A high-throughput FTIR spectroscopy approach to assess adaptive variation in the chemical composition of pollen.
The two factors defining male reproductive success in plants are pollen quantity and quality, but our knowledge about the importance of pollen quality is limited due to methodological constraints. Pollen quality in terms of chemical composition may be either genetically fixed for high performance independent of environmental conditions, or it may be plastic to maximize reproductive output under different environmental conditions. In this study, we validated a new approach for studying the role of chemical composition of pollen in adaptation to local climate. The approach is based on high-throughput Fourier infrared (FTIR) characterization and biochemical interpretation of pollen chemical composition in response to environmental conditions. The study covered three grass species, Poa alpina, Anthoxanthum odoratum, and Festuca ovina. For each species, plants were grown from seeds of three populations with wide geographic and climate variation. Each individual plant was divided into four genetically identical clones which were grown in different controlled environments (high and low levels of temperature and nutrients). In total, 389 samples were measured using a high-throughput FTIR spectrometer. The biochemical fingerprints of pollen were species and population specific, and plastic in response to different environmental conditions. The response was most pronounced for temperature, influencing the levels of proteins, lipids, and carbohydrates in pollen of all species. Furthermore, there is considerable variation in plasticity of the chemical composition of pollen among species and populations. The use of high-throughput FTIR spectroscopy provides fast, cheap, and simple assessment of the chemical composition of pollen. In combination with controlled-condition growth experiments and multivariate analyses, FTIR spectroscopy opens up for studies of the adaptive role of pollen that until now has been difficult with available methodology. The approach can easily be extended to other species and environmental conditions and has the potential to significantly increase our understanding of plant male function.


Metabolic syndrome and obesity among workers at Kanye Seventh-Day Adventist Hospital, Botswana.
Metabolic syndrome and obesity are risk factors for developing type 2 diabetes mellitus and/or cardiovascular disease, especially stroke. There is evidence worldwide of the high prevalence of these pathologies in health care providers. To determine the frequency of metabolic syndrome, overweight, obesity and risk of developing metabolic syndrome in workers at Kanye Seventh-day Adventist Hospital, Kanye, Botswana. An observational and cross-sectional study. For the detection of metabolic syndrome, the criteria of the Adult Treatment Panel III were used; for obesity, the body mass index of 150 workers was applied. Data were grouped and analysed according to gender, age and type of work. Thirty-four per cent of the hospital's workers had metabolic syndrome, the same percentage were at high risk of developing metabolic syndrome, 28.7% were obese, and 27.3% were overweight. Female gender was found to be strongly associated with obesity and metabolic syndrome. The age group of 35-54 years was most affected. There is a high prevalence of obesity and metabolic syndrome among Kanye Seventh-day Adventist Hospital workers. We recommend the implementation of programmes to screen these risk factors by means of routine medical exams and improving the lifestyles of Botswana health care workers. The study findings could be the basis for future research among hospital staff and the general population.


Bacillus bogoriensis sp. nov., a novel alkaliphilic, halotolerant bacterium isolated from a Kenyan soda lake.
Strain LBB3(T) isolated from Bogoria soda lake in Kenya is an alkaliphilic, Gram-positive, strictly aerobic, non-motile, spore-forming bacterium. It was identified as a member of the genus Bacillus on the basis of phenotypic and phylogenetic analyses. The organism grows optimally at 37 degrees C and pH 10. The G+C content of the genomic DNA is 37.5 mol%. 16S rRNA gene sequence analysis showed 95 and 96 % sequence similarity with Bacillus pseudofirmus (DSM 8715(T)) and Bacillus alcalophilus (DSM 485(T)), respectively. Furthermore, DNA-DNA hybridization against these two Bacillus species showed 39.0 and 55.5 % similarity, respectively. Based on our observations, strain LBB3(T) is proposed to represent a novel species of the genus Bacillus, for which the name Bacillus bogoriensis sp. nov. is proposed. The type strain of B. bogoriensis is LBB3(T) (=ATCC BAA-922(T)=LMG 22234(T)).


Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast.
Aβ (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.


Epidemiology of cervical radiculopathy. A population-based study from Rochester, Minnesota, 1976 through 1990.
An epidemiological survey of cervical radiculopathy in Rochester, Minnesota, 1976-90, through the records-linkage system of the Mayo Clinic ascertained 561 patients (332 males and 229 females). Ages ranged from 13 to 91 years; the mean age +/- SD was 47.6 +/- 13.1 years for males and 48.2 +/- 13.8 years for females. A history of physical exertion or trauma preceding the onset of symptoms occurred in only 14.8% of cases. A past history of lumbar radiculopathy was present in 41%. The median duration of symptoms prior to diagnosis was 15 days. A monoradiculopathy involving C7 nerve root was the most frequent, followed by C6. A confirmed disc protrusion was responsible for cervical radiculopathy in 21.9% of patients; 68.4% were related to spondylosis, disc or both. During the median duration of follow-up of 4.9 years, recurrence of the condition occurred in 31.7%, and 26% underwent surgery for cervical radiculopathy. A combination of radicular pain and sensory deficit, and objective muscle weakness were predictors of a decision to operate. At last follow-up 90% of our population-based patients were asymptomatic or only midly incapacitated due to cervical radiculopathy. The average annual age-adjusted incidence rates per 100,000 population for cervical radiculopathy in Rochester were 83.2 for the total, 107.3 for males and 63.5 for females. The age-specific annual incidence rate per 100,000 population reached a peak of 202.9 for the age group 50-54 years.


Women's Perceived Reasons for Their Excessive Postpartum Weight Retention: A Qualitative Interview Study.
Obesity in Sweden has doubled to 14% over the last 20 years. New strategies for treatment and prevention are needed. Excessive gestational weight gain has been found to contribute substantially to obesity, and there is a consistent association between postpartum weight retention and obesity later in life. We aimed to explore what factors women perceive as reasons for having substantial postpartum weight retention, to identify areas for new and improved interventions. Qualitative interview study (semi-structured) using an emergent design. Fifteen women, with a postpartum weight retention ≥ 10 kg, were interviewed by a trained cognitive therapist. Eight women had pre-pregnancy BMI below 30 kg/m2. Interviews were transcribed verbatim and data analysed using inductive manifest content analysis. Salient text passages were extracted, shortened, coded and clustered into categories. Participants reported no knowledge of current gestational weight gain recommendations or of risks for adverse pregnancy outcomes with excessive weight gain or postpartum weight retention. Excessive eating emerged as a common strategy to provide relief of psychological, emotional and physical discomfort, such as depression and morning sickness. Women perceived medical staff as being unconcerned about weight, and postpartum weight loss support was scarce or absent. Some women reported eating more due to a belief that breastfeeding would automatically lead to weight loss. There is a need to raise awareness about risks with unhealthy gestational weight development and postpartum weight retention in women of childbearing age. The common strategy to cope with psychological, emotional or physical discomfort by eating is an important factor to target with intervention. The postpartum year is a neglected period where additional follow-up on weight and weight loss support is strongly indicated.


Corticosterone effects on BDNF expression in the hippocampus. Implications for memory formation.
The adrenal steroid corticosterone has profound effect on the structure and function of the hippocampus. Probably as a result of that, it modulates memory formation. In this review, the question is addressed if the corticosterone effects on memory processes are mediated by alterations in the expression of the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) in the hippocampus. First, studies are described investigating the effect of corticosterone on BDNF expression in the rat hippocampus. It appears that corticosterone suppresses the BDNF expression at the mRNA and protein level in a subfield-specific way. Second, a model for the mechanism of action is proposed. In this model, activated mineralocorticoid and glucocorticoid receptors repress transcriptional activity of the BDNF promoter site-specifically via interaction with other transcription factors. Third, the implications for learning and memory are discussed. Studies show that during water maze training, corticosterone levels rise significantly, but the BDNF expression is not suppressed in any hippocampal subfield. Furthermore, high BDNF expression levels in specific subfields correlate with a good memory performance. Therefore, we suggest that the resistance of the hippocampal BDNF expression to suppression by corticosterone, as seen after water maze training, may contribute to an optimal memory performance.


Identification of a novel Pseudomonas syringae Psy61 effector with virulence and avirulence functions by a HrpL-dependent promoter-trap assay.
The hrp pathogenicity island of Pseudomonas syringae encodes a type III secretion system (TTSS) that translocates effectors into plant cells. Most genes encoding effectors are dispersed in the P. syringae genome. Regardless of location, all are regulated coordinately by the alternative sigma factor HrpL. An HrpL-dependent promoter-trap assay was developed to screen genomic libraries of P. syringae strains for promoters whose activity in Escherichia coli is dependent on an inducible hrpL construct. Twenty-two HrpL-dependent promoter fragments were isolated from P. syringae Psy61 that included promoters for known HrpL-dependent genes. One fragment also was isolated that shared no similarity with known genes but retained a near consensus HrpL-dependent promoter. The sequence of the region revealed a 375-amino acid open reading frame encoding a 40.5-kDa product that was designated HopPsyL. HopPsyL was structurally similar to other secreted effectors and carried a putative chloroplast-targeting signal and two predicted transmembrane domains. HopPsyL':'AvrRpt2 fusions were translocated into host cells via the P. syringae pv. tomato DC3000 hrp TTSS. A hopPsyL::kan mutant of Psy61 exhibited strongly reduced virulence in Phaseolus vulgaris cv. Kentucky Wonder, but did not appear to act as a defense response suppressor. The ectopically expressed gene reduced the virulence of Pseudomonas syringae DC3000 transformants in Arabidopsis thaliana Col-0. The gene was shown to be conserved in 6 of 10 P. syringae pv. syringae strains but was not detected in 35 strains of other pathovars. HopPsyL appears to be a novel TTSS-dependent effector that functions as a host-species-specific virulence factor in Psy61.


