, our results suggest that the interaction of Lisinopril, an ACE inhibitor commonly prescribed for hypertension, and the antidepressant sertraline can potentially increase the likelihood and possibly the severity of psoriasis. We also assessed the relationships extracted by SemRep from a linguistic perspective and found that the precision of SemRep was 0.58 for 300 randomly selected sentences from MEDLINE. Our study demonstrates that the use of structured knowledge in the form of relationships from the biomedical literature can support the discovery of potential drug-drug interactions occurring in patient clinical data. Moreover, SemMedDB provides a good knowledge resource for expanding the range of drugs, genes, and biological functions considered as elements in various drug-drug interaction pathways.


Leeds-Keio artificial ligament: a new concept for the anterior cruciate ligament reconstruction of the knee.
The features of the Leeds-Keio artificial ligament, which was developed as a collaborative project between the University of Leeds in the UK and Keio University, are introduced. The ligament is made of polyester, and has a mesh structure. The diameter of the polyester fibers is 22 microns. The ligament has a tensile strength sufficient for anterior cruciate ligament (ACL) reconstruction, and fatigue tests have shown satisfactory durability of the ligament. The stiffness of the Leeds-Keio artificial ligament is about 200 N/mm, which is similar to the natural ACL. A combination of a bone plug and stapling is used for the bone fixation, taking into consideration the strength in both the initial mechanical fixation and the long term fixation. From an animal study, it was shown that fibrous tissue was induced around the artificial ligament, and the collagen fibers became aligned in the longitudinal direction of the ligament. For the clinical experience, one-hundred and thirty five cases were reviewed. The Lachaman sign disappeared in 87.4%, and the pivot shift sign disappeared in 88.1%. Side-to-side difference of anterior displacement of the knee, measured with a KT-2000 knee arthrometer at 30 degrees of flexion, was less than 3 mm in 85.9%. More than 90% of the patients experienced full range of motion. Thus, from the clinical results, it can be concluded that reasonable stability was obtained with the operation. If the Leeds-Keio artificial ligament may not be the perfect substitute for the ACL, both experimental and clinical studies indicate that it represents a major forward step in the history of knee ligament surgery.


Ovulation monitoring and reproductive heterosex: living the conceptive imperative?
Using biosensors, or devices that provide biological information to users about their own bodies, to map ovulation and time intercourse is a practice of rising significance in economically privileged countries. Based on an ethnographic study of ovulation biosensing, this paper explores the contradictions between device manufacturers' figurations of reproductive heterosex as a natural and pleasurable experience facilitated by fertility monitoring technology, and heterosexual women users' accounts of the pleasures and difficulties of ovulation monitoring and associated sexual encounters. Drawing on Science and Technology Studies and the concept of 'script', we examine the frameworks of action defined by makers of ovulation biosensors and how these are accepted, refused or remade by users. Within the scientific romance configured by manufacturers, reproductive heterosex emerges as exciting and fun, whilst the hard, 'technical' work of conception is done by ovulation technologies. Yet ovulation monitoring is described by many heterosexual women users as an exciting and yet anxiety-producing practice through which they come to know their bodies differently, often through online discussions with other women. Living a 'conceptive imperative', women engaging with ovulation sensing reconfigure their reproductive embodiment and shift their relationship to male partners in ways that reveal heterosexual 'baby-making' as a complex and nuanced practice worthy of critical engagement.


Peripheral arterial disease and diabetes: a clinical update.
Peripheral arterial disease is characterized by a gradual reduction in blood to the extremities secondary to atherosclerosis. In diabetes, the pattern of atherosclerotic occlusion typically shows a propensity toward the infrapopliteal vessels. Additionally, impairment of the microcirculation manifests in diminished vasoreactivity and a functional ischemia that is not always correctable with surgery. However, when a nonhealing wound is complicated by peripheral arterial disease, revascularization is paramount to wound healing. Revascularization can be accomplished through traditional bypass surgery or newer endovascular interventions, such as angioplasty and stenting. These less invasive techniques of revascularization offer the advantages of quicker recovery and lower morbidity but durability may be compromised. Ultimately, the choice of revascularization procedure should be based on the clinical characteristics of the atherosclerotic lesion along with the individual patient history.


Maternal and neonatal outcomes of antenatal anemia in a Scottish population: a retrospective cohort study.
Antenatal anemia is a major public health problem in the UK, yet there is limited high quality evidence for associated poor clinical outcomes. The objectives of this study were to estimate the incidence and clinical outcomes of antenatal anemia in a Scottish population. A retrospective cohort study of 80 422 singleton pregnancies was conducted using data from the Aberdeen Maternal and Neonatal Databank between 1995 and 2012. Antenatal anemia was defined as haemoglobin ≤ 10 g/dl during pregnancy. Incidence was calculated with 95% confidence intervals and compared over time using a chi-squared test for trend. Multivariable logistic regression was used to adjust for confounding variables. Results are presented as adjusted odds ratios with 95% confidence interval. The overall incidence of antenatal anemia was 9.3 cases/100 singleton pregnancies (95% confidence interval 9.1-9.5), decreasing from 16.9/100 to 4.1/100 singleton pregnancies between 1995 and 2012 (p < 0.001). Maternal anemia was associated with antepartum hemorrhage (adjusted odds ratio 1.26, 95% confidence interval 1.17-1.36), postpartum infection (adjusted odds ratio 1.89, 95% confidence interval 1.39-2.57), transfusion (adjusted odds ratio 1.87, 95% confidence interval 1.65-2.13) and stillbirth (adjusted odds ratio 1.42, 95% confidence interval 1.04-1.94), reduced odds of postpartum hemorrhage (adjusted odds ratio 0.92, 95% confidence interval 0.86-0.98) and low birthweight (adjusted odds ratio 0.77, 95% confidence interval 0.69-0.86). No other outcomes were statistically significant. This study shows the incidence of antenatal anemia is decreasing steadily within this Scottish population. However, given that anemia is a readily correctable risk factor for major causes of morbidity and mortality in the UK, further work is required to investigate appropriate preventive measures.


Glucose-responsive insulin and glucagon delivery (dual-hormone artificial pancreas) in adults with type 1 diabetes: a randomized crossover controlled trial.
Most patients with type 1 diabetes do not achieve their glycemic targets. We aimed to assess the efficacy of glucose-responsive insulin and glucagon closed-loop delivery for controlling glucose levels in adults with type 1 diabetes. We conducted a randomized crossover trial involving 15 adults with type 1 diabetes, comparing standard insulin-pump therapy with dual-hormone, closed-loop delivery. Patients were admitted twice to a clinical research facility and received, in random order, both treatments. Each 15-hour visit (from 1600 to 0700) included an evening exercise session, followed by a medium-sized meal, a bedtime snack and an overnight stay. During visits that involved closed-loop delivery, basal insulin and glucagon miniboluses were delivered according to recommendations based on glucose sensor readings and a predictive dosing algorithm at 10-minute intervals. During visits involving standard insulin-pump therapy (control visits), patients used conventional treatment. Dual-hormone closed-loop delivery increased the percentage of time for which patients' plasma glucose levels were in the target range (median 70.7% [interquartile range (IQR) 46.1%-88.4%] for closed-loop delivery v. 57.3% [IQR 25.2%-71.8%] for control, p = 0.003) and decreased the percentage of time for which plasma glucose levels were in the low range (bottom of target range [< 4.0 mmol/L], 0.0% [IQR 0.0%-3.0%] for closed-loop delivery v. 10.2% [IQR 0.0%-13.0%] for control, p = 0.01; hypoglycemia threshold [< 3.3 mmol/L], 0.0% [IQR 0.0%-0.0%] for closed-loop delivery v. 2.8% [IQR 0.0%-5.9%] for control, p = 0.006). Eight participants (53%) had at least 1 hypoglycemic event (plasma glucose < 3.0 mmol/L) during standard treatment, compared with just 1 participant (7%) during closed-loop treatment (p = 0.02). Dual-hormone, closed-loop delivery guided by advanced algorithms improved short-term glucose control and reduced the risk of hypoglycemia in a group of 15 adults with type 1 diabetes. ClinicalTrials.gov, no. NCT01297946.


[Ophthalmic diseases in childhood].
Tear duct obstruction is a common problem in the neonatal period. It usually has a good natural course and rarely needs treatment. In contrast the less frequent diseases like congenital cataract, childhood glaucoma and retinopathy of prematurity need urgent treatment because of their sight threatening nature. Pediatricians and parents have a most important role in the early diagnosis of severe early childhood eye diseases.


Source of funding and outcome of clinical trials.
Because of recent concerns about conflicts of interest and published research, the author analyzed 107 controlled clinical trials. Studies were classified as favoring either a new therapy or a traditional therapy, and as being supported by a pharmaceutical manufacturer or as being generally supported. Seventy-one per cent of the trials favored new therapies; 43% of these were funded by pharmaceutical firms. Of the 31 trials favoring traditional therapy, only four (13%) were supported by a pharmaceutical firm. There was a statistically significant association between the source of funding and the outcome of the study (p = 0.002). Few trials supported by pharmaceutical manufacturers favored traditional therapy; some reasons for this finding may include selection of drugs likely to be proven efficacious, Type II errors (false-negative studies), and fear of discontinuation of funding should such studies be submitted. Important clinical information may be lost if negative studies are not published.


