Subband image coding using watershed and watercourse lines of the wavelet transform.
Reports progress in primitive-based image coding using nonorthogonal dyadic wavelets. A 3D isotropic wavelet is used to approximate the difference-of-Gaussians (D-o-G) operator. Convolution of the image with dilated versions of the wavelet produces three band-pass signals that approximate multiscale smoothed second derivatives. An additional convolution of the image with a Gaussian-shaped low-pass wavelet creates a fourth subband signal that preserves low-frequency information not described by the three band-pass signals. The authors show that the original image can be recovered from the watershed and watercourse lines of the three band-pass signals plus the lowpass subband signal. By thresholding the watershed/watercourse representation, subsampling the low-pass subband, and using edge post emphasis, the authors achieve data reduction with little loss of fidelity. Further compression of the watersheds and watercourses is achieved by chain coding their shapes and predictive coding their amplitudes prior to lossless arithmetic coding. Results are presented for grey-level test images at data rates between 0.1 and 0.3 b/pixel.


Absence of filipin-sterol complexes from the membranes of active zones and acetylcholine receptor aggregates at frog neuromuscular junctions.
The polyene antibiotic filipin reacts specifically with membrane cholesterol and produces distinctive membrane lesions. We treated frog cutaneous and sartorius muscles with 0.04% filipin in a glutaraldehyde solution with or without prefixation with glutaraldehyde. Freeze-fracture of these muscles revealed numerous 19 to 38-nm protuberances and depressions (filipin-sterol complexes) in most areas of muscle, axon, and Schwann cell membranes. In the presynaptic membrane, however, these filipin-sterol complexes were absent from active zones consisting of ridges bordered with double rows of particles. In the postsynaptic membrane, filipin-sterol complexes were also virtually absent from the areas occupied by aggregates of large particles representing acetylcholine receptors. These results suggest that the membrane regions of active zones and acetylcholine receptor aggregates have a low cholesterol content.


Air travel and vector-borne disease movement.
Recent decades have seen substantial expansions in the global air travel network and rapid increases in traffic volumes. The effects of this are well studied in terms of the spread of directly transmitted infections, but the role of air travel in the movement of vector-borne diseases is less well understood. Increasingly however, wider reaching surveillance for vector-borne diseases and our improving abilities to map the distributions of vectors and the diseases they carry, are providing opportunities to better our understanding of the impact of increasing air travel. Here we examine global trends in the continued expansion of air transport and its impact upon epidemiology. Novel malaria and chikungunya examples are presented, detailing how geospatial data in combination with information on air traffic can be used to predict the risks of vector-borne disease importation and establishment. Finally, we describe the development of an online tool, the Vector-Borne Disease Airline Importation Risk (VBD-Air) tool, which brings together spatial data on air traffic and vector-borne disease distributions to quantify the seasonally changing risks for importation to non-endemic regions. Such a framework provides the first steps towards an ultimate goal of adaptive management based on near real time flight data and vector-borne disease surveillance.


A Systematic Review on the Investigation of SARS-CoV-2 in Semen.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a virus that is present in most bodily fluids. However, whether SARS-CoV-2 is present in the semen remains underexplored. Thus, we systematically reviewed the existing studies on the presence of SARS-CoV-2 in semen. A literature search of the PubMed, Embase, Cochrane, Web of Science, Google Scholar, and Ovid databases was performed for articles from the dates of their inception to August 2020 using the following keywords: COVID-19, SARS-CoV2, seminal, semen, and sperm. After excluding non-human studies and articles that were not in the English language, we identified 19 relevant studies. The full text of the articles were reviewed and a total of eight articles remained after applying our selection criteria. After reviewing the presence of SARS-CoV-2 in the eight different studies using semen samples, only one reported the presence of the virus. Six out of 160 total semen samples with SARS-CoV-2 positive demonstrated the presence of viral RNA, of which 2 were from males in the recovery phase and 4 from the acute phase of the infection. The novel nature of SARS-CoV-2 has limited the number and size of studies on semen. Nevertheless, the current literature, while limited, has confirmed the presence of SARS-CoV-2 in semen in one out of the eight reported studies and totaling 4.3% of the population screened. Taken together, the risk of the presence of SARS-CoV-2 in semen appears to be extremely low and likely negligible in recovered men. Future studies need to focus on whether complete viral particles can be seen in semen and the possibility of sexual transmission.