Change in differential diagnosis and patient management with the use of portable ultrasound in a remote setting.
Physicians practicing in remote areas are typically limited in their choice of diagnostic tools. The goal of this study was to determine whether the use of a portable ultrasound (US) device on selected patients in a remote setting would alter physician diagnosis and management. This was a prospective observational study of the affects of US on physician decision making deep in the Amazon jungle. A battery-operated Sonosite 180 Plus with 2 interchangeable transducers (4-7-MHz broadband intercavitary transducer and 2-5-MHz broadband abdominal transducer) was used. The patient population consisted of local tribal people. Two of the physicians on the team performed all US examinations. Team physicians requesting US examinations filled out a survey before and after the US examination. Before the US, the referring physician filled out a survey describing the patient's initial complaint, pertinent past medical history and physical findings, and an initial (pre-US) differential diagnosis and planned treatment with expected disposition. After the results of the US were reviewed with the referring physicians, the doctors were asked to fill out the remainder of the survey, allowing comparison of pre- and post-US differential diagnosis, treatment plan, and disposition. A total of 25 US studies were performed during this study (1 trauma US scan, 6 hepatobiliary studies, 5 transabdominal pelvic scans, 7 transvaginal pelvic studies, 3 renal studies, and 3 abdominal aortic scans). The monitor on the US unit experienced a rare failure shortly after being used at 17,000 ft and then 10 times at sea level, and no further US scans could be performed. US scan results dramatically altered the disposition of 7 patients, including 4 patients who avoided a potentially dangerous 2-day evacuation to more definitive medical care. Three patients were found to need rapid referral to the nearest clinic for surgical evaluation. When used in a remote location, portable US provides a significant benefit that can dramatically alter disposition and treatment.


The impact of functional groups of poly(ethylene glycol) macromers on the physical properties of photo-polymerized hydrogels and the local inflammatory response in the host.
Poly(ethylene glycol) (PEG) can be functionalized and modified with various moieties allowing for a multitude of cross-linking chemistries. Here, we investigate how vinyl sulfone, acrylate, and maleimide functional end groups affect hydrogel formation, physical properties, viability of encapsulated cells, post-polymerization modification, and inflammatory response of the host. We have shown that PEG-VS hydrogels, in the presence of a co-monomer, N-vinyl-2-pyrrolidone (NVP), form more efficiently than PEG-Ac and PEG-Mal hydrogels, resulting in superior physical properties after 6 min of ultraviolet light exposure. PEG-VS hydrogels exhibited hydrolytic stability and non-fouling characteristics, as well as the ability to be modified with biological motifs, such as RGD, after polymerization. Additionally, unmodified PEG-VS hydrogels resulted in lesser inflammatory response, cellular infiltration, and macrophage recruitment after implantation for 28 days in mice. These findings show that altering the end group chemistry of PEG macromer impacts characteristics of the photo-polymerized network. We have developed a tunable non-degradable PEG system that is conducive for cell or tissue encapsulation and evokes a minimal inflammatory response, which could be utilized for future immunoisolation applications. The objective of this study was to develop a tunable non-degradable PEG system that is conducive for encapsulation and evokes a minimal inflammatory response, which could be utilized for immunoisolation applications. This study has demonstrated that reactive functional groups of the PEG macromers impact free radical mediated network formation. Here, we show PEG-VS hydrogels meet the design criteria for an immunoisolating device as PEG-VS hydrogels form efficiently via photo-polymerization, impacting bulk properties, was stable in physiological conditions, and elicited a minimal inflammatory response. Further, NVP can be added to the precursor solution to expedite the cross-linking process without impacting cellular response upon encapsulation. These findings present an additional approach/chemistry to encapsulate cells or tissue for immunoisolation applications.


Spatial patterns of human gene frequencies in Europe.
The aims of this study of spatial patterns of human gene frequencies in Europe are twofold. One is to present new methodology developed for the analysis of such data. The other is to report on the diversity of spatial patterns observed in Europe and their interpretation as evidence of population processes. Spatial variation in 59 allele and haplotype frequencies (26 genetic systems) for polymorphisms in blood antigens, enzymes, and proteins is analyzed for an aggregate of 3,384 localities, using homogeneity tests, one-dimensional and directional spatial correlograms, and SYMAP interpolated surfaces. The data matrices are reduced to reveal the principal patterns by clustering techniques. The findings of this study can be summarized as follows: 1) There is significant heterogeneity in allele frequencies among the localities for all but one genetic system. 2) There are significant spatial patterns for most allele frequencies. 3) There is a substantial minority of clinal patterns in these populations. Clinal trends are found more frequently in HLA alleles than for other variables. North-south and northwest-southwest gradients predominate. 4) There is a strong decline in overall genetic similarity with geographic distance for most variables. 5) There are few, if any, appreciable correlations in pairs of allele frequencies over the continent, and there is little interesting correlation structure in the resulting correlation matrix. 6) Few spatial correlograms are markedly similar to each other, yet they form well-defined clusters. Spatial variation patterns, therefore, differ among allele frequencies. Patterns of human gene frequencies in modern Europe are diverse and complex. No single model suffices for interpretation of the observed genetic structure. Some clinal patterns reported here support the Neolithic demic-expansion hypothesis, others suggest latitudinal selection. Most of the clinal patterns are in HLA alleles, but there is also evidence from ABO for east-west migration diffusion. The majority of patterns are patchy, consistent with hypotheses of isolation by distance or of settlement of genetically differing, subsequently expanding ethnic groups. While undoubtedly there has been an ongoing stochastic process of differentiation consistent with the isolation-by-distance model, this has not obscured the directional patterns caused by migration (demic diffusion), and has perhaps only reinforced the contribution from settlement of ethnic units to patterns of genetic variation. However, the impact of the latter is most difficult to discern and requires further methodological developments.


The Heme Metabolite Carbon Monoxide Facilitates KSHV Infection by Inhibiting TLR4 Signaling in Endothelial Cells.
Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS) and certain rare B cell lymphoproliferative disorders. KSHV infection of endothelial cells (EC) in vitro increases expression of the inducible host-encoded enzyme heme oxygenase-1 (HO-1), which is also strongly expressed in KS tumors. HO-1 catalyzes the rate-limiting step in the conversion of heme into iron, biliverdin and the gasotransmitter carbon monoxide (CO), all of which share anti-apoptotic, anti-inflammatory, pro-survival, and tumorigenic activities. Our previous work has shown that HO-1 expression in KSHV-infected EC is characterized by a rapid yet transient induction at early times post-infection, followed by a sustained upregulation co-incident with establishment of viral latency. These two phases of expression are independently regulated, suggesting distinct roles for HO-1 in the virus life cycle. Here, we investigated the role of HO-1 during acute infection, prior to the onset of viral gene expression. The early infection phase involves a series of events that culminate in delivery of the viral genome to the nucleus. Primary infection also leads to activation of host innate immune effectors, including the pattern recognition receptor TLR4, to induce an antiviral response. It has been shown that TLR4-deficient EC are more susceptible to KSHV infection than wild-type controls, suggesting an important inhibitory role for TLR4 in the KSHV life cycle. TLR4 signaling is in turn subject to regulation by several virus-encoded immune evasion factors. In this report we identify HO-1 as a host protein co-opted by KSHV as part of a rapid immune evasion strategy. Specifically, we show that early HO-1 induction by KSHV results in increased levels of endogenous CO, which functions as a TLR4 signaling inhibitor. In addition, we show that CO-mediated inhibition of TLR4 signaling leads to reduced expression of TLR4-induced antiviral genes, thus dampening the host antiviral response and facilitating KSHV infection. Conversely, inhibition of HO-1 activity decreases intracellular CO, enhances the host antiviral response and inhibits KSHV infection. In conclusion, this study identifies HO-1 as a novel innate immune evasion factor in the context of KSHV infection and supports HO-1 inhibition as a viable therapeutic strategy for KS.


Practical measurement of affordability: an application to medicines.
To develop two practical methods for measuring the affordability of medicines in developing countries. The proposed methods--catastrophic and impoverishment methods--rely on easily accessible aggregated expenditure data and take into account a country's income distribution and absolute level of income. The catastrophic method quantifies the proportion of the population whose resources would be catastrophically reduced by spending on a given medicine; the impoverishment method estimates the proportion of the population that would be pushed below the poverty line by procuring a given medicine. These methods are illustrated by calculating the affordability of glibenclamide, an antidiabetic drug, in India and Indonesia. The results were validated by comparing them with the results obtained by using household micro data for India and Indonesia. When accurate aggregate data are available, the proposed methods offer a practical way to obtain informative and accurate estimates of affordability. Their results are very similar to those obtained with household micro data analysis and are easily compared across countries. The catastrophic and impoverishment methods, based on macro data, can provide a suitable estimate of medicine affordability when the household level micro data needed to carry out more sophisticated studies are not available. Their usefulness depends on the availability of accurate aggregated data.


Distinct Roles of Extracellular Domains in the Epstein-Barr Virus-Encoded BILF1 Receptor for Signaling and Major Histocompatibility Complex Class I Downregulation.
The Epstein-Barr virus (EBV) BILF1 gene encodes a constitutively active G protein-coupled receptor (GPCR) that downregulates major histocompatibility complex (MHC) class I and induces signaling-dependent tumorigenesis. Different BILF1 homologs display highly conserved extracellular loops (ECLs) including the conserved cysteine residues involved in disulfide bridges present in class A GPCRs (GPCR bridge between transmembrane helix 3 [TM-3] and ECL-2) and in chemokine receptors (CKR bridge between the N terminus and ECL-3). In order to investigate the roles of the conserved residues in the receptor functions, 25 mutations were created in the extracellular domains. Luciferase reporter assays and flow cytometry were used to investigate the G protein signaling and MHC class I downregulation in HEK293 cells. We find that the cysteine residues involved in the GPCR bridge are important for both signaling and MHC class I downregulation, whereas the cysteine residues in the N terminus and ECL-3 are dispensable for signaling but important for MHC class I downregulation. Multiple conserved residues in the extracellular regions are important for the receptor-induced MHC class I downregulation, but not for signaling, indicating distinct structural requirements for these two functions. In an engineered receptor containing a binding site for Zn+2 ions in a complex with an aromatic chelator (phenanthroline or bipyridine), a ligand-driven inhibition of both the receptor signaling and MHC class I downregulation was observed. Taken together, this suggests that distinct regions in EBV-BILF1 can be pharmacologically targeted to inhibit the signaling-mediated tumorigenesis and interfere with the MHC class I downregulation.IMPORTANCE G protein-coupled receptors constitute the largest family of membrane proteins. As targets of >30% of the FDA-approved drugs, they are valuable for drug discovery. The receptor is composed of seven membrane-spanning helices and intracellular and extracellular domains. BILF1 is a receptor encoded by Epstein-Barr virus (EBV), which evades the host immune system by various strategies. BILF1 facilitates the virus immune evasion by downregulating MHC class I and is capable of inducing signaling-mediated tumorigenesis. BILF1 homologs from primate viruses show highly conserved extracellular domains. Here, we show that conserved residues in the extracellular domains of EBV-BILF1 are important for downregulating MHC class I and that the receptor signaling and immune evasion can be inhibited by drug-like small molecules. This suggests that BILF1 could be a target to inhibit the signaling-mediated tumorigenesis and interfere with the MHC class I downregulation, thereby facilitating virus recognition by the immune system.