CD10-Equipped Melanoma Cells Acquire Highly Potent Tumorigenic Activity: A Plausible Explanation of Their Significance for a Poor Prognosis.
CD10 has been widely used in cancer diagnosis. We previously demonstrated that its expression in melanoma increased with tumor progression and predicted poor patient survival. However, the mechanism by which CD10 promotes melanoma progression remains unclear. In order to elucidate the role of CD10 in melanoma, we established CD10-overexpressing A375 melanoma cells and performed DNA microarray and qRT-PCR analyses to identify changes in the gene expression profile. The microarray analysis revealed that up-regulated genes in CD10-A375 were mostly involved in cell proliferation, angiogenesis, and resistance to apoptosis; down-regulated genes mostly belonged to the categories associated with cell adhesion and migration. Accordingly, in functional experiments, CD10-A375 showed significantly greater cell proliferation in vitro and higher tumorigenicity in vivo; CD10 enzymatic inhibitors, thiorphan and phosphoramidon, significantly blocked the tumor growth of CD10-A375 in mice. In migration and invasion assays, CD10-A375 displayed lower migratory and invasive capacity than mock-A375. CD10 augmented melanoma cell resistance to apoptosis mediated by etoposide and gemcitabine. These findings indicate that CD10 may promote tumor progression by regulating the expression profiles of genes related to cell proliferation, angiogenesis, and resistance to apoptosis.


Analogic versus digital mammographic examination a radiological study of mammary microcalcifications on 52 surgical samples.
Digital mammography is known to have lower spatial resolution compared to conventional analogic mammography. The aim of this study was to evaluate whether this physical feature could compromise the perception of microcalcifications in radiological findings. Fifty-two surgical samples of non-palpable breast lesions with microcalcifications were imaged using both techniques. The images were examined by four different radiologists. Data processing was limited to comparing the number of microcalcifications found on the conventional and digital images, in both standard and magnified modality. The cases were classified into 3 groups according to the number of calcifications demonstrated in the surgical sample: less than 10, 10 to 30, and more than 30. The differences in the count of microcalcifications with the two acquisition modalities were evaluated with the Kappa test. In order to compare the differences we synthesised by percentage those cases exhibiting a larger or lesser number of calcifications. The Kappa test was 0.546 in standard analogic vs standard digital, 0.582 in magnified analogic vs magnified digital, 0.828 in standard analogic vs magnified analogic and 0.492 in standard digital vs magnified digital. The most significant results were observed on comparing the magnifications produced with the two modalities: in 25% of cases, digital magnification detected more calcifications than did traditional magnification. The number of cases where standard digital images allowed the detection of more calcifications than standard analogic images was significant, although less important (17.8%). The study was able to provide data that confirm the overall equivalence of the two techniques, as far as subtle mammographic findings (such as microcalcifications) are concerned. In particular, as applied to the series we examined, there is a cautious advantage in favour of the digital technique. More clinical studies, on larger series, will be necessary for a further and more thorough comparison of the two techniques, so that the results might be consistently useful in clinical practice.


Perseverance time of informal caregivers for people with dementia: construct validity, responsiveness and predictive validity.
Informal care is essential for many people with dementia (PwD), but it often results in a considerable burden for the caregiver. The perseverance time instrument integrates the aspect of perceived burden with the caregiver's capacity to cope with the burden, in contrast to most available instruments, which measure solely the burden of caregiving. The aim of this study was to extend insight into psychometric properties of the perseverance time instrument, specifically the construct validity, responsiveness, and predictive validity, within the population of informal caregivers for PwD. Data from two studies among informal caregivers of community-dwelling PwD in the Netherlands were used. The first study included 198 caregivers from a single region in the Netherlands and lasted 1 year. The second was a cross-sectional nationwide study with 166 caregivers for PwD. Questionnaires of both studies included questions regarding demographics and informal care, perseverance time, and other informal caregiver outcomes (Caregiver Strain Index, Self-rated Burden scale, Care-related Quality of Life instrument, and visual analogue scale health scores). Construct validity and responsiveness were assessed using a hypothesis-testing approach. The predictive validity of demographic characteristics and perseverance time for living situation after 1 year (living at home, institutionalized, or deceased) was assessed with multivariable multinomial regression. All but one of the hypotheses regarding construct validity were met. Three of five hypotheses regarding responsiveness were met. Perseverance time scores at baseline were associated with living situation after 1 year (p < 0.01), unlike age, sex, and relationship with PwD. Perseverance time strongly increased predictive power for living situation after 1 year (c-index between 0.671 and 0.775) in addition to demographic characteristics. This study supports previous findings regarding the construct validity of the perseverance time instrument and adds new evidence of good construct validity, responsiveness, and predictive validity. The predictive power of perseverance time scores for living situation exceeds the predictive power of other burden measures and indicates informal care as an important factor for maintaining the patient at home.


A study of metabolic compartmentation in the rat heart and cardiac mitochondria using high-resolution magic angle spinning 1H NMR spectroscopy.
High-resolution magic angle spinning (MAS) (1)H nuclear magnetic resonance (NMR) spectroscopy is increasingly being used to monitor metabolic abnormalities within cells and intact tissues. Many toxicological insults and metabolic diseases affect subcellular organelles, particularly mitochondria. In this study high-resolution (1)H NMR spectroscopy was used to examine metabolic compartmentation between the cytosol and mitochondria in the rat heart to investigate whether biomarkers of mitochondrial dysfunction could be identified and further define the mitochondrial environment. High-resolution MAS spectra of mitochondria revealed NMR signals from lactate, alanine, taurine, choline, phosphocholine, creatine, glycine and lipids. However, spectra from mitochondrial extracts contained additional well-resolved resonances from valine, methionine, glutamine, acetoacetate, succinate, and aspartate, suggesting that a number of metabolites bound within the mitochondrial membranes occur in 'NMR invisible' environments. This effect was further investigated using diffusion-weighted measurements of water and NMR spectroscopy during state 2 and state 3 respiration. State 3 respiration caused a decrease in the resonance intensity of endogenous succinate compared with state 2 respiration, suggesting that coupled respiration may also modulate the NMR detection of metabolites within mitochondria.


Experiments in interdisciplinarity: Responsible research and innovation and the public good.
In Europe, responsible research and innovation (RRI) has emerged as a science policy measure that demands the early integration of a broad range of social actors and perspectives into research and development (R&D). More collaboration of the social sciences and humanities (SSH) with science and engineering appears within this policy framework as a crucial element that will enable better technological development. However, RRI is new to both natural scientists and SSH scholars, and interdisciplinary collaborations are challenging for many reasons. In this paper, we discuss these challenges while suggesting that what RRI can be in a particular project is not a given but remains an empirical question. Natural scientists and SSH scholars need to coresearch RRI in an experimental mode.


Interpol: An R package for preprocessing of protein sequences.
Most machine learning techniques currently applied in the literature need a fixed dimensionality of input data. However, this requirement is frequently violated by real input data, such as DNA and protein sequences, that often differ in length due to insertions and deletions. It is also notable that performance in classification and regression is often improved by numerical encoding of amino acids, compared to the commonly used sparse encoding. The software "Interpol" encodes amino acid sequences as numerical descriptor vectors using a database of currently 532 descriptors (mainly from AAindex), and normalizes sequences to uniform length with one of five linear or non-linear interpolation algorithms. Interpol is distributed with open source as platform independent R-package. It is typically used for preprocessing of amino acid sequences for classification or regression. The functionality of Interpol widens the spectrum of machine learning methods that can be applied to biological sequences, and it will in many cases improve their performance in classification and regression.


Comparative epigenomics of human and mouse mammary tumors.
Gene silencing by aberrant epigenetic chromatin alteration is a well-recognized event contributing to tumorigenesis. Although genetically engineered tumor-prone mouse models have proven a powerful tool in understanding many aspects of carcinogenesis, to date few studies have focused on epigenetic alterations in mouse tumors. To uncover epigenetically silenced tumor suppressor genes (TSGs) in mouse mammary tumor cells, we conducted initial genome-wide screening by combining the treatment of cultured cells with the DNA demethylating drug 5-aza-2'-deoxycytidine (5-azadC) and the histone deacetylase inhibitor trichostatin A (TSA) with expression microarray. By conducting this initial screen on EMT6 cells and applying protein function and genomic structure criteria to genes identified as upregulated in response to 5-azadC/TSA, we were able to identify two characterized breast cancer TSGs (Timp3 and Rprm) and four putative TSGs (Atp1B2, Dusp2, FoxJ1 and Smpd3) silenced in this line. By testing a panel of 10 mouse mammary tumor lines, we determined that each of these genes is commonly hypermethylated, albeit with varying frequency. Furthermore, by examining a panel of human breast tumor lines and primary tumors we observed that the human orthologs of ATP1B2, FOXJ1 and SMPD3 are aberrantly hypermethylated in the human disease whereas DUSP2 was not hypermethylated in primary breast tumors. Finally, we examined hypermethylation of several genes targeted for epigenetic silencing in human breast tumors in our panel of 10 mouse mammary tumor lines. We observed that the orthologs of Cdh1, RarB, Gstp1, RassF1 genes were hypermethylated, whereas neither Dapk1 nor Wif1 were aberrantly methylated in this panel of mouse tumor lines. From this study, we conclude that there is significant, but not absolute, overlap in the epigenome of human and mouse mammary tumors.