Mast Cells and Sensory Nerves Contribute to Neurogenic Inflammation and Pruritus in Chronic Skin Inflammation.
The intimate interaction between mast cells and sensory nerves can be illustrated by the wheal and surrounding flare in an urticarial reaction in human skin. This reaction is typically associated with an intense itch at the reaction site. Upon activation, cutaneous mast cells release powerful mediators, such as histamine, tryptase, cytokines, and growth factors that can directly stimulate corresponding receptors on itch-mediating sensory nerves. These include, e.g., H1- and H4-receptors, protease-activated receptor-2, IL-31 receptor, and the high-affinity receptor of nerve growth factor (TrkA). On the other hand, sensory nerves can release neuropeptides, including substance P and vasoactive intestinal peptide, that are able to stimulate mast cells to release mediators leading to potentiation of the reciprocal interaction, inflammation, and itch. Even though mast cells are well recognized for their role in allergic skin whealing and urticaria, increasing evidence supports the reciprocal function between mast cells and sensory nerves in neurogenic inflammation in chronic skin diseases, such as psoriasis and atopic dermatitis, which are often characterized by distressing itch, and exacerbated by psychological stress. Increased morphological contacts between mast cells and sensory nerves in the lesional skin in psoriasis and atopic dermatitis as well as experimental models in mice and rats support the essential role for mast cell-sensory nerve communication in consequent pruritus. Therefore, we summarize here the present literature pointing to a close association between mast cells and sensory nerves in pruritic skin diseases as well as review the essential supporting findings on pruritic models in mice and rats.


Percutaneous vertebroplasty or kyphoplasty.
Percutaneous vertebral augmentation techniques performed with vertebroplasty or kyphoplasty are safe and effective for the treatment of osteoporotic vertebral compression fractures, primary or secondary spine tumors, and selected traumatic fractures. This article compares the procedures and outlines their advantages and disadvantages. It concludes that vertebroplasty should be performed in most cases, but kyphoplasty is preferable in selected cases.


Stability of secondary structural elements in a solvent-free environment. II: the beta-pleated sheets.
The stability of single beta-strands and multistrand beta-pleated sheets as elements of secondary structure is examined in the absence of intermolecular interactions. Such experimental conditions (e.g., complete removal of solvent molecules and counterions) are achieved by placing the peptide ions in the gas phase. The metastable multiply- charged peptide ions produced by electrospray ionization undergo unimolecular dissociation. Intercharge repulsion within the precursor ions gives rise to the elevated kinetic energy of fragment ions, which is measured using Mass-analyzed Ion Kinetic Energy (MIKE) spectrometry. Intercharge distances calculated based on these measurements are compared to the numbers derived from molecular mechanics calculations with charge site assignments based on relative proton affinities. Evidence is presented suggesting that single beta-strands form collapsed structures in the absence of solvents, while multistrand beta-pleated sheets are likely to retain "native-like" secondary structures under the same conditions. These results indicate that intramolecular hydrogen bonds are the major factor determining the three-dimensional arrangements of polypeptides in the gas phase, compensating both long- and short-range electrostatic repulsions. This is in good agreement with our earlier findings (Proteins 27:165170, 1997) concerning stability of helical conformation of melittin in the absence of solvent.


HLA-G expressing DC-10 and CD4(+) T cells accumulate in human decidua during pregnancy.
Multiple mechanisms underlie the surprising willingness of mothers to tolerate the semi-allogeneic fetal tissues during pregnancy. Chief among these is the expression of the HLA-G molecules that has been largely demonstrated to be responsible for reprogramming the local maternal immune response towards tolerance. We recently identified a subset of tolerogenic dendritic cells, DC-10 that secrete high amounts of IL-10 and express high levels of HLA-G and its ligand ILT4. DC-10 are present in the peripheral blood and are essential in inducing adaptive regulatory T cells. We investigated the presence of DC-10 and HLA-G-expressing CD4(+) T cells in human decidua in the first trimester of pregnancy. Results showed that these cells are highly represented in human decidua as compared to the peripheral blood. This is the first report describing decidual DC-10 and CD4(+)HLA-G(+) T cells, strongly suggesting that they may accumulate or be induced at the fetal maternal interface to promote tolerance.