Treatment of gastric epithelial tumours by endoscopic submucosal dissection using an insulated-tip diathermic knife.
Endoscopic submucosal dissection (ESD) is a promising technique for the treatment of large, pre- and early malignant gastrointestinal lesions. To assess the rates of en bloc resection, incidence of complications, procedure times and therapeutic outcomes of ESD using an insulated-tip diathermic knife; and to investigate predictors of these outcomes based on the final pathological features of biopsy specimens. One hundred twenty patients with endoscopically suspected gastric epithelial tumours who were treated with ESD from January 2006 to December 2009 were evaluated. The mean diameter of the gastric epithelial tumours in the present cohort was 1.88 cm. The mean diameter of the resected specimens was 3.33 cm. The en bloc resection rate was 90% (108 of 120). The median length of the operation was 64.6 min. The bleeding and perforation complication rates were 5.0% (six of 120) and 2.5% (three of 120), respectively. Of 10 gastric tumours initially diagnosed as adenocarcinoma on biopsy, four were found to be low-grade dysplasia and six were found to be high-grade dysplasia after resection and final pathological examination. A total of 112 (93.33%) patients underwent curative treatment, eight patients (6.67%) underwent noncurative treatment with ESD, and two patients (1.67%) experienced local recurrence and subsequently underwent surgery. ESD is a promising local curative treatment option for gastric epithelial tumours, but still carries the risks of bleeding and⁄or perforation. Differences in the interpretation of histological results among different pathologists and⁄or between biopsy specimens before ESD and the en bloc tissue specimens after ESD will result in discrepancies.


The Role of Celestial Compass Information in Cataglyphis Ants during Learning Walks and for Neuroplasticity in the Central Complex and Mushroom Bodies.
Central place foragers are faced with the challenge to learn the position of their nest entrance in its surroundings, in order to find their way back home every time they go out to search for food. To acquire navigational information at the beginning of their foraging career, Cataglyphis noda performs learning walks during the transition from interior worker to forager. These small loops around the nest entrance are repeatedly interrupted by strikingly accurate back turns during which the ants stop and precisely gaze back to the nest entrance-presumably to learn the landmark panorama of the nest surroundings. However, as at this point the complete navigational toolkit is not yet available, the ants are in need of a reference system for the compass component of the path integrator to align their nest entrance-directed gazes. In order to find this directional reference system, we systematically manipulated the skylight information received by ants during learning walks in their natural habitat, as it has been previously suggested that the celestial compass, as part of the path integrator, might provide such a reference system. High-speed video analyses of distinct learning walk elements revealed that even exclusion from the skylight polarization pattern, UV-light spectrum and the position of the sun did not alter the accuracy of the look back to the nest behavior. We therefore conclude that C. noda uses a different reference system to initially align their gaze directions. However, a comparison of neuroanatomical changes in the central complex and the mushroom bodies before and after learning walks revealed that exposure to UV light together with a naturally changing polarization pattern was essential to induce neuroplasticity in these high-order sensory integration centers of the ant brain. This suggests a crucial role of celestial information, in particular a changing polarization pattern, in initially calibrating the celestial compass system.


Patient experiences of nurse-facilitated advance care planning in a general practice setting: a qualitative study.
Advance care planning (ACP) can offer benefits to patients and their families, especially when delivered in outpatient settings, but uptake remains low. Common barriers for health professionals include a perceived lack of time and adequate training, experience, and confidence in conducting ACP. Patient-reported barriers include a lack of awareness of ACP or discomfort initiating or engaging in discussions about end-of-life. We aimed to explore patients' perspectives of an ACP intervention designed to address common barriers to uptake in the general practice setting. We provided training and support to doctors and general practice nurses (GPNs) to initiate and lead ACP discussions at their respective practices (2014 to 2015). Following the intervention, we conducted interviews with patients to explore their experience of engaging in ACP in the general practice setting. Thematic analysis was used to inductively code transcripts and identify key themes from semi-structured interviews with patients. Six major themes relating to patient experiences of GPN-facilitated ACP were identified: working through ideas, therapeutic relationship with nurses, significance of making wishes known, protecting family from burden, autonomy in decision-making, and challenges of family communication. The patients valued the opportunity to speak about issues that are important to them with the GPN who they found to be compassionate and caring. The patients felt that ACP would lead to significant benefits not only to themselves but also for their family. Despite encouragement to involve other family members, most patients attended the ACP discussions alone or as a couple; many did not see the relevance of their family being involved in the discussions. Some patients felt uncomfortable or reluctant in communicating the results of their discussion with their family. With adequate training and support, GPNs are able to initiate and facilitate ACP conversations with patients. Their involvement in ACP can have significant benefits for patients. Psychosocial and relational elements of care are critical to patient satisfaction. Our findings show that some patients may feel uncomfortable or reluctant to communicate the results of their ACP discussions with their family. A future larger study is required to verify the findings of this pilot study.


The Cyp2c44 epoxygenase regulates epithelial sodium channel activity and the blood pressure responses to increased dietary salt.
Hypertension is a major risk factor for cerebral, cardiovascular, and renal disease, and its prevalence and devastating consequences raises a need for new strategies for its early diagnosis and treatment. We show here that lack of a Cyp2c44 epoxygenase causes dietary salt-sensitive hypertension, a common form of the human disease. Cyp2c44(-/-) mice on normal salt diets are normotensive but become hypertensive when fed high salt. Hypertensive Cyp2c44(-/-) mice show a hyperactive kidney epithelial sodium channel (ENaC) and reductions in ERK1/2 and ENaC subunit phosphorylation. The demonstration that amiloride, an ENaC inhibitor, lowers the blood pressure of hypertensive Cyp2c44(-/-) mice identifies a role for the channel in the hypertensive phenotype of the animals. These studies: (a) identify an antihypertensive role for the kidney Cyp2c44 epoxygenase and for its epoxyeicosatrienoic acid (EET) metabolites in the in vivo control of ENaC activity and the activation of mitogenic kinase pathways; (b) provide evidence for a Cyp2c44 epoxygenase, EET-mediated mechanism of ENaC regulation involving an ERK1/2-catalyzed threonine phosphorylation of the channel γ subunit: and (c) characterize a common scientific platform that could explain the seemingly unrelated biological activities attributed to the epoxygenase metabolites in cell proliferation, angiogenesis, channel activity, and blood pressure control. It is expected that these results will serve as a basis for the development of novel strategies for the early diagnosis and treatment of hypertension and of pathophysiologies associated with dysfunctional mitogenic signaling.


Relationship between inflammatory biomarkers and depressive symptoms during late pregnancy and the early postpartum period: a longitudinal study.
Perinatal depressive symptoms often co-occur with other inflammatory morbidities of pregnancy. The goals of our study were 1) to examine whether changes in inflammatory markers from the third trimester of pregnancy to 12 weeks postpartum were associated with changes in depressive symptoms; 2) to examine whether third trimester inflammatory markers alone were predictive of postpartum depressive symptoms; and 3) to examine the relationship between inflammatory markers and depressive symptoms during the third trimester of pregnancy and at 12 weeks postpartum. Thirty-three healthy pregnant women were recruited from the Women's Health Concerns Clinic at St. Joseph's Healthcare in Hamilton, Canada. The impact of depressive symptoms on the levels of interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) at the third trimester of pregnancy, at 12 weeks postpartum, and across time was assessed using linear and mixed-model regression. Regression analysis revealed no significant association between depressive symptoms and any of the candidate biomarkers during pregnancy, at 12 weeks postpartum, or over time. Pregnancy depressive symptoms (p > 0.001), IL-6 (p = 0.025), and IL-10 (p = 0.006) were significant predictors of postpartum Edinburgh Perinatal Depression Scale (EPDS) score. Our study supports previous reports from the literature showing no relationship between inflammatory biomarkers and depressive symptoms during late pregnancy, early postpartum, or across time. Our study is the first to observe an association between late pregnancy levels of IL-6 and IL-10 and postpartum depressive symptoms. Further studies with larger samples are required to confirm these findings.


Chest physiotherapy revisited: evaluation of its influence on the pulmonary morbidity after pulmonary resection.
The study aimed to evaluate if perioperative chest physiotherapy modifies the risk of pulmonary morbidity after lobectomy for lung cancer. We have reviewed a prospectively recorded database of 784 lung cancer patients treated by scheduled lobectomy (361 operated after implementing a new physiotherapy program). No other changes were introduced in the patients' perioperative management during the study period. A propensity matching score was generated for all eligible patients and two logistic models were constructed and adjusted. The first one (model A) included age of the patient, forced expiratory volume in 1s (percent) (FEV1%) and predicted postoperative forced expiratory volume in 1s (percent) (ppoFEV1%); for the second model (model B); chest physiotherapy was added to the previous ones. Using each model, patients' individual probability of postoperative complication was calculated and maintained in the database as a new variable (risk A and risk B). Individual risks calculated by both models were plotted on a time series and presented in two different graphs. Rates of pulmonary morbidity were 15.5% before the intensive physiotherapy program and 4.7% for patients included in the implemented program (p = 0.000). The propensity score identified 359 pairs of patients. Model A included age (p = 0.012), FEV1% (p = 0.000), and ppoFEV1% (p = 0.031) as prognostic variables. Model B included age (p = 0.012), FEV1% (p = 0.000), and physiotherapy (p = 0.000). On graphic representation, a great decrease of the estimated risk could be seen after the onset of the physiotherapy program. Implementing a program of perioperative intensive chest physiotherapy reduced the overall pulmonary morbidity after lobectomy for lung cancer.