A narrative systematic review of factors affecting diabetes prevention in primary care settings.
Type 2 diabetes is impacting millions of people globally; however, many future cases can be prevented through lifestyle changes and interventions. Primary care is an important setting for diabetes prevention, for at-risk populations, because it is a patient's primary point of contact with the health care system and professionals can provide lifestyle counselling and support, as well as monitoring health outcomes. These are all essential elements for diabetes prevention for at-risk adults. To understand the factors related to the delivery and uptake of type 2 diabetes prevention interventions within primary care in higher income countries. For this narrative systematic review, we combined qualitative and quantitative studies of diabetes prevention within a primary care setting for patients at-risk of developing the condition. We used an iterative approach for evidence collection, which included using several databases (MEDLINE, Embase, Pysch info, BNI, SSCI, CINAHL, ASSIA), where we combined diabetes terms with primary care terms. Narrative and thematic synthesis were utilised to identify the prominent themes emerging from the data. A database of 6646 records was screened by the research team, and 18 papers were included. Three major themes were identified in this review. The first theme of context and setting of diabetes progression includes the risk and progression of diabetes, primary care as a setting, and where the responsibility for change is thought to lie. This review also found mixed views on the value of preventative services within primary care. The second theme focused on the various patient factors associated with diabetes prevention such as a patient's motivation to modify their current lifestyle, perceptions and knowledge (or lack thereof) of the impacts of diabetes, lack of follow-up in healthcare settings, and trust in healthcare professionals. The third theme was centred on professional factors impacting on diabetes prevention which included workload, time constraints, resources, self-efficacy and knowledge as well as professionals' perception of patient motivations towards change. This review explored the factors influencing diabetes prevention in primary care, and identified the context of prevention, as well as patient and professional factors related to preventative services being offered in primary care. This systematic review complements previous reviews of real-world settings by exploring the significant factors in prevention, and the findings are relevant to academics, policymakers, patients and practitioners interested in understanding the factors associated with the delivery and uptake of diabetes prevention interventions.


Proteomics Analysis of Tangeretin-Induced Apoptosis through Mitochondrial Dysfunction in Bladder Cancer Cells.
Tangeretin is one of the most abundant compounds in citrus peel, and studies have shown that it possesses anti-oxidant and anti-cancer properties. However, no study has been conducted on bladder cancer cells. Bladder cancer has the second highest mortality rate among urological cancers and is the fifth most common malignancy in the world. Currently, combination chemotherapy is the most common approach by which to treat patients with bladder cancer, and thus identifying more effective chemotherapeutic agents that can be safely administered to patients is a very important research issue. Therefore, this study investigated whether tangeretin can induce apoptosis and identified the signaling pathways of tangeretin-induced apoptosis in human bladder cancer cells using two-dimensional gel electrophoresis (2DGE). The results of the study demonstrated that 60 μM tangeretin reduced the cell survival of a BFTC-905 bladder carcinoma cell line by 42%, and induced early and late apoptosis in the cells. In this study 2DGE proteomics technology identified 41 proteins that were differentially-expressed in tangeretin-treated cells, and subsequently LC⁻MS/MS analysis was performed to identify the proteins. Based on the functions of the differentially-expressed proteins, the results suggested that tangeretin caused mitochondrial dysfunction and further induced apoptosis in bladder cancer cells. Moreover, western blotting analysis demonstrated that tangeretin treatment disturbed calcium homeostasis in the mitochondria, triggered cytochrome C release, and activated caspase-3 and caspase-9, which led to apoptosis. In conclusion, our results showed that tangeretin-induced apoptosis in human bladder cancer cells is mediated by mitochondrial inactivation, suggesting that tangeretin has the potential to be developed as a new drug for the treatment of bladder cancer.


Reduction of reset pulse in resonant frequency servo loop for resonant fiber-optic gyro by an auto-controlled reset technique.
Resonant fiber-optic gyro (RFOG) based on the Sagnac effect has the potential to achieve the inertial navigation system requirement with a short sensing coil. A high-accuracy resonant frequency servo loop is indispensable for a high-performance RFOG. A digital proportional-integral (PI) controller is always adopted in the resonant frequency servo loop. The resonant frequency of the optical fiber ring resonator drifts with environmental temperature changes. When the resonant frequency drift is beyond the tracking range of the resonant frequency servo loop, the digital PI controller overflows and outputs a reset signal. A large reset pulse, which is equivalent to a rotation rate error of 26°/h, has been observed at the output of the RFOG, while a long time is required for returning to the lock-in state simultaneously. To reduce the effect of the overflow resetting in the digital PI controller, an auto-controlled reset technique is proposed and experimentally demonstrated. As a result, the time for returning to the lock-in state is reduced to 5 ms from 8 s. With the integration time of 1 s, the equivalent accuracy of the resonant frequency servo loop is improved to 0.18°/h.


Taurine alleviates the progression of diabetic nephropathy in type 2 diabetic rat model.
The overexpression of vascular endothelial growth factor (VEGF) is known to be involved in the pathogenesis of diabetic nephropathy. In this study, the protective effects of taurine on diabetic nephropathy along with its underlying mechanism were investigated. Experimental animals were divided into three groups: LETO rats as normal group (n = 10), OLETF rats as diabetic control group (n = 10), and OLETF rats treated with taurine group (n = 10). We treated taurine (200 mg/kg/day) for 20 weeks and treated high glucose (HG, 30 mM) with or without taurine (30 mM) in mouse cultured podocyte. After taurine treatment, blood glucose level was decreased and insulin secretion was increased. Taurine significantly reduced albuminuria and ACR. Also it decreased glomerular volume, GBM thickness and increased open slit pore density through decreased VEGF and increased nephrin mRNA expressions in renal cortex. The antioxidant effects of taurine were confirmed by the reduction of urine MDA in taurine treated diabetic group. Also reactive oxygen species (ROS) levels were decreased in HG condition with taurine treated podocytes compared to without taurine. These results indicate that taurine lowers glucose level via increased insulin secretion and ameliorates the progression of diabetic nephropathy through antifibrotic and antioxidant effects in type 2 diabetes rat model.


NFAT is required for spontaneous pulmonary hypertension in superoxide dismutase 1 knockout mice.
Elevated reactive oxygen species are implicated in pulmonary hypertension (PH). Superoxide dismutase (SOD) limits superoxide bioavailability, and decreased SOD activity is associated with PH. A decrease in SOD activity is expected to increase superoxide and reduce hydrogen peroxide levels. Such an imbalance of superoxide/hydrogen peroxide has been implicated as a mediator of nuclear factor of activated T cells (NFAT) activation in epidermal cells. We have shown that NFATc3 is required for chronic hypoxia-induced PH. However, it is unknown whether NFATc3 is activated in the pulmonary circulation in a mouse model of decreased SOD1 activity and whether this leads to PH. Therefore, we hypothesized that an elevated pulmonary arterial superoxide/hydrogen peroxide ratio activates NFATc3, leading to PH. We found that SOD1 knockout (KO) mice have elevated pulmonary arterial wall superoxide and decreased hydrogen peroxide levels compared with wild-type (WT) littermates. Right ventricular systolic pressure (RVSP) was elevated in SOD1 KO and was associated with pulmonary arterial remodeling. Vasoreactivity to endothelin-1 was also greater in SOD1 KO vs. WT mice. NFAT activity and NFATc3 nuclear localization were increased in pulmonary arteries from SOD1 KO vs. WT mice. Administration of A-285222 (selective NFAT inhibitor) decreased RVSP, arterial wall thickness, vasoreactivity, and NFAT activity in SOD1 KO mice to WT levels. The SOD mimetic, tempol, also reduced NFAT activity, NFATc3 nuclear localization, and RVSP to WT levels. These findings suggest that an elevated superoxide/hydrogen peroxide ratio activates NFAT in pulmonary arteries, which induces vascular remodeling and increases vascular reactivity leading to PH.


The Impact of Job Role on Health-Care Workers' Definitions of Patient-Centered Care.
While patient-centered care (PCC) is a widely accepted aspect of health-care quality, its definition is still the subject of debate. We investigated health-care workers' definitions of PCC by level of patient contact in job roles. Our qualitative study involved semi-structured interviews with key stakeholder employees (n = 66) at 6 Veterans' Affairs health-care locations in Southern California. Interviews were recorded, transcribed, coded for definitions of PCC, and analyzed by participants' self-described level of patient contact. Stakeholders whose role primarily involved patient contact tended to define PCC through: patient as a person, patient preferences, and shared decision-making. Stakeholders whose role did not primarily involve patient contact tended to define PCC through: patient-centered redesign, customer service, and access to services. Stakeholders with more patient contact emphasized patient-level and interpersonal concepts, while those with less patient contact emphasized system-level and business-oriented concepts. The focus on PCC-as-access may reflect influence of changing institutional climate on definitions of PCC for some stakeholders. To facilitate successful PCC efforts, health-care systems may need to leverage differing but complementary definitions of PCC within its workforce.