A Report of Zika Virus Seroprevalence in Republic of the Congo.
Zika virus (ZIKV) is an arthropod-borne RNA virus (arbovirus), belonging to the Spondweni serogroup. ZIKV was first described in Africa in 1947 and remained sporadic until Micronesia outbreak in 2007, which was followed by outbreaks in the Pacific Islands, Latin America, and the Caribbean. Subsequent to the epidemics, ZIKV revealed its severity as virus was sexually transmissible, and it was associated with serious fetal and neurological complications. ZIKV originated from Africa; however, little is known about the epidemiology of the virus in African populations. Following a recent study in Cameroon that evidenced low ZIKV epidemiology associated with a presumptive (peri-)sylvatic transmission, we performed a seroepidemiological study in Republic of the Congo, neighbor of Cameroon. To accomplish this, 386 serum specimens from volunteer blood donors collected in 2011 from rural and urban areas of Republic of the Congo were tested with ZIKV-specific methodology; primary screening with anti-NS1 ZIKV IgG ELISA followed by confirmation with cytopathic effect (CPE)-based virus neutralization test (VNT). ZIKV seropositivity was determined as low as 1.8%, varying slightly between urban and rural areas (1.7% and 3.6%). These results demonstrate that the majority of the population of Republic of the Congo is immunologically naïve against ZIKV with a presumptive (peri-)sylvatic transmission cycle, which emphasizes the importance of surveillance studies in Africa.


Progranulin regulates neuronal outgrowth independent of sortilin.
Progranulin (PGRN), a widely secreted growth factor, is involved in multiple biological functions, and mutations located within the PGRN gene (GRN) are a major cause of frontotemporal lobar degeneration with TDP-43-positive inclusions (FLTD-TDP). In light of recent reports suggesting PGRN functions as a protective neurotrophic factor and that sortilin (SORT1) is a neuronal receptor for PGRN, we used a Sort1-deficient (Sort1-/-) murine primary hippocampal neuron model to investigate whether PGRN's neurotrophic effects are dependent on SORT1. We sought to elucidate this relationship to determine what role SORT1, as a regulator of PGRN levels, plays in modulating PGRN's neurotrophic effects. As the first group to evaluate the effect of PGRN loss in Grn knockout primary neuronal cultures, we show neurite outgrowth and branching are significantly decreased in Grn-/- neurons compared to wild-type (WT) neurons. More importantly, we also demonstrate that PGRN overexpression can rescue this phenotype. However, the recovery in outgrowth is not observed following treatment with recombinant PGRN harboring missense mutations p.C139R, p.P248L or p.R432C, indicating that these mutations adversely affect the neurotrophic properties of PGRN. In addition, we also present evidence that cleavage of full-length PGRN into granulin peptides is required for increased neuronal outgrowth, suggesting that the neurotrophic functions of PGRN are contained within certain granulins. To further characterize the mechanism by which PGRN impacts neuronal morphology, we assessed the involvement of SORT1. We demonstrate that PGRN induced-outgrowth occurs in the absence of SORT1 in Sort1-/- cultures. We demonstrate that loss of PGRN impairs proper neurite outgrowth and branching, and that exogenous PGRN alleviates this impairment. Furthermore, we determined that exogenous PGRN induces outgrowth independent of SORT1, suggesting another receptor(s) is involved in PGRN induced neuronal outgrowth.