Listeria monocytogenes, a model in infection biology.
Listeria monocytogenes causes listeriosis, a systemic infection which manifests as bacteremia, often complicated by meningoencephalitis in immunocompromised individuals and the elderly, and fetal-placental infection in pregnant women. It has emerged over the past decades as a major foodborne pathogen, responsible for numerous outbreaks in Western countries, and more recently in Africa. L. monocytogenes' pathogenic properties have been studied in detail, thanks to concomitant advances in biological sciences, in particular molecular biology, cell biology and immunology. L. monocytogenes has also been instrumental to basic advances in life sciences. L. monocytogenes therefore stands both a tool to understand biology and a model in infection biology. This review briefly summarises the clinical and some of the pathophysiological features of listeriosis. In the context of this special issue, it highlights some of the major discoveries made by Pascale Cossart in the fields of molecular and cellular microbiology since the mid-eighties regarding the identification and characterisation of multiple bacterial and host factors critical to L. monocytogenes pathogenicity. It also briefly summarises some of the key findings from our laboratory on this topic over the past years.


In-line skating injuries.
To assess the type and site of injuries associated with in-line skating in patients encountered during an 18-month period. We retrospectively reviewed the medical records of patients in our emergency department and Sports Medicine Center with injuries that had resulted from in-line skating between July 1992 and December 1993. A computer search was conducted to identify medical records on which in-line skating was denoted as the mechanism of injury. The records were then manually reviewed to confirm that the injury had occurred during in-line skating. The patient's sex, age, type of injury, and injured body part were recorded. During the designated study period, 32 in-line skating injuries were recorded in 32 patients (19 female and 13 male skaters). The mean age of the study group of injured skaters was 17 years (range, 6 to 46). An upper extremity was involved in 78% of all injuries, and the wrist was the body part most often injured (56%). A lower extremity was involved in 16% of all injuries, including two that were severe. Of the 32 injuries, 62% were fractures, and surgical treatment was necessary for only 1 injury during the study period. In this study, in-line skating injuries most commonly involved the upper extremities. Fractures, particularly of the distal radius, were the most common type of injury. Lower extremity trauma was less frequent, but severe injuries can occur. Further prospective studies are needed.


Acute effects of scapular Kinesio Taping® on shoulder rotator strength, ROM and acromiohumeral distance in asymptomatic overhead athletes.
There is limited information in the literature that shows whether scapular taping has an effect on the acromiohumeral distance (AHD) and shoulder functions. The aim of this study was to investigate the acute effects of scapular Kinesio Taping® on shoulder internal rotation (IR) and external rotation (ER) strength, IR and ER range of motion (ROM) and AHD in asymptomatic overhead athletes. Forty-one volleyball athletes (24 men, 17 women; mean age: 16.1±1.5 years, body mass: 66.5±9.6 kg, body height: 179.6±8.4 cm, Body Mass Index: 20.5±2.3 kg/m2, time participating in overhead sports activity: 6.2±1.4 h/week, experience in sport: 4.1±2.4 years) were included in this study. Shoulder IR and ER ROM, total rotation ROM, AHD, shoulder isometric IR and ER strength and ER:IR strength ratio of the dominant side were tested before and after taping. Scapular taping increased the shoulder IR (P<0.001) and total ROM (P<0.001), AHD (P<0.001), shoulder IR (P=0.002) and ER (P=0.006) strength. ER ROM and ER:IR ratio did not change after taping (P=0.26, P=0.98, respectively). The results of this study suggest that scapular taping could be an effective method for enhancing the acromiohumeral distance, shoulder rotator strength and range of motion. Therefore, scapular taping could be recommended for not only in the asymptomatic athletes' shoulder exercise training but also in the prevention of subacromial impingement syndrome.


The in vivo and in vitro characterisation of an engineered human antibody to E-selectin.
E-selectin is an endothelial cell specific adhesion molecule that is believed to play an important role in the early stages of leukocyte extravasation. Here we describe the construction and evaluation of an engineered human monoclonal antibody that blocks E-selectin function. SPLAT-1 is an engineered human monoclonal antibody that has a very similar affinity for E-selectin as its murine parent antibody. In vitro SPLAT-1 blocks the binding of human leukocytes to E-selectin and does not mediate antibody-dependent cellular cytotoxicity (ADCC) or complement-mediated lysis of endothelial cells. In vivo, SPLAT-1 inhibits the recruitment of leukocytes to cytokine-inflamed human skin grafted on to SCID mice and has a long circulating half-life in primates. It does not appear to provoke an immune response in primates even on repeat administration. SPLAT-1 has the characteristics of a antibody suitable for human therapy studies.


Pulsatile urea excretion in the gulf toadfish: mechanisms and controls.
Opsanus beta expresses a full complement of ornithine-urea cycle (OUC) enzymes and is facultatively ureotelic, reducing ammonia-N excretion and maintaining urea-N excretion under conditions of crowding/confinement. The switch to ureotelism is keyed by a modest rise in cortisol associated with a substantial increase in cytosolic glutamine synthetase for trapping of ammonia-N and an upregulation of the capacity of the mitochondrial OUC to use glutamine-N. The entire day's urea-N production is excreted in 1 or 2 short-lasting pulses, which occur exclusively through the gills. The pulse event is not triggered by an internal urea-N threshold, is not due to pulsatile urea-N production, but reflects pulsatile activation of a specific branchial excretion mechanism that rapidly clears urea-N from the body fluids. A bidirectional facilitated diffusion transporter, with pharmacological similarity to the UT-A type transporters of the mammalian kidney, is activated in the gills, associated with an increased trafficking of dense-cored vesicles in the pavement cells. An 1814 kB cDNA ('tUT') coding for a 475-amino acid protein with approximately 62% homology to mammalian UT-A's has been cloned and facilitates phloretin-sensitive urea transport when expressed in Xenopus oocytes. tUT occurs only in gill tissue, but tUT mRNA levels do not change over the pulse cycle, suggesting that tUT regulation occurs at a level beyond mRNA. Circulating cortisol levels consistently decline prior to a pulse event and rise thereafter. When cortisol is experimentally clamped at high levels, natural pulse events are suppressed in size but not in frequency, an effect mediated through glucocorticoid receptors. The cortisol decline appears to be permissive, rather than the actual trigger of the pulse event. Fluctuations in circulating AVT levels do not correlate with pulses; and injections of AVT (at supraphysiological levels) elicit only minute urea-N pulses. However, circulating 5-hydroxytryptamine (5-HT) levels fluctuate considerably and physiological doses of 5-HT cause large urea-N pulse events. When the efferent cranial nerves to the gills are sectioned, natural urea pulse events persist, suggesting that direct motor output from the CNS to the gill is not the proximate control.


Medical student research opportunities: a survey of osteopathic medical schools in the United States.
It is important for colleges of osteopathic medicine (COMs) to provide opportunities for osteopathic medical students (OMSs) to conduct research under the guidance of professional researchers. However, COMs historically lag behind allopathic medical schools in research offerings for medical students. The literature would benefit from a synopsis of research opportunities for OMSs at COMs. This study aims to assess the availability of research opportunities currently offered to OMSs and to identify structured research programs (SRPs) to provide data that may help COMs expand such opportunities. Two online surveys were developed. The General Survey asked about general research opportunities, research requirements, and SRPs, which we define as optional, intramural, and mentored research programs. The follow-up SRP Survey sought to understand the history, funding, and organizational structure of SRPs. Between February and June 2021, the General and SRP Surveys were sent to all COMs in the United States. Response data were analyzed descriptively. Responses were received from 32 (84.2%) of 38 COMs. Nearly all COMs offered research symposia, offered third- or fourth-year research elective rotations, and provided some form of funding for OMSs to participate in research. Fourteen (43.8%) COMs had mandatory research requirements. Twenty COMs (62.5%) offered 31 SRPs, and surveys were completed for 25 (80.6%) SRPs. SRPs were founded a median (range) of 7 (1-43) years prior and accommodated 20 (4-50) OMSs annually. Among the responding SRPs, 12.0% had external funding, 96.0% required applications, 50.0% interviewed applicants prior to acceptance into the program, 72.0% required OMSs to identify their own mentors, 68.0% offered stipends to OMSs, 28.0% offered course credits, 96.0% had clinical research opportunities, and 68.0% offered research-oriented didactics. In 84.0% of SRPs, OMSs worked predominantly in the summer after OMS-I; for these SRPs, students had 4-10 weeks of dedicated time for participation in research. Findings from our surveys provide a synopsis of the research opportunities currently provided by COMs in the United States. Our data demonstrated wide variability of research opportunities among COMs.


Variations in risk and protective factors for life satisfaction and mental wellbeing with deprivation: a cross-sectional study.
Improving life satisfaction (LS) and mental wellbeing (MWB) is important for better public health. Like other health issues, LS and MWB are closely related to deprivation (i.e. lack of resources). Developing public health measures that reduce inequalities in wellbeing requires an understanding of how factors associated with high and low LS and MWB vary with deprivation. Here, we examine such variations and explore which public health measures are likely to improve wellbeing while reducing related inequalities. A self-administered questionnaire measuring LS and MWB was used with a cross-sectional sample of adults from the North West of England (n = 15,228). Within deprivation tertiles, analyses examined how demographics, health status, employment, relationships and behaviours (alcohol, tobacco, physical exercise) were associated with LS and MWB. Deprivation was strongly related to low LS and MWB with, for instance, 17.1% of the most deprived tertile having low LS compared to 8.9% in the most affluent. After controlling for confounders, across all deprivation tertiles, better self-assessed health status and being in a relationship were protective against low LS and MWB. Unemployment increased risks of low LS across all tertiles but only risks of low MWB in the deprived tertile. For this tertile, South Asian ethnicity and higher levels of exercise were protective against low MWB. In the middle tertile retired individuals had a reduced risk of low MWB and an increased chance of high LS even in comparison to those in employment. Alcohol's impact on LS was limited to the most deprived tertile where heavy drinkers were at most risk of poor outcomes. In this study, positive outcomes for LS and MWB were strongly associated with lower deprivation and good health status. Public health measures already developed to promote these issues are likely to improve LS and MWB. Efforts to increase engagement in exercise are also likely to have positive impacts, particularly in deprived communities. The development of future initiatives that address LS and MWB must take account of variations in their risk and protective factors at different levels of deprivation.