Child dental fear and behavior: the role of environmental factors in a hospital cohort.
Information on the origin of dental fear and uncooperative behavior in a child patient is important for behavior management strategy. The effects of environmental factors have been comparatively less studied, especially in an Indian scenario. To find the association of (1) age, gender, family characteristics, previous medical, and dental experiences with dental fear and behavior (2) dental fear with dental behavior. A cross-sectional questionnaire study involving 125 children aged between 7 and 14 years undergoing dental treatment under local anesthesia. The parent completed a questionnaire on family situation, medical history, and past dental experiences of the child. Child's dental fear was recorded using Children's Fear Survey Schedule-Dental Subscale and behavior was rated using Frankl Behaviour Rating Scale. Data were analyzed using chi square test and binary logistic regression analysis. Unpleasant experience in dental clinic and age of the child significantly influenced dental behavior. Visited pediatrician in the past one year, prior history of hospital admission, previous visit to dentist, experience at the first dental visit, and age of the child were contributing factors for dental fear. There was also significant association between dental fear levels and behavior. In 7 to 14 year olds, dental fear influences dental behavior, but the factors affecting them are not the same. Although dental fear decreases and dental behavior improves with age, experiences at the previous dental visits seem to influence both dental fear and behavior. Past medical experiences are likely to influence dental fear but not dental behavior.


Timely approaches to identify probiotic species of the genus Lactobacillus.
Over the past decades the use of probiotics in food has increased largely due to the manufacturer's interest in placing "healthy" food on the market based on the consumer's ambitions to live healthy. Due to this trend, health benefits of products containing probiotic strains such as lactobacilli are promoted and probiotic strains have been established in many different products with their numbers increasing steadily. Probiotics are used as starter cultures in dairy products such as cheese or yoghurts and in addition they are also utilized in non-dairy products such as fermented vegetables, fermented meat and pharmaceuticals, thereby, covering a large variety of products.To assure quality management, several pheno-, physico- and genotyping methods have been established to unambiguously identify probiotic lactobacilli. These methods are often specific enough to identify the probiotic strains at genus and species levels. However, the probiotic ability is often strain dependent and it is impossible to distinguish strains by basic microbiological methods.Therefore, this review aims to critically summarize and evaluate conventional identification methods for the genus Lactobacillus, complemented by techniques that are currently being developed.


ORCA.IT: A New Web-Based Tool for Assessing Online Reading, Search and Comprehension Abilities in Students Reveals Effects of Gender, School Type and Reading Ability.
ORCA.IT, a new online test of online research and comprehension was developed for the Italian population. A group of 183 students attending various types of upper secondary schools in Northern Italy were tested with the new tool and underwent further cognitive and neuropsychological assessment. The different school types involved in the study are representative of the school population in the Italian system, but can also be easily compared with the educational systems of other countries. The new test turned out to have good psychometric properties after accurate item construction and final selection. In particular, Version 1 showed better characteristics than Version 2. Subsequently, comparison with one-way ANOVAs were performed to test whether differences exist between different school types, between groups with and without reading difficulties, and between males and females. Such differences are sometimes reported in the literature, but many remain controversial. Further, Pearson's bivariate correlations were calculated to analyze associations between scores on the ORCA.IT and cognitive/neuropsychological variables. Finally, a stepwise regression analysis was performed on aggregated scores to identify the predictors of performance on each of the two versions. The test, especially in the most complete version (Version 1), appears to accurately and reliably capture students' web searching abilities and online reading comprehension. The tool could highlight differences in online search and comprehension ability between students with and without reading difficulties, not penalizing overall performance but allowing very specific weaknesses to be pointed out. Further, it seems to be able to capture differences due to both educational pathways (different school types) and social attitudes (differences between males and females). Most interestingly, it shows to be clearly resting on specific cognitive and neuropsychological abilities, including language, memory, and attentional skills, which explain a large portion of the total variance. Offline text reading comprehension is a crucial predictor of online reading performance, while decoding ability is not. Prior knowledge also influences the results, as expected. The new tool turns out to be rather independent of previous Internet experience and to measure more cognitively grounded processes related to information gathering, processing, and communicating.


Diversity of coelomycetous fungi in human infections: A 10-y experience of two European reference centres.
The coelomycetous fungi are difficult to properly identify from their phenotypic characterization and their role as etiologic agents of human infections is not clear. We studied the species distribution of these fungi among clinical isolates that had been collected and stored over a ten-year period in two European reference laboratories (France and Spain). We identified phenotypically and molecularly 97 isolates by sequencing the D1-D2 fragment of the 28S nrRNA (LSU) gene and we provided the in vitro antifungal susceptibility pattern of seven antifungals against 46 isolates. Species of the orders Pleosporales and Glomerellales were present in both collections, and Botryosphaeriales and Diaporthales only in the French one. The most prevalent species were Medicopsis romeroi, Neocucurbitaria keratinophila, Neocucurbitaria unguis-hominis and Paraconiothyrium cyclothyrioides, which had been recovered primarily from superficial tissues. The Didymellaceae was the most common family represented, with 27 isolates distributed into five genera. Most of the isolates tested were susceptible to antifungals, and only the geometric mean (GM) and minimal inhibitory concentration (MIC) values of itraconazole and caspofungin had higher values. This study provides a good picture of the great diversity of coelomycetous fungi in the European clinical context, and the basis for future studies on this interesting but neglected group of fungi.


Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme.
Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immunodeficiencies in adults. They comprise a heterogeneous group of pathologies, with frequent non-infectious complications in addition to the bacterial infections that usually characterize their presentation. Complications include a high risk of malignancy, especially lymphoma and gastric cancer. Helicobacter pylori infection and pernicious anaemia are risk predictors for gastric cancer in the general population and probably in patients with CVIDs. Screening for gastric cancer in a high-risk population appears to improve survival. Given the increased risk of gastric cancer in patients with CVIDs and prompted by a case of advanced gastric malignancy in a patient with a CVID and concomitant pernicious anaemia, we performed a review of the literature for gastric cancer and conducted a cohort study of gastric pathology in 116 patients with CVIDs under long-term follow-up in Oxford. Regardless of the presence of pernicious anaemia or H. pylori infection, patients with CVIDs have a 10-fold increased risk of gastric cancer and are therefore a high-risk population. Although endoscopic screening of all patients with CVIDs could be considered, a more selective approach is appropriate and we propose a surveillance protocol that should reduce modifiable risk factors such as H. pylori, in order to improve the management of patients with CVIDs at risk of gastric malignancy.


Call cultures in orang-utans?
Several studies suggested great ape cultures, arguing that human cumulative culture presumably evolved from such a foundation. These focused on conspicuous behaviours, and showed rich geographic variation, which could not be attributed to known ecological or genetic differences. Although geographic variation within call types (accents) has previously been reported for orang-utans and other primate species, we examine geographic variation in the presence/absence of discrete call types (dialects). Because orang-utans have been shown to have geographic variation that is not completely explicable by genetic or ecological factors we hypothesized that this will be similar in the call domain and predict that discrete call type variation between populations will be found. We examined long-term behavioural data from five orang-utan populations and collected fecal samples for genetic analyses. We show that there is geographic variation in the presence of discrete types of calls. In exactly the same behavioural context (nest building and infant retrieval), individuals in different wild populations customarily emit either qualitatively different calls or calls in some but not in others. By comparing patterns in call-type and genetic similarity, we suggest that the observed variation is not likely to be explained by genetic or ecological differences. These results are consistent with the potential presence of 'call cultures' and suggest that wild orang-utans possess the ability to invent arbitrary calls, which spread through social learning. These findings differ substantially from those that have been reported for primates before. First, the results reported here are on dialect and not on accent. Second, this study presents cases of production learning whereas most primate studies on vocal learning were cases of contextual learning. We conclude with speculating on how these findings might assist in bridging the gap between vocal communication in non-human primates and human speech.


The impact of medical students on rural general practitioner perceptors.
As universities rely more heavily on rural GPs to precept medical students, the formation of symbiotic partnerships benefiting students, universities and GPs, becomes imperative. In order to develop and consolidate these partnerships Universities must understand who their rural GP preceptors are and how precepting impacts on them. A review of the literature was undertaken to determine the significant themes of student impacts from articles where conclusions were clearly based on empirical findings. Forty-three articles were included in the final review, but only nine specifically looked at impacts on rural GPs. Impacts were categorised into six domains: personal; time; patient care; professional relationships and professional development; business and infrastructure; and recognition and remuneration. Literature specifically addressing the impact of precepting on rural GPs is scarce. Further studies are required to evaluate the relationship between the quality of teaching delivered to students, the type and length of student attachments and the likely impacts on rural GPs.


Depression in end-stage renal disease: current advances and research.
Depression or the presence of significant depressive symptoms remains common in patients with end-stage renal disease (ESRD). It is thought that 20-30% of ESRD patients have significant depressive symptoms, although there are issues surrounding the assessment of depression among patients with physical illness. Screening tools may be useful in this setting to identify patients with low affect, accompanied by formal diagnostic approaches which are important to consider following a positive screen. Recent evidence highlights the impact of depression upon mortality, and its association with non-adherence and immune parameters, work that supports past investigations. Further studies are required to better our understanding of the mechanisms behind depression in patients with ESRD identifying both psychological and clinical antecedents. A focus on the treatment of depression is now critical given the evidence that depression impacts upon outcome in ESRD. Antidepressants seem effective, but the prevalence of negative side effect profiles and drug-drug interactions suggest a role for psychotherapeutic approaches. Of these, cognitive behavioral therapy shows real promise.