Spectrum of hemoglobinopathies in the state of Orissa, India: a ten years cohort study.
i) To determine the pattern of spectrum of hemoglobinopathies in the state of Orissa, ii) To find the ethnic groups at high risk of hemoglobinopathies, iii) Geographical distribution of hemoglobinopathies, and iv). To know epidemiological aspects of hemoglobinopathy cases in Orissa. One thousand fifteen cases of anemia were analysed referred from different peripheral hospitals and Medical Colleges and Hospitals of Orissa state for diagnosis and counseling during 1994 to 2003. About 2-3 ml. intravenous blood samples were collected after obtaining informed consent from each individual. Hematological indices were measured using MS4 Cell Counter. Background data of each individual were recorded like age, sex, caste, place of origin, consanguinity, etc. Hemoglobin electrophoresis was carried out on CAM in Tris-EDTA-Borate buffer at pH 8.9 and quantification of A2 fraction of hemoglobin by elution method. The value more than 3.5% of A2 fraction of hemoglobin was taken as cut off point for beta-thalassemia trait and more than 10% as Hb E. Hb electrophoresis in acidic medium (pH 6.2) was also carried out to confirm Hb D or E band. Estimation of fetal hemoglobin was done. Family studies were carried out to confirm the diagnosis. Most common hemoglobinopathies observed out of 1015 cases were: sickle cell trait (29.8%), sickle cell disease (7.5%), sickle cell-beta-thalassemia (1.7%), beta-thalassemia trait (18.2%), thalassemia major (5.3%), thalassemia intermedia (0.9%), Hb E trait (0.9%), Hb E disease (0.3%), E-beta-thalassemia (0.7%), Hb D trait (0.2%) and SD disease (0.2%). Sickle cell disorders with high level of fetal hemoglobin were common in general castes (0.3-20.7%), scheduled castes (0-8.9%) and scheduled tribals (0-5.5%). Transfusion dependent beta-thalassemia syndrome was prevalent in Brahmin, Karan, Khandyat, Teli, etc. Most of the cases belong to Anugul district, followed by Khurda, Nayagarh, Phulbani, Cuttack, Jajpur, Dhenkanal, Ganjam, Keonjhar, Mayurbhanj, etc. The heterogeneous population is harbouring almost all major hemoglobinopathies in general castes, scheduled castes and tribes, belonging to Coastal and South-Western regions of Orissa. This study provides for the first time a comprehensive database on the pattern of spectrum of hemoglobinopathies in Orissa.


Two Cases of Respiratory Insufficiency Secondary to Pre-procedural Nerve Blocks for Upper Extremity Injuries.
Interscalene nerve blocks are common procedures performed before upper extremity surgeries in order to provide post-op pain relief and improve recovery time. Here we present two cases of patients who underwent a unilateral supraclavicular and bilateral interscalene nerve block, respectively. The first patient had no risk factors but the second presented with a body mass index of 45.5 and a history of symptoms consistent with obstructive sleep apnea but never diagnosed. Both patients experienced some form of respiratory distress diagnosed via changes in chest x-ray and clinical presentation. The mechanism of injury that occurs in these procedures is typically from inadvertent damage to the phrenic nerve. Mild adverse effects in interscalene nerve block are relatively common. However, there is minimal data in regards to performing bilateral interscalene nerve blocks. The purpose of this study is to highlight that severe complication in both high and low-risk patients can occur but may be reduced with a safer approach and more effective communication among multidisciplinary team members.


Insulin and insulin-like growth factor 1 stimulate the phosphorylation on tyrosine of a 160 kDa cytosolic protein in 3T3-L1 adipocytes.
Insulin and IGF-1 (insulin-like growth factor 1) rapidly stimulate the phosphorylation on tyrosine of a 160 kDa cytosolic protein (pp160) in intact 3T3-L1 adipocytes. Half-maximal phosphorylation of pp160 is attained with either 4 nM-insulin or 20 nM-IGF-1. A semi-quantitative immunoblotting procedure using anti-phosphotyrosine antibody revealed that the insulin-stimulated 3T3-L1 adipocyte possesses approx. 3 x 10(5) and 0.6 x 10(5) phosphotyrosyl sites, respectively, in pp160 and insulin receptor beta-subunit. Removal of insulin from stimulated cells results in the rapid (within 15 min) loss of phosphate groups from tyrosyl residues in both pp160 and receptor beta-subunit. Whereas pp160 remains maximally phosphorylated on tyrosine for up to 60 min in the presence of 100 nM-insulin, IGF-1 at the same concentration induces only a transient response that is maximally 50% of that observed with insulin. pp160 is not phosphorylated on tyrosine in response to platelet-derived growth factor or epidermal growth factor. Although pp160 appears to be a soluble cytoplasmic protein, in the presence of 1 mM-ZnCl2 it becomes membrane-associated. In view of its apparent cytoplasmic localization and its inability to bind to either wheat-germ agglutinin or concanavalin A, pp160 does not appear to be a typical glycoprotein growth-factor receptor. Our results suggest that pp160 may be a physiologically important cellular substrate of the insulin-receptor tyrosine kinase in the intact 3T3-L1 adipocyte.