BMP signaling during bone pattern determination in the developing limb.
To examine the role of BMP signaling during limb pattern formation, we isolated chicken cDNAs encoding type I (BRK-1 and BRK-2) and type II (BRK-3) receptors for bone morphogenetic proteins. BRK-2 and BRK-3, which constitute dual-affinity signaling receptor complexes for BMPs, are co-expressed in condensing precartilaginous cells, while BRK-1 is weakly expressed in the limb mesenchyme. BRK-3 is also expressed in the apical ectodermal ridge and interdigital limb mesenchyme. BRK-2 is intensely expressed in the posterior-distal region of the limb bud. During digit duplication by implanting Sonic hedgehog-producing cells, BRK-2 expression is induced anteriorly in the new digit forming region as observed for BMP-2 and BMP-7 expression in the limb bud. Dominant-negative effects on BMP signaling were obtained by over-expressing kinase domain-deficient forms of the receptors. Chondrogenesis of limb mesenchymal cells is markedly inhibited by dominant-negative BRK-2 and BRK-3, but not by BRK-1. Although the bone pattern was not disturbed by expressing individual dominant-negative BRK independently, preferential distal and posterior limb truncations resulted from co-expressing the dominant-negative forms of BRK-2 and BRK-3 in the whole limb bud, thus providing evidence that BMPs are essential morphogenetic signals for limb bone patterning.


Contextual Learning in Fourier Complex Field for VHR Remote Sensing Images.
Very high-resolution (VHR) remote sensing (RS) image classification is the fundamental task for RS image analysis and understanding. Recently, Transformer-based models demonstrated outstanding potential for learning high-order contextual relationships from natural images with general resolution ( ≈ 224 × 224 pixels) and achieved remarkable results on general image classification tasks. However, the complexity of the naive Transformer grows quadratically with the increase in image size, which prevents Transformer-based models from VHR RS image ( ≥ 500 × 500 pixels) classification and other computationally expensive downstream tasks. To this end, we propose to decompose the expensive self-attention (SA) into real and imaginary parts via discrete Fourier transform (DFT) and, therefore, propose an efficient complex SA (CSA) mechanism. Benefiting from the conjugated symmetric property of DFT, CSA is capable to model the high-order contextual information with less than half computations of naive SA. To overcome the gradient explosion in Fourier complex field, we replace the Softmax function with the carefully designed Logmax function to normalize the attention map of CSA and stabilize the gradient propagation. By stacking various layers of CSA blocks, we propose the Fourier complex Transformer (FCT) model to learn global contextual information from VHR aerial images following the hierarchical manners. Universal experiments conducted on commonly used RS classification datasets demonstrate the effectiveness and efficiency of FCT, especially on VHR RS images. The source code of FCT will be available at https://github.com/Gao-xiyuan/FCT.


Postinjury Induction of Activated ErbB2 Selectively Hyperactivates Denervated Schwann Cells and Promotes Robust Dorsal Root Axon Regeneration.
Following nerve injury, denervated Schwann cells (SCs) convert to repair SCs, which enable regeneration of peripheral axons. However, the repair capacity of SCs and the regenerative capacity of peripheral axons are limited. In the present studies we examined a potential therapeutic strategy to enhance the repair capacity of SCs, and tested its efficacy in enhancing regeneration of dorsal root (DR) axons, whose regenerative capacity is particularly weak. We used male and female mice of a doxycycline-inducible transgenic line to induce expression of constitutively active ErbB2 (caErbB2) selectively in SCs after DR crush or transection. Two weeks after injury, injured DRs of induced animals contained far more SCs and SC processes. These SCs had not redifferentiated and continued to proliferate. Injured DRs of induced animals also contained far more axons that regrew along SC processes past the transection or crush site. Remarkably, SCs and axons in uninjured DRs remained quiescent, indicating that caErbB2 enhanced regeneration of injured DRs, without aberrantly activating SCs and axons in intact nerves. We also found that intraspinally expressed glial cell line-derived neurotrophic factor (GDNF), but not the removal of chondroitin sulfate proteoglycans, greatly enhanced the intraspinal migration of caErbB2-expressing SCs, enabling robust penetration of DR axons into the spinal cord. These findings indicate that SC-selective, post-injury activation of ErbB2 provides a novel strategy to powerfully enhance the repair capacity of SCs and axon regeneration, without substantial off-target damage. They also highlight that promoting directed migration of caErbB2-expressing SCs by GDNF might be useful to enable axon regrowth in a non-permissive environment.SIGNIFICANCE STATEMENT Repair of injured peripheral nerves remains a critical clinical problem. We currently lack a therapy that potently enhances axon regeneration in patients with traumatic nerve injury. It is extremely challenging to substantially increase the regenerative capacity of damaged nerves without deleterious off-target effects. It was therefore of great interest to discover that caErbB2 markedly enhances regeneration of damaged dorsal roots, while evoking little change in intact roots. To our knowledge, these findings are the first demonstration that repair capacity of denervated SCs can be efficaciously enhanced without altering innervated SCs. Our study also demonstrates that oncogenic ErbB2 signaling can be activated in SCs but not impede transdifferentiation of denervated SCs to regeneration-promoting repair SCs.


Attitude and preferences towards oral and long-acting injectable antipsychotics in patients with psychosis in KwaZulu-Natal, South Africa.
Patient attitudes to and satisfaction with their treatment are associated with improved adherence. There is a paucity of data on patient drug attitudes and preference to oral compared to long-acting injectable (LAI) antipsychotic treatment. To describe patients attitudes and preferences towards oral versus LAI antipsychotic formulations and explore factors associated with their drug attitudes. Two psychiatric hospitals in KwaZulu-Natal, South Africa. A cross-sectional survey of 140 adult outpatients with schizophrenia spectrum disorders receiving LAI with or without oral antipsychotics (a total of 70) were compared to patients receiving oral antipsychotics only (N = 70). A sociodemographic-clinical questionnaire, chart review and the Drug Attitude Inventory scale (DAI-30) were used. Of the 140 participants, 98 (70%) preferred the medication formulation currently prescribed, and 132 (94.3%) reported a positive drug attitude towards their antipsychotic medication. The adjusted regression analysis indicated that study participants who were currently on a formulation that matched their preference scored better on the DAI-30 than individuals with a mismatch in use and preference (p < 0.04). In terms of covariates, we found, on one hand, that study participants who are divorced (compared to single) with schizophrenia diagnosis (compared to other psychotic or schizoaffective disorder) are more likely to have lower score on DAI-30. On the other hand, we found that study participants with a higher household income and longer duration of the psychotic illness were associated with greater DAI-30 score. The majority of participants preferred their current oral and LAI formulation. Drug attitude was influenced by several factors, including matched medication use. Focused psychoeducation should be considered for newly diagnosed, lower socio-economic groups and patients with non-affective psychosis to improve drug attitude.


Comparison of two packable hemostatic Gauze dressings in a porcine hemorrhage model.
Uncontrolled hemorrhage remains the primary cause of preventable battlefield mortality and a significant cause of domestic civilian mortality. Rapid hemorrhage control is crucial for survival. ChitoGauze and Combat Gauze are commercially available products marketed for rapid hemorrhage control. These products were selected because they are packable gauze that work via differing mechanisms of action (tissue adhesion versus procoagulant). To compare the effectiveness of ChitoGauze and Combat Gauze in controlling arterial hemorrhage in a swine model. Fourteen swine were studied. Following inguinal dissection and after achieving minimum hemodynamic parameters (mean arterial pressure [MAP] ≥ 70 mmHg), a femoral arterial injury was created using a 6-mm vascular punch. Free bleeding was allowed for 45 seconds, and then the wound was packed alternatively with ChitoGauze or Combat Gauze. Direct pressure was applied to the wound for 2 minutes, followed by a three-hour monitoring period. Resuscitation fluids were administered to maintain an MAP of ≥ 65 mmHg. Time to hemostasis, hemodynamic parameters, total blood loss, and amount of resuscitation fluid were recorded every 15 minutes. Data were analyzed using the Wilcoxon rank sum test. Histologic sections of the vessels were examined using regular and polarized light. No statistically significant differences were found between the groups regarding any measured end point. Data trends, however, favor ChitoGauze over Combat Gauze for time to hemostasis, fluid requirements, and blood loss. There was no evidence of retained foreign material on histologic analysis. ChitoGauze and Combat Gauze appear to be equally efficacious in their hemostatic properties, as demonstrated in a porcine hemorrhage model.


Manipulating Bodily Presence Affects Cross-Modal Spatial Attention: A Virtual-Reality-Based ERP Study.
Earlier studies have revealed cross-modal visuo-tactile interactions in endogenous spatial attention. The current research used event-related potentials (ERPs) and virtual reality (VR) to identify how the visual cues of the perceiver's body affect visuo-tactile interaction in endogenous spatial attention and at what point in time the effect takes place. A bimodal oddball task with lateralized tactile and visual stimuli was presented in two VR conditions, one with and one without visible hands, and one VR-free control with hands in view. Participants were required to silently count one type of stimulus and ignore all other stimuli presented in irrelevant modality or location. The presence of hands was found to modulate early and late components of somatosensory and visual evoked potentials. For sensory-perceptual stages, the presence of virtual or real hands was found to amplify attention-related negativity on the somatosensory N140 and cross-modal interaction in somatosensory and visual P200. For postperceptual stages, an amplified N200 component was obtained in somatosensory and visual evoked potentials, indicating increased response inhibition in response to non-target stimuli. The effect of somatosensory, but not visual, N200 enhanced when the virtual hands were present. The findings suggest that bodily presence affects sustained cross-modal spatial attention between vision and touch and that this effect is specifically present in ERPs related to early- and late-sensory processing, as well as response inhibition, but do not affect later attention and memory-related P3 activity. Finally, the experiments provide commeasurable scenarios for the estimation of the signal and noise ratio to quantify effects related to the use of a head mounted display (HMD). However, despite valid a-priori reasons for fearing signal interference due to a HMD, we observed no significant drop in the robustness of our ERP measurements.