Gene conversion of major histocompatibility complex genes is associated with CpG-rich regions.
We examined 32 DNA sequences of mouse and human major histocompatibility complex (MHC) genes believed to have been subjected to gene conversion events. All regions of the mouse H2 genes as well as the human HLA genes which have been implied to be involved in gene conversion events had elevated levels of CpG dinucleotides, whereas the rest of the genes showed extensive CpG suppression. Mouse MHC genes which have been suspected but not directly implied to be involved in gene conversion events also showed elevated levels of CpG dinucleotides. Moreover, both mouse and human MHC genes which have never been suspected of undergoing gene conversion had low levels of CpG throughout the genes. These results indicate that high CpG levels are correlated with gene conversion rather than with polymorphism, as non-polymorphic genes that have been implicated as gene conversion donors also have elevated levels of CpG dimers in the involved regions, whereas polymorphic genes which have never been considered to undergo gene conversion events have a low level of CpG dinucleotides. We also studied the methylation pattern of CpG dimers in the Abk gene by restriction enzyme digestion of mouse testis DNA followed by Southern blot and hybridization to an Abk-specific probe. The examined CpG dimers in prepubescent mice, where the latest germline stages are spermatogonia, leptene, or pachytene, are respectively non-methylated. Accordingly, the CpG dimers appear to be non-methylated in germline DNA from the testis of prepubescent mice, where gene conversions have been reported to occur.


Use of a patient-entered family health history tool with decision support in primary care: impact of identification of increased risk patients on genetic counseling attendance.
Several barriers inhibit collection and use of detailed family health history (FHH) in primary care. MeTree, a computer-based FHH intake and risk assessment tool with clinical decision support, was developed to overcome these barriers. Here, we describe the impact of MeTree on genetic counseling (GC) referrals and attendance. Non-adopted, English speaking adults scheduled for a well-visit in two community-based primary-care clinics were invited to participate in an Implementation-Effectiveness study of MeTree. Participants' demographic characteristics and beliefs were assessed at baseline. Immediately after an appointment with a patient for whom GC was recommended, clinicians indicated whether they referred the patient and, if not, why. The study genetic counselor kept a database of patients with a GC recommendation and contacted those with a referral. Of 542 patients completing MeTree, 156 (29 %) received a GC recommendation. Of these, 46 % (n = 72) were referred and 21 % (n = 33) underwent counseling. Patient preferences, additional clinical information unavailable to MeTree, and an incomplete clinician evaluation of the FHH accounted for the 85 patients clinicians chose not to refer. Although MeTree identified a significant proportion of patients for whom GC was recommended, persistent barriers indicate the need for improved referral processes and patient and physician education about the benefits of GC.


Combining data from multiple inbred line crosses improves the power and resolution of quantitative trait loci mapping.
Rodent inbred line crosses are widely used to map genetic loci associated with complex traits. This approach has proven to be powerful for detecting quantitative trait loci (QTL); however, the resolution of QTL locations, typically approximately 20 cM, means that hundreds of genes are implicated as potential candidates. We describe analytical methods based on linear models to combine information available in two or more inbred line crosses. Our strategy is motivated by the hypothesis that common inbred strains of the laboratory mouse are derived from a limited ancestral gene pool and thus QTL detected in multiple crosses are likely to represent shared ancestral polymorphisms. We demonstrate that the combined-cross analysis can improve the power to detect weak QTL, can narrow support intervals for QTL regions, and can be used to separate multiple QTL that colocalize by chance. Moreover, combined-cross analysis can establish the allelic states of a QTL among a set of parental lines, thus providing critical information for narrowing QTL regions by haplotype analysis.


DUPLEXITY THEORY OF TASTE.
When two different taste stimuli are presented, one to the left and the other to the right side of the tongue, they may add together to a sensation in the middle of the tongue, or they may stay separated. This phenomenon can be used to show that the four primary taste sensations seem to form two well-differentiated groups. Warm and cold stimuli act similarly to the four primary taste stimuli, thus separating the sensations on the tongue into two groups: bitter, warm, sweet; and sour, cold, salty.


Synthesizing epidemiological and economic optima for control of immunizing infections.
Epidemic theory predicts that the vaccination threshold required to interrupt local transmission of an immunizing infection like measles depends only on the basic reproductive number and hence transmission rates. When the search for optimal strategies is expanded to incorporate economic constraints, the optimum for disease control in a single population is determined by relative costs of infection and control, rather than transmission rates. Adding a spatial dimension, which precludes local elimination unless it can be achieved globally, can reduce or increase optimal vaccination levels depending on the balance of costs and benefits. For weakly coupled populations, local optimal strategies agree with the global cost-effective strategy; however, asymmetries in costs can lead to divergent control optima in more strongly coupled systems--in particular, strong regional differences in costs of vaccination can preclude local elimination even when elimination is locally optimal. Under certain conditions, it is locally optimal to share vaccination resources with other populations.


Surface and magnetic polaritons on two-dimensional nanoslab-aligned multilayer structure.
The present study theoretically investigates the radiative properties of a two-dimensional (2-D) multilayer structure that has a dielectric spacer between a metallic substrate and square cross-sectional metallic gratings. Differently from the one-dimensional metallic strips coated on a dielectric spacer atop an opaque metallic film [Opt. Express 16, 11328 (2008)], the 2-D metallic gratings can support the localized surface plasmon in addition to the propagating surface plasmon along the metal-dielectric interface. Moreover, the presence of a dielectric spacer also allows the excitation of magnetic polaritons. Underlying mechanisms of the surface and magnetic polartions on the proposed structure are elucidated by employing the 2-D rigorous coupled-wave analysis. The results obtained in this study will advance our fundamental understanding of light-matter interaction at the nanometer scale and will facilitate the development of engineered nanostructures for real-world applications, such as thermophotovoltaic and photovoltaic devices.


Comparative landscape genetics and the adaptive radiation of Darwin's finches: the role of peripheral isolation.
We use genetic divergence at 16 microsatellite loci to investigate how geographical features of the Galápagos landscape structure island populations of Darwin's finches. We compare the three most genetically divergent groups of Darwin's finches comprising morphologically and ecologically similar allopatric populations: the cactus finches (Geospiza scandens and Geospiza conirostris), the sharp-beaked ground finches (Geospiza difficilis) and the warbler finches (Certhidea olivacea and Certhidea fusca). Evidence of reduced genetic diversity due to drift was limited to warbler finches on small, peripheral islands. Evidence of low levels of recent interisland migration was widespread throughout all three groups. The hypothesis of distance-limited dispersal received the strongest support in cactus and sharp-beaked ground finches as evidenced by patterns of isolation by distance, while warbler finches showed a weaker relationship. Support for the hypothesis that gene flow constrains morphological divergence was only found in one of eight comparisons within these groups. Among warbler finches, genetic divergence was relatively high while phenotypic divergence was low, implicating stabilizing selection rather than constraint due to gene flow. We conclude that the adaptive radiation of Darwin's finches has occurred in the presence of ongoing but low levels of gene flow caused by distance-dependent interisland dispersal. Gene flow does not constrain phenotypic divergence, but may augment genetic variation and facilitate evolution due to natural selection. Both microsatellites and mtDNA agree in that subsets of peripheral populations of two older groups are genetically more similar to other species that underwent dramatic morphological change. The apparent decoupling of morphological and molecular evolution may be accounted for by a modification of Lack's two-stage model of speciation: relative ecological stasis in allopatry followed by secondary contact, ecological interactions and asymmetric phenotypic divergence.


Effect of Follicular Unit Extraction on the Donor Area.
Hair restoration surgery is one of the most commonly performed cosmetic surgery procedure in men. The main aim of the study was to know the effect of follicular unit extraction (FUE) follicular unit extraction (FUE) on donor area in terms of hair mass/density. Ten male patients undergoing hair restoration by FUE were included. In each patient, ten boxes of 1 cm2 each were marked. The first box was marked in the midline and the 2nd and 3rd boxes were marked about 3 cm from the midline. Another two boxes, each of 1 cm2 were also marked at the distance of 3 cm. Two boxes of 1 cm2 were marked on either side. The extraction was performed using 0.9 mm punch. The number of extracted hair were counted. The mean age of the patients was 31.7 years. The average hair count in the donor area was 154.76 hair per cm2. The extracted hair count was 54.85 hair per cm2 which was about 35.44% of the total donor density (range: 28.9-42.8%). The graft to hair ratio in the extracted follicular units was 1:2.3 (range: 1:1.65-1:2.75). As the donor density varies, the FUE should be performed with caution.