Biogeochemical changes and mercury methylation beneath an in-situ sediment cap.
In-situ capping has shown promise as a management strategy for contaminated aquatic sediments, however, little is known about how mercury methylation in underlying sediments will be affected. Changes to the location and extent of sulfate reduction and other biological processes were studied in estuarine sediment using laboratory microcosms. Observations in a model sediment showed increases of in situ total methylmercury concomitant with an upward extension of anaerobic bacterial activity beneath a sediment cap and under anoxic conditions. Increased methylmercury (up to 50%) was observed beneath a sediment cap in a region 2-3 cm higher than in an uncapped sediment. A 1-dimensional, unsteady, reaction transport model was used to simulate the transient response to mercury-related biogeochemical processes. The location, magnitude, and expected duration of the increased methylmercury was such that a significant impact on near cap-water interface methylmercury was not expected for the sediments studied. Explicit consideration of the biogeochemical effects of capping on mercury contaminated sediment, however, may be necessary for very thin or unstable capping layers where the physical sequestration provided by a cap may be compromised.


Acute respiratory distress due to thymoma in a patient treated with TK inhibitor: a case report and review of the current treatment options.
Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage. Surgery is the cornerstone of the management of thymomas: it is significant for the definite histopathological diagnosis and staging, and in most cases, it constitutes the first step of the treatment strategy. For patients with primary unresectable thymomas, the multimodal treatment schedule nowadays includes neoadjuvant chemotherapy, extensive surgery, adjuvant radiotherapy, and in some cases, adjuvant chemotherapy. A patient with a history of stage III COPD and an undiagnosed thoracic mass was admitted to the intensive care unit with acute respiratory distress. A radiologic evaluation by CT scan revealed a mass of 13 cm in diameter at the mediastinum. Fine needle aspiration was performed and revealed a thymoma. Due to poor performance status, the patient was not able to undergo surgery. He refused to be treated with neither chemotherapy nor radiotherapy, but due to EGFR overexpression, treatment with TK inhibitor was suggested. Fine needle aspiration biopsy is commonly used to identify metastasis to the mediastinum. However, it is less often employed as a primary diagnostic tool for tumors, particularly thymic neoplasms. The use of targeted therapies for the treatment of thymic malignancies has been described in the literature. Over the past years, significant efforts have been made to dissect the molecular pathways involved in the carcinogenesis of these tumors. Insights have been obtained following anecdotal clinical responses to targeted therapies, and large-scale genomic analyses have been conducted.


Treatment for Diabetic Peripheral Neuropathy: What have we Learned from Animal Models?
Animal models have been widely used to investigate the etiology and potential treatments for diabetic peripheral neuropathy. What we have learned from these studies and the extent to which this information has been adapted for the human condition will be the subject of this review article. A comprehensive search of the PubMed database was performed, and relevant articles on the topic were included in this review. Extensive study of diabetic animal models has shown that the etiology of diabetic peripheral neuropathy is complex, with multiple mechanisms affecting neurons, Schwann cells, and the microvasculature, which contribute to the phenotypic nature of this most common complication of diabetes. Moreover, animal studies have demonstrated that the mechanisms related to peripheral neuropathy occurring in type 1 and type 2 diabetes are likely different, with hyperglycemia being the primary factor for neuropathology in type 1 diabetes, which contributes to a lesser extent in type 2 diabetes, whereas insulin resistance, hyperlipidemia, and other factors may have a greater role. Two of the earliest mechanisms described from animal studies as a cause for diabetic peripheral neuropathy were the activation of the aldose reductase pathway and increased non-enzymatic glycation. However, continuing research has identified numerous other potential factors that may contribute to diabetic peripheral neuropathy, including oxidative and inflammatory stress, dysregulation of protein kinase C and hexosamine pathways, and decreased neurotrophic support. In addition, recent studies have demonstrated that peripheral neuropathy-like symptoms are present in animal models, representing pre-diabetes in the absence of hyperglycemia. This complexity complicates the successful treatment of diabetic peripheral neuropathy, and results in the poor outcome of translating successful treatments from animal studies to human clinical trials.