Identification, purification, and characterization of antigen-activated and antigen-specific human B lymphocytes.
Activated pneumococcal polysaccharide (PPS)-specific human B lymphocytes have been purified and examined in vitro. They are large cells that are refractory to further activation by antigen, anti-Ig, or Staphylococcus aureus Cowan strain I, but they respond directly by proliferation to B cell growth factors. In addition, they express the isotype pattern of activated cells and a surface marker of activated lymphocytes called 4F2. Finally, they contain a subset of cells that spontaneously secrete PPS-specific antibody.


Unscrupulous marketing of snake bite antivenoms in Africa and Papua New Guinea: choosing the right product--'what's in a name?'.
Snake bite envenoming, mainly caused by the saw-scaled or carpet viper (Echis ocellatus), is a neglected disease of West Africa. Specific antivenoms can save life and limb but, for various reasons, supply of these essential drugs to Africa has dwindled to less than 2% of estimated requirements. Other problems include maldistribution, inadequate conservation and inappropriate clinical use of antivenoms. In the face of this crisis, several promising new antivenoms have been developed. However, some dangerously inappropriate products of Indian origin are being marketed by unscrupulous manufacturers or distributors in Africa and Papua New Guinea, with disastrous results. A major source of confusion is labelling antivenom with ambiguous snake names that fail to distinguish the Asian species whose venoms are used in their production from the local snakes whose venoms are antigenically dissimilar.


Five-port optical router for photonic networks-on-chip.
We experimentally demonstrate a spatially non-blocking five-port optical router, which is based on microring resonators tuned through the thermo-optic effect. The characteristics of the microring-resonator-based switching element are investigated to achieve balanced performances in its two output ports. The optical router is fabricated on the SOI platform using standard CMOS processing. The effective footprint of the device is about 440×660 μm2. The microring resonators have 3-dB bandwidths of larger than 0.31 nm (38 GHz), and extinction ratios of better than 21 dB for through ports and 16 dB for drop ports. Finally, 12.5 Gbps high-speed signal transmission experiments verify the routing functionality of the optical router.


Contribution of K(+) channels to endothelium-derived hypolarization-induced renal vasodilation in rats in vivo and in vitro.
We investigated the mechanisms behind the endothelial-derived hyperpolarization (EDH)-induced renal vasodilation in vivo and in vitro in rats. We assessed the role of Ca(2+)-activated K(+) channels and whether K(+) released from the endothelial cells activates inward rectifier K(+) (Kir) channels and/or the Na(+)/K(+)-ATPase. Also, involvement of renal myoendothelial gap junctions was evaluated in vitro. Isometric tension in rat renal interlobar arteries was measured using a wire myograph. Renal blood flow was measured in isoflurane anesthetized rats. The EDH response was defined as the ACh-induced vasodilation assessed after inhibition of nitric oxide synthase and cyclooxygenase using L-NAME and indomethacin, respectively. After inhibition of small conductance Ca(2+)-activated K(+) channels (SKCa) and intermediate conductance Ca(2+)-activated K(+) channels (IKCa) (by apamin and TRAM-34, respectively), the EDH response in vitro was strongly attenuated whereas the EDH response in vivo was not significantly reduced. Inhibition of Kir channels and Na(+)/K(+)-ATPases (by ouabain and Ba(2+), respectively) significantly attenuated renal vasorelaxation in vitro but did not affect the response in vivo. Inhibition of gap junctions in vitro using carbenoxolone or 18α-glycyrrhetinic acid significantly reduced the endothelial-derived hyperpolarization-induced vasorelaxation. We conclude that SKCa and IKCa channels are important for EDH-induced renal vasorelaxation in vitro. Activation of Kir channels and Na(+)/K(+)-ATPases plays a significant role in the renal vascular EDH response in vitro but not in vivo. The renal EDH response in vivo is complex and may consist of several overlapping mechanisms some of which remain obscure.


Intrauterine programming of adult body composition.
Epidemiological studies suggest an association between weight in infancy and the risk of osteoporosis in later life. The extent to which this reflects environmental influences on skeletal growth and metabolism before birth or during the first year of postnatal life remains uncertain. We therefore examined the association between birth weight and adult body composition (bone, lean, and fat mass) in a cohort of 143 men and women, aged 70-75 yr, who were born in Sheffield, UK, and still lived there. The subjects underwent assessment of body composition by dual energy x-ray absorptiometry. Neonatal anthropometric information included birth weight, birth length, head size, and abdominal circumference. There were significant (P < 0.01) positive associations between birth weight and adult, whole body, bone, and lean mass among men and women. These were mirrored in significant (P < 0.03) associations between birth weight and bone mineral content at the lumbar spine and femoral neck. Associations between birth weight and whole body fat were weaker and not statistically significant. The associations of birth weight with whole body bone mineral and lean mass remained statistically significant after adjustment for age, sex, and adult height. They also remained significant after adjustment for cigarette smoking, alcohol consumption, dietary calcium intake, and physical inactivity. These data are in accord with previous observations that anthropometric measures in infancy are associated with skeletal size in adulthood. The presence of these relationships at birth adds to the evidence that bone and muscle growth may be programmed by genetic and/or environmental influences during intrauterine life.


Funding new cancer drugs in Ontario: closing the loop in the practice guidelines development cycle.
The previously described practice guidelines development cycle follows an iterative model in which recommendations are reached by a process that incorporates practitioners at all phases. A key feature is the separation of the evidence-based systematic review and the generation of recommendations from policy decisions surrounding implementation. This article describes how this implementation phase has evolved in Ontario and how implementation has affected the guidelines process. The development of the New Drug Funding Program in Ontario and the appointment of a policy advisory committee (PAC) to make funding recommendations were reviewed. The decision-making framework of the PAC is described in this article. The PAC has had to address a number of issues in making funding recommendations. These issues have included dealing with evidence arising solely from phase II versus phase III trials, using economic information, and involving community representatives in its deliberations. Its activities have had a substantial impact on the practice guidelines initiative. It is possible to integrate an evidence-based, practitioner-driven approach to clinical guideline development with a funding program that takes policy considerations into account. However, even though these two roles are conceptually separate, the needs of the funding program have inevitably had an impact on the guidelines process.


Autopsy of a disaster: the Martinez bus accident.
On 21 May 1975 a chartered bus carrying 51 members of a student choir rolled from a sharply curved freeway off-ramp and fell 22 feet, landing on its roof, which collapsed. Twenty-nine passengers died (25 before extrication) and 22, plus the driver, survived. An analysis of factors leading up to the accident reveals several contributing causes, among them inadequate design of the ramp, poor warning signs, driver inexperience with the bus, and deficient bus maintenance. Bus design itself contributed to the lethality of the event. Structural support for the roof was inadequate and no access was available to the interior for extrication of victims. Problems with organization at the scene, triage, and communications among agencies involved in the rescue and receiving hospitals contributed to confusion in the transport of victims, although it appears this had little impact on outcome. An analysis of the accident allows several lessons to be learned which might prevent, or reduce, the fatalities from future accidents involving multipassenger vehicles, and other disasters with 10 to 25, or more than 25 fatalities. In the present report ten of 25 killed were judged possibly salvageable with immediate extrication.


14 day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by Helicobacter pylori status.
Bisphosphonates are effective treatment for osteoporosis but have been associated with gastrointestinal (GI) mucosal injury. This study compared the incidence of gastric ulcers after treatment with risedronate, a pyridinyl bisphosphonate, or alendronate, a primary amino bisphosphonate, in healthy postmenopausal women stratified by Helicobacter pylori status. Subjects were randomized to receive risedronate 5 mg (n = 318) or alendronate 10 mg (n = 317) daily for 14 days. Endoscopy and evaluator-blind assessments of the esophageal, gastric, and duodenal mucosa were performed at baseline and on Days 8 and 15. Overall, gastric ulcers > or = 3 mm were observed in 18 (6.0%) of 300 evaluable subjects in the risedronate group and 36 (12.1%) of 297 in the alendronate group during treatment (p = 0.013). On Day 8, the incidences of gastric ulcers in the risedronate and alendronate groups were 3.6% and 6.6%, respectively (p = 0.133), and on Day 15, they were 3.3% and 8.7% (p = 0.008). The incidence of gastric ulcers was not affected by H. pylori status. Mean gastric endoscopy scores at Days 8 and 15 were significantly lower in the risedronate group than in the alendronate group (p < 0.001). Mean esophageal and duodenal endoscopy scores were similar in the 2 groups at Days 8 and 15. When the treatment groups were combined, gastric endoscopy scores were significantly higher among H. pylori negative than H. pylori positive subjects at Days 8 and 15 (p < 0.05). Upper GI adverse events were reported by 18 (5.7%) subjects in the risedronate group (19 events) and 28 (8.8%) subjects in the alendronate group (32 events). Symptoms did not predict the presence of mucosal damage. Risedronate was associated with a significantly lower incidence of gastric ulcers than alendronate. H. pylori infection did not increase the incidence of bisphosphonate related gastric ulcers. The findings from this 14 day study in healthy volunteers support the hypothesis that bisphosphonates may differ from one another in their potential to produce upper GI mucosal damage.


Identification of Specific Long Non-Coding Ribonucleic Acid Signatures and Regulatory Networks in Prostate Cancer in Fine-Needle Aspiration Biopsies.
Prostate cancer (PCa) is one of the most common tumors in men and can be lethal, especially if left untreated. A substantial majority of PCa patients not only are diagnosed based on fine needle aspiration (FNA) biopsies, but their treatment choices are also largely driven by the pathological findings obtained with these FNA specimens. It is widely believed that lncRNAs have strong biological significance, but their specific functions and regulatory networks have not been elucidated. LncRNAs may serve as key players and regulators of PCa carcinogenesis and could be novel biomarkers of this cancer. To identify potential markers for early detection of PCa, in this study, we employed a competing endogenous RNA (ceRNA) microarray to identify differentially expressed lncRNAs (DelncRNAs) in PCa tissue and quantitative real-time PCR (qRT-PCR) analysis to validate these DelncRNAs in FNA biopsies. We demonstrated that a total of 451 lncRNAs were differentially expressed in four pairs of PCa/adjacent tissues, and upregulation of the lncRNAs RP11-33A14.1, RP11-423H2.3, and LAMTOR5-AS1 was confirmed in FNA biopsies of PCa by qRT-PCR and was consistent with the ceRNA array data. The association between the expression of the lncRNA LAMTOR5-AS1 and aggressive cancer was also investigated. Regulatory network analysis of DelncRNAs showed that the lncRNAs RP11-33A14.1 and RP11-423H2.3 targeted miR-7, miR-24-3p, and miR-30 and interacted with the RNA binding protein FUS. Knockdown of these DelncRNAs in PCa cells also demonstrated the effects of RP11-423H2.3 on miR-7/miR-24/miR-30 or LAMTOR5-AS1 on miR-942-5p/miR-542-3p via direct interaction. The results of these studies indicate that these three specific lncRNA signatures and regulatory networks might serve as risk prediction and diagnostic biomarkers for prostate cancer, even in biopsies obtained by FNA.