Effects of oxysterols on cell viability, inflammatory cytokines, VEGF, and reactive oxygen species production on human retinal cells: cytoprotective effects and prevention of VEGF secretion by resveratrol.
Oxysterols are assumed to play important roles in age-related macular degeneration, a major cause of blindness. So we characterized the cytotoxic, oxidative, inflammatory, and angiogenic activities of oxysterols (7β-hydroxycholesterol (7β-OH), 7-ketocholesterol (7KC), 25-hydroxycholesterol (25-OH)) in human retinal ARPE-19 cells, and evaluated the protective effects of resveratrol (Rsv: 1 μM), a polyphenol from red wine. ARPE-19 cells were treated with 7β-OH, 7KC, or 25-OH (5-40 μg/mL; 24-48 h) without or with Rsv. Cell viability was determined using trypan blue and the MTT assay. Cell death was characterized by electron microscopy and in situ detection of activated caspases with fluorochrome-labeled inhibitors of caspases. Reactive oxygen species (ROS) production was measured with hydroethidine. ELISA methods and a cytometric bead assay were used to quantify cytokines involved in inflammation (IL-8, IL-1β, IL-6, IL-10, IL-12p70, TNF-α, MCP-1) and VEGF. 7β-OH and 7KC triggered a caspase-independent cell death process associated with the presence of multilamellar cytoplasmic structures evocating phospholipidosis, increased ROS production, and IL-8 secretion. 7β-OH enhanced VEGF secretion. No cytotoxic effects were identified with 25-OH, which highly stimulated ROS production, MCP-1, and VEGF secretion. With oxysterols, no IL-10, TNF-α, and IL-12p70 secretion were detected. 25-OH induced IL-8 secretion through the MEK/ERK½ signaling pathway, and Rsv showed cytoprotective activities and inhibited VEGF secretion. 7β-OH, 7KC, and 25-OH have cytotoxic, oxidative, inflammatory, and/or angiogenic activities on ARPE-19 cells. As Rsv has some protective effects against oxysterol-induced cell death and VEGF secretion it could be valuable in ARMD treatment.


Determining sequence length or content in zero, one, and two dimensions.
High-throughput assays are essential for the practical application of mutation detection in medicine and research. Moreover, such assays should produce informative data of high quality that have a low-error rate and a low cost. Unfortunately, this is not currently the case. Instead, we typically witness legions of people reviewing imperfect data at astronomical expense yielding uncertain results. To address this problem, for the past decade we have been developing methods that exploit the inherent quantitative nature of DNA experiments. By generating high-quality data, careful DNA-signal quantification permits robust analysis for determining true alleles and certainty measures. We will explore several assays and methods. In a one-dimensional readout, short tandem repeat (STR) data display interesting artifacts. Even with high-quality data, PCR artifacts such as stutter and relative amplification can confound correct or automated scoring. However, by appropriate mathematical analysis, these artifacts can be essentially removed from the data. The result is fully automated data scoring, quality assessment, and new types of DNA analysis. These approaches enable the accurate analysis of pooled DNA samples, for both genetic and forensic applications. On a two-dimensional surface (comprised of zero-dimensional spots) one can perform assays of extremely high-throughput at low cost. The question is how to determine DNA sequence length or content from nonelectrophoretic intensity data. Here again, mathematical analysis of highly quantitative data provides a solution. We will discuss new lab assays that can produce data containing such information; mathematical transformation then determines DNA length or content.


"If my husband leaves me, I will go home and suffer, so better cling to him and hide this thing": The influence of gender on Option B+ prevention of mother-to-child transmission participation in Malawi and Uganda.
The role of gender in prevention of mother-to-child transmission (PMTCT) participation under Option B+ has not been adequately studied, but it is critical for reducing losses to follow-up. This study used qualitative methods to examine the interplay of gender and individual, interpersonal, health system, and community factors that contribute to PMTCT participation in Malawi and Uganda. We conducted in-depth interviews with women in PMTCT, women lost to follow-up, government health workers, and stakeholders at organizations supporting PMTCT as well as focus group discussions with men. We analyzed the data using thematic content analysis. We found many similarities in key themes across respondent groups and between the two countries. The main facilitators of PMTCT participation were knowledge of the health benefits of ART, social support, and self-efficacy. The main barriers were fear of HIV disclosure and stigma and lack of social support, male involvement, self-efficacy, and agency. Under Option B+, women learn about their HIV status and start lifelong ART on the same day, before they have a chance to talk to their husbands or families. Respondents explained that very few husbands accompanied their wives to the clinic, because they felt it was a female space and were worried that others would think their wives were controlling them. Many respondents said women fear disclosing, because they fear HIV stigma as well as the risk of divorce and loss of economic support. If women do not disclose, it is difficult for them to participate in PMTCT in secret. If they do disclose, they must abide by their husbands' decisions about their PMTCT participation, and some husbands are unsupportive or actively discouraging. To improve PMTCT participation, Ministries of Health should use evidence-based strategies to address HIV stigma, challenges related to disclosure, insufficient social support and male involvement, and underlying gender inequality.


Development of the food-based Lifelines Diet Score (LLDS) and its application in 129,369 Lifelines participants.
Many diet quality scores exist, but fully food-based scores based on contemporary evidence are scarce. Our aim was to develop a food-based diet score based on international literature and examine its discriminative capacity and socio-demographic determinants. Between 2006 and 2013, dietary intake of 129,369 participants of the Lifelines Cohort (42% male, 45 ± 13 years (range 18-93)) was assessed with a 110-item food frequency questionnaire. Based on the 2015 Dutch Dietary Guidelines and underlying literature, nine food groups with positive (vegetables, fruit, whole grain products, legumes&nuts, fish, oils&soft margarines, unsweetened dairy, coffee and tea) and three food groups with negative health effects (red&processed meat, butter&hard margarines and sugar-sweetened beverages) were identified. Per food group, the intake in grams per 1000 kcal was categorized into quintiles, awarded 0 to 4 points (negative groups scored inversely) and summed. Food groups with neutral, unknown or inconclusive evidence are described but not included. The Lifelines Diet Score (LLDS) discriminated well between high and low consumers of included food groups. This is illustrated by e.g. a 2-fold higher vegetable intake in the highest, compared to the lowest LLDS quintile. Differences were 5.5-fold for fruit, 3.5-fold for fish, 3-fold for dairy and 8-fold for sugar-sweetened beverages. The LLDS was higher in females and positively associated with age and educational level. The LLDS is based on the latest international evidence for diet-disease relations at the food group level and has high capacity to discriminate people with widely different intakes. Together with the population-based quintile approach, this makes the LLDS a flexible, widely applicable tool for diet quality assessment.


Generation of healthy mice from gene-corrected disease-specific induced pluripotent stem cells.
Using the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase [FAH] deficiency; FAH⁻/⁻ mice) as a paradigm for orphan disorders, such as hereditary metabolic liver diseases, we evaluated fibroblast-derived FAH⁻/⁻-induced pluripotent stem cells (iPS cells) as targets for gene correction in combination with the tetraploid embryo complementation method. First, after characterizing the FAH⁻/⁻ iPS cell lines, we aggregated FAH⁻/⁻-iPS cells with tetraploid embryos and obtained entirely FAH⁻/⁻-iPS cell-derived mice that were viable and exhibited the phenotype of the founding FAH⁻/⁻ mice. Then, we transduced FAH cDNA into the FAH⁻/⁻-iPS cells using a third-generation lentiviral vector to generate gene-corrected iPS cells. We could not detect any chromosomal alterations in these cells by high-resolution array CGH analysis, and after their aggregation with tetraploid embryos, we obtained fully iPS cell-derived healthy mice with an astonishing high efficiency for full-term development of up to 63.3%. The gene correction was validated functionally by the long-term survival and expansion of FAH-positive cells of these mice after withdrawal of the rescuing drug NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione). Furthermore, our results demonstrate that both a liver-specific promoter (transthyretin, TTR)-driven FAH transgene and a strong viral promoter (from spleen focus-forming virus, SFFV)-driven FAH transgene rescued the FAH-deficiency phenotypes in the mice derived from the respective gene-corrected iPS cells. In conclusion, our data demonstrate that a lentiviral gene repair strategy does not abrogate the full pluripotent potential of fibroblast-derived iPS cells, and genetic manipulation of iPS cells in combination with tetraploid embryo aggregation provides a practical and rapid approach to evaluate the efficacy of gene correction of human diseases in mouse models.


Mid-infrared gas filled photonic crystal fiber laser based on population inversion.
We demonstrate for the first time an optically pumped gas laser based on population inversion using a hollow core photonic crystal fiber (HC-PCF). The HC-PCF filled with 12C2H2 gas is pumped with ~5 ns pulses at 1.52 μm and lases at 3.12 μm and 3.16 μm in the mid-infrared spectral region. The maximum measured laser pulse energy of ~6 nJ was obtained at a gas pressure of 7 torr with a fiber with 20 dB/m loss near the lasing wavelengths. While the measured slope efficiencies of this prototype did not exceed a few percent due mainly to linear losses of the fiber at the laser wavelengths, 25% slope efficiency and pulse energies of a few mJ are the predicted limits of this laser. Simulations of the laser's behavior agree qualitatively with experimental observations.