Changes over time in the utilization of disease-related Internet information in newly diagnosed breast cancer patients 2007 to 2013.
As the number of people with Internet access rises, so does the use of the Internet as a potentially valuable source for health information. Insight into patient use of this information and its correlates over time may reveal changes in the digital divide based on patient age and education. Existing research has focused on patient characteristics that predict Internet information use and research on treatment context is rare. This study aims to (1) present data on the proportion of newly diagnosed breast cancer patients treated in German breast centers from 2007 to 2013 who used the Internet for information on their disease, (2) look into correlations between Internet utilization and sociodemographic characteristics and if these change over time, and (3) determine if use of Internet information varies with the hospitals in which the patients were initially treated. Data about utilization of the Internet for breast cancer-specific health information was obtained in a postal survey of breast cancer patients that is conducted annually in Germany with a steady response rate of 87% of consenting patients. Data from the survey were combined with data obtained by hospital personnel (eg, cancer stage and type of surgery). Data from 27,491 patients from 7 consecutive annual surveys were analyzed for this paper using multilevel regression modeling to account for clustering of patients in specific hospitals. Breast cancer patients seeking disease-specific information on the Internet increased significantly from 26.96% (853/3164) in 2007 to 37.21% (1485/3991) in 2013. Similar patterns of demographic correlates were found for all 7 cohorts. Older patients (≥70 years) and patients with <10 years of formal education were less likely to use the Internet for information on topics related to their disease. Internet use was significantly higher among privately insured patients and patients living with a partner. Higher cancer stage and a foreign native language were associated with decreased use in the overall model. Type of surgery was not found to be associated with Internet use in the multivariable models. Intraclass correlation coefficients were small (0.00-0.03) suggesting only a small contribution of the hospital to the patients' decision to use Internet information. There was no clear indication of a decreased digital divide based on age and education. Use of the Internet for health information is on the rise among breast cancer patients. The strong age- and education-related differences raise the question of how relevant information can be adequately provided to all patients, especially to those with limited education, older age, and living without a partner.


Fecal calprotectin excretion in preterm infants during the neonatal period.
Fecal calprotectin has been proposed as a non-invasive marker of intestinal inflammation in inflammatory bowel disease in adults and children. Fecal calprotectin levels have been reported to be much higher in both healthy full-term and preterm infants than in children and adults. To determine the time course of fecal calprotectin (f-calprotectin) excretion in preterm infants from birth until hospital discharge and to identify factors influencing f-calprotectin levels in the first weeks of life, including bacterial establishment in the gut. F-calprotectin was determined using an ELISA assay in 147 samples obtained prospectively from 47 preterm infants (gestational age, and birth-weight interquartiles 27-29 weeks, and 880-1320 g, respectively) at birth, and at 2-week intervals until hospital discharge. Although median f-calprotectin excretion was 138 microg/g, a wide range of inter- and intra-individual variation in f-calprotectin values (from day 3 to day 78) was observed (86% and 67%, respectively). In multivariate regression analysis, f-calprotectin correlated negatively with ante and per natal antibiotic treatment (p = 0.001), and correlated positively with the volume of enteral feeding (mL/kg/d) (p = 0.009), the need to interrupt enteral feeding (p = 0.001), and prominent gastrointestinal colonization by Clostridium sp (p = 0.019) and Staphylococcus sp (p = 0.047). During the first weeks of life, the high f-calprotectin values observed in preterm infants could be linked to the gut bacterial establishment.