Cloning, chromosomal localization and characterization of the murine mucin gene orthologous to human MUC4.
We report here the full coding sequence of a novel mouse putative membrane-associated mucin containing three extracellular EGF-like motifs and a mucin-like domain consisting of at least 20 tandem repeats of 124-126 amino acids. Screening a cosmid and a BAC libraries allowed to isolate several genomic clones. Genomic and cDNA sequence comparisons showed that the gene consists of 25 exons and 24 introns covering a genomic region of approximately 52 kb. The first intron is approximately 16 kb in length and is followed by an unusually large exon (approximately 9.5 kb) encoding Ser/Thr-rich tandemly repeated sequences. Radiation hybrid mapping localized this new gene to a mouse region of chromosome 16, which is the orthologous region of human chromosome 3q29 encompassing the large membrane-anchored mucin MUC4. Contigs analysis of the Human Genome Project did not reveal any other mucin on chromosome 3q29 and, interestingly, our analysis allowed the determination of the genomic organization of the human MUC4 and showed that its exon/intron structure is identical to that of the mouse gene we cloned. Furthermore, the human MUC4 shares considerable homologies with the mouse gene. Based on these data, we concluded that we isolated the mouse ortholog of MUC4 we propose as Muc4. Expression studies showed that Muc4 is ubiquitous like SMC and MUC4, with highest levels of expression in trachea and intestinal tract.


Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy.
Tumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment. This leads to effector T-cell anergy and enhanced Treg function through upregulation of FoxP3. As a nexus for the induction of key immunosuppressive mechanisms, IDO1 represents an important immunotherapeutic target in oncology. Here, we report the identification and characterization of the novel selective, orally bioavailable IDO1 inhibitor EOS200271/PF-06840003. It reversed IDO1-induced T-cell anergy in vitro In mice carrying syngeneic tumor grafts, PF-06840003 reduced intratumoral kynurenine levels by over 80% and inhibited tumor growth both in monotherapy and, with an increased efficacy, in combination with antibodies blocking the immune checkpoint ligand PD-L1. We demonstrate that anti-PD-L1 therapy results in increased IDO1 metabolic activity thereby providing additional mechanistic rationale for combining PD-(L)1 blockade with IDO1 inhibition in cancer immunotherapies. Supported by these preclinical data and favorable predicted human pharmacokinetic properties of PF-06840003, a phase I open-label, multicenter clinical study (NCT02764151) has been initiated.


Death receptors: signaling and modulation.
Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.


Humoral nitric oxide levels and antibody immune response of symptomatic and indeterminate Chagas' disease patients to commercial and autochthonous Trypanosoma cruzi antigen.
We report here the evaluation of chagasic patients for the presence and/or severity of the disease, antibody to Trypanosoma cruzi, and nitric oxide (NO) serum levels. Serum samples tested by ELISA with autochthonous and commercial antigen revealed that 10% and 7.5% of the individuals were anti-T. cruzi antibody-positive, respectively. Ten of 21 seropositive individuals had no clinical signs, the other 11 cases presented cardiomyopathy and/or mega-gastrointestinal syndromes, and three patients presented a combined form. A statistical difference (P < 0.001) in antibody titer between asymptomatic and symptomatic patients with autochthonous antigen was detected, and serum NO levels was found to be three times higher in cases than in controls. These results suggest that it is recommended to use a sole source of antigen (autochthonous) for the serodiagnosis of Chagas' disease, and that the pathogenic role of NO in this disease should be evaluated.


Allicin protects traumatic spinal cord injury through regulating the HSP70/Akt/iNOS pathway in mice.
Allicin is a major component of garlic, extracted as an oily liquid. The present study was designed to investigate the beneficial effects of allicin on traumatic spinal cord injury (TSCI) in mice, and whether the effects are mediated via regulation of the heat shock protein 70 (HSP70), v‑akt murine thymoma viral oncogene homolog 1 (Akt) and inducible nitric oxide synthase (iNOS) pathways. Adult BALB/c mice (30‑40 g) received a laminectomy at the T9 vertebral level as a model of TSCI. In the present study, treatment of the TSCI mice with allicin significantly increased their Basso, Beattie and Bresnahan (BBB) scores (P<0.01) and reduced the spinal cord water content (P<0.01). This protective effect was associated with the inhibition of oxidative stress and inflammatory responses in TSCI mice. Western blot analysis demonstrated that allicin increased the protein levels of HSP70, increased the phosphorylation of Akt and reduced the iNOS protein expression levels in TSCI mice. Additionally, treatment with allicin significantly reduced the levels of ROS and enhanced the NADH levels in TSCI mice. Collectively, these data demonstrate that the effects of allicin on TSCI are mediated via regulation of the HSP70, Akt and iNOS pathways in mice.


High-dose oral vitamin D3 supplementation in the elderly.
Daily dosing with vitamin D often fails to achieve optimal outcomes, and it is uncertain what the target level of 25-hydroxyvitamin D should be. This study found that large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels, and that monthly dosing is similarly effective after 3-5 months. With baseline 25OHD > 50 nmol/L, vitamin D supplementation does not reduce PTH levels. There is concern that vitamin D supplementation doses are frequently inadequate, and that compliance with daily medication is likely to be suboptimal. This randomized double-blind trial compares responses to three high-dose vitamin D(3) regimens and estimates optimal 25-hydroxyvitamin D (25OHD) levels, from changes in parathyroid hormone (PTH), and procollagen type I amino-terminal propeptide (P1NP) in relation to baseline 25OHD. Sixty-three elderly participants were randomized to three regimens of vitamin D supplementation: a 500,000-IU loading dose; the loading dose plus 50,000 IU/month; or 50,000 IU/month. The Loading and Loading + Monthly groups showed increases in 25OHD of 58 +/- 28 nmol/L from baseline to 1 month. Thereafter, levels gradually declined to plateaus of 69 +/- 5 nmol/L and 91 +/- 4 nmol/l, respectively. In the Monthly group, 25OHD reached a plateau of ~80 +/- 20 nmol/L at 3-5 months. There were no changes in serum calcium concentrations. PTH and P1NP were only suppressed by vitamin D treatment in those with baseline 25OHD levels <50 and <30 nmol/L, respectively. Large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels in the frail elderly. Monthly dosing is similarly effective and safe, but takes 3-5 months for plateau 25OHD levels to be reached.


Additive Effects of Millimeter Waves and 2-Deoxyglucose Co-Exposure on the Human Keratinocyte Transcriptome.
Millimeter Waves (MMW) will be used in the next-generation of high-speed wireless technologies, especially in future Ultra-Broadband small cells in 5G cellular networks. Therefore, their biocompatibilities must be evaluated prior to their massive deployment. Using a microarray-based approach, we analyzed modifications to the whole genome of a human keratinocyte model that was exposed at 60.4 GHz-MMW at an incident power density (IPD) of 20 mW/cm2 for 3 hours in athermic conditions. No keratinocyte transcriptome modifications were observed. We tested the effects of MMWs on cell metabolism by co-treating MMW-exposed cells with a glycolysis inhibitor, 2-deoxyglucose (2dG, 20 mM for 3 hours), and whole genome expression was evaluated along with the ATP content. We found that the 2dG treatment decreased the cellular ATP content and induced a high modification in the transcriptome (632 coding genes). The affected genes were associated with transcriptional repression, cellular communication and endoplasmic reticulum homeostasis. The MMW/2dG co-treatment did not alter the keratinocyte ATP content, but it did slightly alter the transcriptome, which reflected the capacity of MMW to interfere with the bioenergetic stress response. The RT-PCR-based validation confirmed 6 MMW-sensitive genes (SOCS3, SPRY2, TRIB1, FAM46A, CSRNP1 and PPP1R15A) during the 2dG treatment. These 6 genes encoded transcription factors or inhibitors of cytokine pathways, which raised questions regarding the potential impact of long-term or chronic MMW exposure on metabolically stressed cells.


Age related clinical manifestation of acute bacterial meningitis in children presenting to emergency department of a tertiary care hospital.
To determine the signs and symptoms of acute bacterial meningitis (ABM) in different age grops of a paediatric population. The retrospective study comprised patients who had been admitted through the Emergency Department of Aga Khan University Hospital, Karachi with the relevant diagnosis from September 2009 to September 2011. Case record forms were used to collect data from patient files. Data was collected using variables such as age, gender, presenting complaints, clinical signs and symptoms, computed tomography scan findings and final outcome of patients. There was a minimal risk of breach in patient confidentiality. SPSS 19 was used for data analysis. A total of 192 patietns were enrolled. The presenting complaint in 165 (86%) patients was fever; vomiting in 93 (48.43%); and 49 (52.68%) of them were more than 5 years old. Irritability was present in 54 (28.12%) children, of whom 27 (50%) were less than one year. Fits were present in 47 (24.47%) cases out of which 21 (44.68%) were less than one year. Neck stiffness and signs of meningeal irritation, Kerning's sign and Brudzincski's sign, were present in 53 (27.60%) patients; 26 (13.54%); and 18 (9.3%) respectively. These signs were more common in children over 5 years of age, reflected by 29 (54.7%), 16 (61.5%) and 11 (61.11%) patients respectively. On presentation, headache was found in 77 (40.10%) children among whom 56 (72.72%) were over 5 years. Besides, 151 (78.6%) patients required admission to the ward, while 40 (20.8%) were admitted in High Dependancy Unit/critical care units Adverse outcome was observed in 6 (3.12%) patients. Younger children with acute bacterial meningitis presented with non-specific signs and symptoms. Headache and signs of meningeal irritation were common findings in children over 5 years.