Nanocuration workflows: Establishing best practices for identifying, inputting, and sharing data to inform decisions on nanomaterials.
There is a critical opportunity in the field of nanoscience to compare and integrate information across diverse fields of study through informatics (i.e., nanoinformatics). This paper is one in a series of articles on the data curation process in nanoinformatics (nanocuration). Other articles in this series discuss key aspects of nanocuration (temporal metadata, data completeness, database integration), while the focus of this article is on the nanocuration workflow, or the process of identifying, inputting, and reviewing nanomaterial data in a data repository. In particular, the article discusses: 1) the rationale and importance of a defined workflow in nanocuration, 2) the influence of organizational goals or purpose on the workflow, 3) established workflow practices in other fields, 4) current workflow practices in nanocuration, 5) key challenges for workflows in emerging fields like nanomaterials, 6) examples to make these challenges more tangible, and 7) recommendations to address the identified challenges. Throughout the article, there is an emphasis on illustrating key concepts and current practices in the field. Data on current practices in the field are from a group of stakeholders active in nanocuration. In general, the development of workflows for nanocuration is nascent, with few individuals formally trained in data curation or utilizing available nanocuration resources (e.g., ISA-TAB-Nano). Additional emphasis on the potential benefits of cultivating nanomaterial data via nanocuration processes (e.g., capability to analyze data from across research groups) and providing nanocuration resources (e.g., training) will likely prove crucial for the wider application of nanocuration workflows in the scientific community.


Experiences and perspectives of the parents of emerging adults living with type 1 diabetes.
Whereas it is widely recognized that emerging adulthood can be a difficult time in the life of an individual living with type 1 diabetes, relatively little is known about the experiences of their parents or guardians. These individuals once shouldered much of the burden for their child's diabetes 'self'-management, yet their contribution is often overlooked by the adult healthcare system. Here, we set out to gain an understanding of the perspectives of parents of emerging adults living with type 1 diabetes. Semi-structured interviews were performed with a purposeful sample of parents of emerging adults with type 1 diabetes recruited from two urban young adult diabetes clinics and through a national diabetes charity. Thematic coding was derived using a constant comparative approach. Analysis of interviews with 16 parents of emerging adults with type 1 diabetes identified three themes: parental experiences of the transition to adult care; negotiating parent-child roles, responsibilities and relationships; and new and evolving fears. Parents spoke in detail about the time surrounding their child's diagnosis of type 1 diabetes to emphasize the complexity of diabetes care and the need to establish a 'new normal' for the family. In turn, adolescence and emerging adulthood required a renegotiation of roles and responsibilities, with many parents continuing to play a role in high-level diabetes management. Several parents of emerging adults with type 1 diabetes (particularly those of young men) vocalized worries about their child's readiness to assume responsibility for their self-care, and some expressed frustration with the apparent dichotomy in the role expectations of parents between the pediatric and adult care settings. Adult healthcare providers should recognize both the ongoing involvement of parents in the 'self'-management of emerging adults with type 1 diabetes and the unique aspects of the caregiver burden that they experience.


Lesbian, gay, bisexual and transgender young people's experiences of distress: resilience, ambivalence and self-destructive behaviour.
The research presented in this paper set out to explore the cultural context of youth suicide and more specifically any connections between sexual identity and self-destructive behaviour, in the light of international evidence about the disproportionate risk of suicidal thoughts and suicide attempts in lesbian, gay, bisexual and transgender (LGBT) young people. The empirical basis for the paper is qualitative research that was carried out in the North West of England and South Wales. Focus groups and interviews were conducted with a total of 69 young people, with a purposive sample to reflect diversity of sexual identity, social class and regional and rural-urban location. The paper presents a thematic analysis of the data specifically relating to the experiences of LGBT young people. A range of strategies that LGBT young people employ in the face of distress are described. These are categorised as resilience, ambivalence and self-destructive behaviour (including self-harm and suicide). The potential implications for health and social care of these strategies include the need for ecological approaches and for sexual cultural competence in practitioners, as well as prioritisation of LGBT risk within suicide prevention policies.


AdaSAM: Boosting sharpness-aware minimization with adaptive learning rate and momentum for training deep neural networks.
Sharpness aware minimization (SAM) optimizer has been extensively explored as it can generalize better for training deep neural networks via introducing extra perturbation steps to flatten the landscape of deep learning models. Integrating SAM with adaptive learning rate and momentum acceleration, dubbed AdaSAM, has already been explored empirically to train large-scale deep neural networks without theoretical guarantee due to the triple difficulties in analyzing the coupled perturbation step, adaptive learning rate and momentum step. In this paper, we try to analyze the convergence rate of AdaSAM in the stochastic non-convex setting. We theoretically show that AdaSAM admits a O(1/bT) convergence rate, which achieves linear speedup property with respect to mini-batch size b. Specifically, to decouple the stochastic gradient steps with the adaptive learning rate and perturbed gradient, we introduce the delayed second-order momentum term to decompose them to make them independent while taking an expectation during the analysis. Then we bound them by showing the adaptive learning rate has a limited range, which makes our analysis feasible. To the best of our knowledge, we are the first to provide the non-trivial convergence rate of SAM with an adaptive learning rate and momentum acceleration. At last, we conduct several experiments on several NLP tasks and the synthetic task, which show that AdaSAM could achieve superior performance compared with SGD, AMSGrad, and SAM optimizers.


Enablers and barriers to primary healthcare for Aboriginal and Torres Strait Islander adolescents: study protocol for participatory mixed-methods research that builds on WHO global standards.
One-third of Australia's Aboriginal and Torres Strait Islander population are adolescents. Recent data highlight their health needs are substantial and poorly met by existing services. To design effective models of primary healthcare, we need to understand the enablers and barriers to care for Aboriginal and Torres Strait Islander adolescents, the focus of this study. This protocol was codesigned with Apunipima Cape York Health Council that supports the delivery of primary healthcare for 11 communities in Far North Queensland. We framed our study around the WHO global standards for high-quality health services for adolescents, adding an additional standard around culturally safe care. The study is participatory and mixed methods in design and builds on the recommended WHO assessment tools. Formative qualitative research with young people and their communities (exploring concepts in the WHO recommended quantitative surveys) seeks to understand demand-side enablers and barriers to care, as well as preferences for an enhanced response. Supply-side enablers and barriers will be explored through: a retrospective audit of clinic data (to identify current reasons for access and what can be strengthened); an objective assessment of the adolescent friendliness of clinical spaces; anonymous feedback from adolescent clients around quality of care received and what can be improved; and surveys and qualitative interviews with health providers to understand their perspectives and needs to provide enhanced care. This codesigned project has been approved by Apunipima Cape York Health Council and Far North Queensland Human Research Ethics Committee. The findings from this project will inform a codesigned accessible and responsive model of primary healthcare for Aboriginal and Torres Strait Islander adolescents.


Suprahepatic space as an alternative site for distal catheter insertion in pseudocyst-associated ventriculoperitoneal shunt malfunction.
Distal catheter malfunction due to pseudocyst formation or intraabdominal adhesion is a significant problem, especially in pediatric patients who have limited sites for distal catheter insertion. In this study, the authors present a series of 12 patients with intractable distal shunt malfunctions due to peritoneal pseudocyst formation who underwent distal catheter replacement in the suprahepatic space to reduce the risk of distal catheter malfunction. Twelve consecutive patients with shunt malfunction due to pseudocyst formation who had undergone ventriculosuprahepatic shunting from 2014 to 2019 were identified. According to medical records, after primary evaluations, shunt removal, and antibiotic therapy, they underwent revision surgeries with placement of a distal catheter into the suprahepatic space. Nine boys and 3 girls, ranging in age from 5 months to 14 years, with one or more episodes of pseudocyst formation, underwent shunt revision with placement of a distal catheter into the suprahepatic space. After a median follow-up of 31 months, none of the patients experienced further distal malfunction. The suprahepatic space appears to be a safe place to secure the distal end of a ventricular catheter following pseudocyst formation, with less risk of re-adhesion. This lower risk might be attributable to the lack of omentum in the suprahepatic space.


Doctors and patients don't agree: cross sectional study of patients' and doctors' perceptions and assessments of disability in multiple sclerosis.
To compare the judgments of clinicians on which domains of health in the short form questionnaire (SF-36) would be most important to patients with multiple sclerosis with the opinions of patients themselves; to compare assessment of physical disability in multiple sclerosis by a clinician using Kurtzke's expanded disability status scale and a non-clinically qualified assistant using the Office of Population Census and Surveys' (OPCS) disability scale with self assessment of disability and other domains of health related quality of life by patients using the SF-36 and the EuroQol questionnaire; and to compare the scores of patients for each domain of the SF-36 with control data matched for age and sex. Cross sectional study. Clinical department of neurology, Edinburgh. 42 consecutive patients with multiple sclerosis attending a neurology outpatient clinic for review or a neurology ward for rehabilitation. Scores on the SF-36; EuroQol; Kurtzke's expanded disability status scale; the OPCS disability scale. Patients and clinicians disagreed on which domains of health status were most important (chi 2 = 21, df = 7, P = 0.003). Patients' assessment of their physical disability using the physical functioning domain of the SF-36 was highly correlated with the clinicians' assessment (r = -0.87, P < 0.001) and the non-clinical assessment (r = -0.90, P < 0.001). However, none of the measures of physical disability correlated with overall health related quality of life measured with EuroQol, Quality of life correlated with vitality, general health, and mental health in the SF-36, each of which patients rated as more important than clinicians and for each of which patients scored lower than the controls. Patients with multiple sclerosis and possibly those with other chronic diseases are less concerned than their clinicians about physical disability in their illness. Clinical trials in multiple sclerosis should assess the effect of treatment on the other elements of health status that patients consider important, which are also affected by the disease process, are more closely related to overall health related quality of life, and may well be adversely affected by side effects of treatment.