Changes in age-structure over four decades were a key determinant of population growth rate in a long-lived mammal.
A changing environment directly influences birth and mortality rates, and thus population growth rates. However, population growth rates in the short term are also influenced by population age-structure. Despite its importance, the contribution of age-structure to population growth rates has rarely been explored empirically in wildlife populations with long-term demographic data. Here we assessed how changes in age-structure influenced short-term population dynamics in a semi-captive population of Asian elephants Elephas maximus. We addressed this question using a demographic dataset of female Asian elephants from timber camps in Myanmar spanning 45 years (1970-2014). First, we explored temporal variation in age-structure. Then, using annual matrix population models, we used a retrospective approach to assess the contributions of age-structure and vital rates to short-term population growth rates with respect to the average environment. Age-structure was highly variable over the study period, with large proportions of juveniles in the years 1970 and 1985, and made a substantial contribution to annual population growth rate deviations. High adult birth rates between 1970 and 1980 would have resulted in large positive population growth rates, but these were prevented by a low proportion of reproductive-aged females. We highlight that an understanding of both age-specific vital rates and age-structure is needed to assess short-term population dynamics. Furthermore, this example from a human-managed system suggests that the importance of age-structure may be accentuated in populations experiencing human disturbance where age-structure is unstable, such as those in captivity or for endangered species. Ultimately, changes to the environment drive population dynamics by influencing birth and mortality rates, but understanding demographic structure is crucial for assessing population growth.


Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis.
There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use. MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case-control, and cross-sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/- NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment. Fifteen case-control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case-control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42). SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has previously been estimated. This risk is significantly elevated when SSRI medications are used in combination with NSAIDs, and physicians prescribing these medications together should exercise caution and discuss this risk with patients.


Multicenter evaluation of the commutability of a potential reference material for harmonization of enzyme activities.
Standardization of laboratory results allows for the use of common reference intervals and can be achieved via calibration of field methods with secondary reference materials. These harmonization materials should be commutable, i.e., they produce identical numerical results independent of assay principle or platform. This study assessed the commutability of a cryolyoprotectant-containing harmonization material, obtained from the Dutch Foundation for Quality Assessment in Clinical Laboratories, that is intended to harmonize measurements of enzyme activities within the Dutch project "Calibration 2000". The catalytic concentrations of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, gamma-glutamyltransferase and creatine kinase were analyzed in pooled patient sera and in the reference material in 14 laboratories. On liquid chemistry analyzers the harmonization material behaves like patient material. The enzyme activities measured in it fall on the regression lines calculated from activities measured in serum samples. For dry chemistry analyzers the activities of all enzymes measured in the harmonizator differ from the serum-based regression line. We show that this is due to the sucrose-containing cryolyoprotectant in the harmonization material. For each enzyme, correction factors were calculated that compensated for the bias and proved to be constant between reagent lots. Depending on the enzyme activity measured, application of these factors leads to 2- to 10-fold reduction of between-laboratory percentage coefficient of variation. Thus, additives to (potential) reference materials may alter their matrix in a way that interferes with analysis on certain test systems. The bias caused may be quantifiable and correctable. Establishment of correction factors leads to analytical uncertainties and costs. Therefore, matrix-based materials without additives should be selected as reference materials.


Modelling of spatial infection spread through heterogeneous population: from lattice to partial differential equation models.
We present a simple model for the spread of an infection that incorporates spatial variability in population density. Starting from first-principle considerations, we explore how a novel partial differential equation with state-dependent diffusion can be obtained. This model exhibits higher infection rates in the areas of higher population density-a feature that we argue to be consistent with epidemiological observations. The model also exhibits an infection wave, the speed of which varies with population density. In addition, we demonstrate the possibility that an infection can 'jump' (i.e. tunnel) across areas of low population density towards areas of high population density. We briefly touch upon the data reported for coronavirus spread in the Canadian province of Nova Scotia as a case example with a number of qualitatively similar features as our model. Lastly, we propose a number of generalizations of the model towards future studies.


Undetectable levels of CSF hypocretin-1 (orexin-A) in two prepubertal boys with narcolepsy.
We report on two prepubertal narcoleptic boys with undetectable levels of hypocretin-1 (orexin-A) in their cerebrospinal fluid (CSF). The disease onset times were 6 and 8 years, and CSF was collected 8 and 20 months after the onset, respectively. The initial symptoms were excessive daytime sleepiness, cataplexy and disrupted nocturnal sleep. Both subjects are DRB1*1501 and DQB1*0602 positive. The measurement of CSF hypocretin-1 is valuable for the decisive diagnosis of narcolepsy and for selecting the type of treatment in prepubertal children. Our results suggest that a significant degree of hypocretin deficiency is already present at the disease onset.