Projection-based geometrical feature extraction for computer vision: algorithms in pipeline architectures.
In this correspondence, some image transforms and features such as projections along linear patterns, convex hull approximations, Hough transform for line detection, diameter, moments, and principal components will be considered. Specifically, we present algorithms for computing these features which are suitable for implementation in image analysis pipeline architectures. In particular, random access memories and other dedicated hardware components which may be found in the implementation of classical techniques are not longer needed in our algorithms. The effectiveness of our approach is demonstrated by running some of the new algorithms in conventional short-pipelines for image analysis. In related papers, we have shown a pipeline architecture organization called PPPE (Parallel Pipeline Projection Engine), which unleashes the power of projection-based computer vision, image processing, and computer graphics. In the present correspondence, we deal with just a few of the many algorithms which can be supported in PPPE. These algorithms illustrate the use of the Radon transform as a tool for image analysis.


Tamoxifen reduces bone turnover and prevents lumbar spine and proximal femoral bone loss in early postmenopausal women.
Although widely used for its anti-estrogen properties tamoxifen has estrogen like effects on a number of tissues including bone and liver. Previous studies suggest a preservation of lumbar spine density in postmenopausal women but the effect on the hip had not been addressed. To determine whether tamoxifen prevents bone loss in the early postmenopausal period bone mineral density at the lumbar spine and femoral neck was measured using dual energy X-ray absorptiometry at presentation and 6 monthly thereafter for 1 year in a prospective controlled study. Also indices of bone turnover, serum osteocalcin and urinary hydroxyproline excretion, were assessed. Fifteen early postmenopausal women with Stage I or II breast cancer treated with tamoxifen and 21 normal postmenopausal women were studied. Sex hormone binding globulin and antithrombin III levels in serum were also measured as indices of the hepatic estrogenic activity. Tamoxifen (20 mg daily) prevented bone loss at the femoral neck and lumbar spine. Median rates of change in bone mineral density (%/year) for the tamoxifen group were +0.09%/year in the lumbar spine and 1.4%/year in the femoral neck compared with -2.3%/year and -1.8%/year for the control group (P = 0.04 and 0.03, respectively). Tamoxifen resulted in a significant decrease in both serum osteocalcin and urinary hydroxyproline by 6 months of treatment and this effect persisted for the 12 months of observation. An increase in sex hormone binding globulin and a decline in antithrombin III levels was also observed. These data indicate that, in recently, postmenopausal women tamoxifen prevented bone loss at both the lumbar spine and femur and reduced bone turnover.


Association between dyslipidemia and plasma levels of branched-chain amino acids in the Japanese population without diabetes mellitus.
Branched-chain amino acids (BCAAs) play a key role in energy homeostasis. We aimed to investigate the association between plasma BCAA levels and dyslipidemia in the Japanese population without diabetes mellitus. This cross-sectional study included 4952 participants without diabetes mellitus, enrolled in the Tsuruoka Metabolomic Cohort Study. Plasma BCAA levels were measured by capillary electrophoresis-mass spectrometry. Correlations between lipid and BCAA profiles were evaluated by sex-stratified multiple linear regression analyses, after adjusting for confounders. Logistic regression was used to identify associations between BCAAs and metabolic dyslipidemia (MD) defined as triglyceride levels ≥150 mg/dL, high-density lipoprotein cholesterol levels ≤40 mg/dL for men and ≤50 mg/dL for women, or low-density lipoprotein cholesterol (LDL-C) levels ≥140 mg/dL. In both sexes, the levels of individual BCAAs and the total BCAA levels correlated positively with triglyceride levels and negatively with high-density lipoprotein cholesterol levels. Valine, leucine, and total BCAA levels were weakly and positively correlated with LDL-C levels. Increased BCAA levels showed positive associations with MD. However, associations between BCAAs and elevated LDL-C levels were unclear. Furthermore, the associations between BCAA levels and MD regardless of fasting blood sugar (FBS) levels (high or low). Although valine, leucine, and total BCAA levels were weakly associated with elevated LDL-C levels in the high-FBS group, no such association was observed in the low-FBS group. BCAAs might be associated with MD independently of the FBS level and might play an important role in lipid metabolism and dyslipidemia.


Scaling up prevention and treatment towards the elimination of hepatitis C: a global mathematical model.
The revolution in hepatitis C virus (HCV) treatment through the development of direct-acting antivirals (DAAs) has generated international interest in the global elimination of the disease as a public health threat. In 2017, this led WHO to establish elimination targets for 2030. We evaluated the impact of public health interventions on the global HCV epidemic and investigated whether WHO's elimination targets could be met. We developed a dynamic transmission model of the global HCV epidemic, calibrated to 190 countries, which incorporates data on demography, people who inject drugs (PWID), current coverage of treatment and prevention programmes, natural history of the disease, HCV prevalence, and HCV-attributable mortality. We estimated the worldwide impact of scaling up interventions that reduce risk of transmission, improve access to treatment, and increase screening for HCV infection by considering six scenarios: no change made to existing levels of diagnosis or treatment; sequentially adding the following interventions: blood safety and infection control, PWID harm reduction, offering of DAAs at diagnosis, and outreach screening to increase the number diagnosed; and a scenario in which DAAs are not introduced (ie, treatment is only with pegylated interferon and oral ribavirin) to investigate the effect of DAA use. We explored the effect of varying the coverage or impact of these interventions in sensitivity analyses and also assessed the impact on the global epidemic of removing certain key countries from the package of interventions. By 2030, interventions that reduce risk of transmission in the non-PWID population by 80% and increase coverage of harm reduction services to 40% of PWID could avert 14·1 million (95% credible interval 13·0-15·2) new infections. Offering DAAs at time of diagnosis in all countries could prevent 640 000 deaths (620 000-670 000) from cirrhosis and liver cancer. A comprehensive package of prevention, screening, and treatment interventions could avert 15·1 million (13·8-16·1) new infections and 1·5 million (1·4-1·6) cirrhosis and liver cancer deaths, corresponding to an 81% (78-82) reduction in incidence and a 61% (60-62) reduction in mortality compared with 2015 baseline. This reaches the WHO HCV incidence reduction target of 80% but is just short of the mortality reduction target of 65%, which could be reached by 2032. Reducing global burden depends upon success of prevention interventions, implemention of outreach screening, and progress made in key high-burden countries including China, India, and Pakistan. Further improvements in blood safety and infection control, expansion or creation of PWID harm reduction services, and extensive screening for HCV with concomitant treatment for all are necessary to reduce the burden of HCV. These findings should inform the ongoing global action to eliminate the HCV epidemic. Wellcome Trust.


Curcumin induces therapeutic angiogenesis in a diabetic mouse hindlimb ischemia model via modulating the function of endothelial progenitor cells.
Neovascularization is impaired in diabetes mellitus, which leads to the development of peripheral arterial disease and is mainly attributed to the dysfunction of endothelial progenitor cells (EPCs). Previous studies proved the promotional effect of curcumin on neovascularization in wound healing of diabetes. Thus, we hypothesize that curcumin could promote neovascularization at sites of hindlimb ischemia in diabetes and might take effect via modulating the function of EPCs. Streptozotocin-induced type 1 diabetic mice and nondiabetic mice both received unilateral hindlimb ischemic surgery. Curcumin was then administrated to the mice by lavage for 14 days consecutively. Laser Doppler perfusion imaging was conducted to demonstrate the blood flow reperfusion. Capillary density was measured in the ischemic gastrocnemius muscle. In addition, angiogenesis, migration, proliferation abilities, and senescence were determined in EPCs isolated from diabetic and nondiabetic mice. Quantitative PCR was then used to determine the mRNA expression of vascular endothelial growth factor (VEGF) and angiopoetin-1 (Ang-1) in EPCs. Curcumin application to type 1 diabetic mice significantly improved blood reperfusion and increased the capillary density in ischemic hindlimbs. The in-vitro study also revealed that the angiogenesis, migration, and proliferation abilities of EPCs and the number of senescent EPCs were reversed by curcumin application. Quantitative PCR confirmed the overexpression of VEGF-A and Ang-1 in EPCs after curcumin treatment. Curcumin could enhance neovascularization via promoting the function of EPCs in a diabetic mouse hindlimb ischemia model.


Residential scene classification for gridded population sampling in developing countries using deep convolutional neural networks on satellite imagery.
Conducting surveys in low- and middle-income countries is often challenging because many areas lack a complete sampling frame, have outdated census information, or have limited data available for designing and selecting a representative sample. Geosampling is a probability-based, gridded population sampling method that addresses some of these issues by using geographic information system (GIS) tools to create logistically manageable area units for sampling. GIS grid cells are overlaid to partition a country's existing administrative boundaries into area units that vary in size from 50 m × 50 m to 150 m × 150 m. To avoid sending interviewers to unoccupied areas, researchers manually classify grid cells as "residential" or "nonresidential" through visual inspection of aerial images. "Nonresidential" units are then excluded from sampling and data collection. This process of manually classifying sampling units has drawbacks since it is labor intensive, prone to human error, and creates the need for simplifying assumptions during calculation of design-based sampling weights. In this paper, we discuss the development of a deep learning classification model to predict whether aerial images are residential or nonresidential, thus reducing manual labor and eliminating the need for simplifying assumptions. On our test sets, the model performs comparable to a human-level baseline in both Nigeria (94.5% accuracy) and Guatemala (96.4% accuracy), and outperforms baseline machine learning models trained on crowdsourced or remote-sensed geospatial features. Additionally, our findings suggest that this approach can work well in new areas with relatively modest amounts of training data. Gridded population sampling methods like geosampling are becoming increasingly popular in countries with outdated or inaccurate census data because of their timeliness, flexibility, and cost. Using deep learning models directly on satellite images, we provide a novel method for sample frame construction that identifies residential gridded aerial units. In cases where manual classification of satellite images is used to (1) correct for errors in gridded population data sets or (2) classify grids where population estimates are unavailable, this methodology can help reduce annotation burden with comparable quality to human analysts.