Effects of an antioxidant beverage on biomarkers of oxidative stress in Alzheimer's patients.
The purpose of the study was to test whether daily consumption of a beverage with high antioxidant power, combining extracts of green tea and apple over a period of 8 months, would affect blood and urinary concentrations of biomarkers of oxidative stress in Alzheimer's patients. The study included 100 subjects, 48 of them were Alzheimer's patients, aged 76.5 ± 3.5 years, and 52 were control subjects, aged 79 ± 4 years, without dementia. Three blood and urine samples were taken from each participant, the first (T i) before starting the antioxidant or placebo beverage intake, the second (T m) 4 months after the antioxidant or placebo beverage intake and the third (T f) 8 months after the antioxidant or placebo beverage intake, and concentrations of biomarkers of oxidative stress were measured on serum, lysed erythrocytes or urine by UV-Vis spectrophotometry or by competitive in vitro enzyme-linked immunosorbent assay, according to the parameter analyzed. The administration of the antioxidant beverage to the Alzheimer's patients prevented the decrease in total antioxidant status in the moderate phase of the disease (T i = 1.40 ± 0.10 mmol/L vs T f = 1.20 ± 0.08 mmol/L), increased values of glutathione peroxidase and superoxide dismutase in initial (165 and 24 % respectively) and moderate phase (75 and 85 % respectively), and prevented the increase in protein carbonyls in moderate phase (T i = 0.17 ± 0.07 nmol/mg protein vs T f = 0.21 ± 0.06 nmol/mg protein), with a significant decrease in protein carbonyls since the fourth month of the intake in initial phase (T m = 0.21 ± 0.06 nmol/mg protein vs T f = 0.11 ± 0.05 nmol/mg protein). Our results suggest that antioxidant beverage could be used as a natural complementary therapy for alleviate or decrease the oxidative stress effects in the stages of Alzheimer's disease.


Obstructive sleep apnea is an important predictor of hepatic fibrosis in patients with nonalcoholic fatty liver disease in a tertiary care center.
The association of obstructive sleep apnea (OSA) with nonalcoholic fatty liver disease (NAFLD) has only been studied in selected subgroups such as the morbidly obese. We aimed to determine the prevalence and effect of OSA on NAFLD and vice versa in unselected patients attending the outpatient department. OSA was diagnosed by polysomnography, done in patients having symptoms of OSA, in patients with NAFLD attending the liver clinic. Polysomnography-proven patients with OSA attending the chest clinic were evaluated for NAFLD by ultrasonography. Anthropometry, liver function tests, metabolic syndrome evaluation and transient elastography were performed in all patients. Three (3%; 95% CI 1.03-8.45%) out of 100 patients with NAFLD (mean age 41 ± 11 years) had symptomatic OSA. Of 23 patients with OSA (mean age 46 ± 12 years,), 3 (13%) had mild, 5 (22%) moderate and 15 (65%) severe OSA. Twenty-one (91.3%; 95% CI 73.2-97.6%) patients with OSA had NAFLD, while raised hepatic transaminase levels were seen in seven (30.4%; 95% CI 15.6-50.9%). Body mass index (OR 1.21, 95% CI 1.02-1.44) and male gender (OR 4.79, 95% CI 1.12-20.48) were significant independent predictors of OSA in NAFLD. The apnea-hypopnea index (OR 1.084, 95% CI 1.002-1.172), a marker of OSA severity, was the only significant independent predictor of significant fibrosis in patients with NAFLD. Prevalence of symptomatic OSA in patients with NAFLD is low and is predicted by male gender and obesity. Prevalence of NAFLD in patients with OSA is very high. Significant hepatic fibrosis in patients with NAFLD is predicted by OSA independent of obesity and metabolic syndrome.


Structure of the Glycosyltransferase Ktr4p from Saccharomyces cerevisiae.
In the yeast Saccharomyces cerevisiae, members of the Kre2/Mnt1 protein family have been shown to be α-1,2-mannosyltransferases or α-1,2-mannosylphosphate transferases, utilising an Mn2+-coordinated GDP-mannose as the sugar donor and a variety of mannose derivatives as acceptors. Enzymes in this family are localised to the Golgi apparatus, and have been shown to be involved in both N- and O-linked glycosylation of newly-synthesised proteins, including cell wall glycoproteins. Our knowledge of the nine proteins in this family is however very incomplete at present. Only one family member, Kre2p/Mnt1p, has been studied by structural methods, and three (Ktr4p, Ktr5p, Ktr7p) are completely uncharacterised and remain classified only as putative glycosyltransferases. Here we use in vitro enzyme activity assays to provide experimental confirmation of the predicted glycosyltransferase activity of Ktr4p. Using GDP-mannose as the donor, we observe activity towards the acceptor methyl-α-mannoside, but little or no activity towards mannose or α-1,2-mannobiose. We also present the structure of the lumenal catalytic domain of S. cerevisiae Ktr4p, determined by X-ray crystallography to a resolution of 2.2 Å, and the complex of the enzyme with GDP to 1.9 Å resolution.


Adrenal cortical carcinoma masquerading as pheochromocytoma: a case report.
Adrenocortical carcinoma (ACC) is a malignant tumour arising from the adrenal cortex, while pheochromocytoma is a catecholamine secreting tumour of the adrenal medulla or extra adrenal sites. Both conditions are very rare, with incidence of approximately 1-2 cases per million adults annually. Most adrenocortical tumours are functioning. ACC can be associated with clinical Cushing syndrome and virilisation due to excessive production of cortisol and androgens, respectively. However, it is rare for ACC to present clinically as pheochromocytoma. We report a case of a 28-year-old lady who presented with paroxysmal hypertension and palpitations associated with raised urinary vanillyl mandelic acid. On examination, there was postural hypotension and ballotable mass in right lumbar region with no obvious features suggestive of Cushing syndrome or virilisation. A huge right suprarenal mass with areas of necrosis and calcification was noted on the abdomen CT. A right adrenalectomy was done. The histology was consistent with ACC. There are reported cases of ACC presenting with clinical features of pheochromocytoma but limited in number, accounting for barely a dozen cases in the literature. This pseudopheochromocytoma may be due to the presence of neuroendocrine features in ACC.


Trust and trust relations from the providers' perspective: the case of the healthcare system in India.
Commentators suggest that there is an erosion of trust in the relations between different actors in the health system in India. This paper presents the results of an exploratory study of the situation of providers in an urban setting in western India, the nature of their relations in terms of trust and what influences these relations. The data on relationships of trust were collected through interviews and focus group discussions with key informants, including public and private providers, regulators, managers and societal actors, such as patients/citizens, politicians and the media.


Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels.
Low voltage-activated (T-type) calcium currents are observed in many central and peripheral neurons and display distinct physiological and functional properties. Using in situ hybridization, we have localized central and peripheral nervous system expression of three transcripts (alpha1G, alpha1H, and alpha1I) of the T-type calcium channel family (CaVT). Each mRNA demonstrated a unique distribution, and expression of the three genes was largely complementary. We found high levels of expression of these transcripts in regions associated with prominent T-type currents, including inferior olivary and thalamic relay neurons (which expressed alpha1G), sensory ganglia, pituitary, and dentate gyrus granule neurons (alpha1H), and thalamic reticular neurons (alpha1I and alpha1H). Other regions of high expression included the Purkinje cell layer of the cerebellum, the bed nucleus of the stria terminalis, the claustrum (alpha1G), the olfactory tubercles (alpha1H and alpha1I), and the subthalamic nucleus (alpha1I and alpha1G). Some neurons expressed high levels of all three genes, including hippocampal pyramidal neurons and olfactory granule cells. Many brain regions showed a predominance of labeling for alpha1G, including the amygdala, cerebral cortex, rostral hypothalamus, brainstem, and spinal cord. Exceptions included the basal ganglia, which showed more prominent labeling for alpha1H and alpha1I, and the olfactory bulb, the hippocampus, and the caudal hypothalamus, which showed more even levels of all three transcripts. Our results are consistent with the hypothesis that differential gene expression underlies pharmacological and physiological heterogeneity observed in neuronal T-type calcium currents, and they provide a molecular basis for the study of T-type channels in particular neurons.


Systematic Review of Occupational Therapy and Adult Cancer Rehabilitation: Part 2. Impact of Multidisciplinary Rehabilitation and Psychosocial, Sexuality, and Return-to-Work Interventions.
This article is the second part of a systematic review of evidence for the effectiveness of cancer rehabilitation interventions within the scope of occupational therapy that address the activity and participation needs of adult cancer survivors. This article focuses on the use of multidisciplinary rehabilitation and interventions that address psychosocial outcomes, sexuality, and return to work. Strong evidence indicates that multidisciplinary rehabilitation benefits cancer survivors and that psychosocial strategies can reduce anxiety and depression. Moderate evidence indicates that interventions can support survivors in returning to the level of sexuality desired and help with return to work. Part 1 of the review also appears in this issue.