RibSeg v2: A Large-scale Benchmark for Rib Labeling and Anatomical Centerline Extraction.
Automatic rib labeling and anatomical centerline extraction are common prerequisites for various clinical applications. Prior studies either use in-house datasets that are inaccessible to communities, or focus on rib segmentation that neglects the clinical significance of rib labeling. To address these issues, we extend our prior dataset (RibSeg) on the binary rib segmentation task to a comprehensive benchmark, named RibSeg v2, with 660 CT scans (15,466 individual ribs in total) and annotations manually inspected by experts for rib labeling and anatomical centerline extraction. Based on the RibSeg v2, we develop a pipeline including deep learning-based methods for rib labeling, and a skeletonization-based method for centerline extraction. To improve computational efficiency, we propose a sparse point cloud representation of CT scans and compare it with standard dense voxel grids. Moreover, we design and analyze evaluation metrics to address the key challenges of each task. Our dataset, code, and model are available online to facilitate open research at https://github.com/M3DV/RibSeg.


Left ventricular underfilling and not septal bulging dominates abnormal left ventricular filling hemodynamics in chronic thromboembolic pulmonary hypertension.
Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with abnormal left ventricular (LV) filling hemodynamics [mitral early passive filling wave velocity/late active filling wave velocity (E/A) < 1]. Pulmonary endarterectomy (PEA) acutely reduces pulmonary vascular resistance, resulting in an increase of mitral E/A. The abolishment of leftward septal bulging and an increase in right ventricular (RV) output are thought to be responsible for the increase of mitral E/A. In this study, we quantified the separate effects of leftward septal bulging and RV output on LV hemodynamics. In 39 CTEPH patients who underwent PEA, transmitral flow velocities and RV hemodynamic data were obtained pre- and postoperatively. A mathematical model describing the mechanics of ventricular interaction was fitted to the preoperative average values of cardiac output (CO; 4.4 l/min), mean pulmonary artery pressure (mPAP; 50 mmHg), mitral E/A (0.74), and mean left atrial pressure (mLAP; 9.8 mmHg). Starting from this preoperative reference state with leftward septal bulging, PEA was simulated by changing mPAP and CO to average postoperative values (28 mmHg and 5.7 l/min, respectively). Simulated and postoperatively measured data on E/A (1.27 vs. 1.48), mLAP (12.6 vs. 11.5 mmHg), and septal curvature (both rightward) were consistent. When an exclusive decrease of mPAP was simulated, mitral E/A increased 26%, mLAP decreased 16%, and septal curvature became rightward. When an exclusive increase of CO was simulated, mitral E/A increased 53% and mLAP increased 62%, whereas leftward septal bulging persisted. Thus, our simulations suggest that the increase of mitral E/A with PEA is caused two-thirds by an increase of RV output and one-third by the abolishment of leftward septal bulging.


Association of SLCO1B1 Polymorphisms and Atorvastatin Safety and Efficacy: A Meta-analysis.
Atorvastatin is the best-selling statin in the market. However, some patients have to reduce drug doses or discontinue atorvastatin therapy mainly due to adverse drug reactions (ADRs). Genetic factors play an important role in the occurrence of ADRs. This study aimed to investigate the association between SLCO1B1 polymorphisms (c.521T>C or c.388A>G) and atorvastatin safety and efficacy. We systematically searched PubMed, Web of Science and Embase to screen relevant studies published before Sep 2018. This meta-analysis was performed to identify the relationship between SLCO1B1 c.521T>C or c.388A>G polymorphisms and atorvastatin-related ADRs by the odds ratios (ORs) and 95% confidence intervals (CIs). The relationship of SLCO1B1 polymorphisms and lipid-lowering effects [low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC)] was assessed in pooled data by calculating the mean difference (MD) with 95% CIs. All statistical tests were performed by the Review Manager 5.3 software. A total of 13 studies involving 1,550 atorvastatin users were included in this analysis. There was a significant association between the SLCO1B1 c.521T>C polymorphism and atorvastatin-related ADRs associated with risk allele C (dominant model: OR=1.57, P=0.01). Allele C is associated with increased lipid-lowering efficacy in people with Hyperlipidemias as compared to allele T (LDL-C/dominant model: MD=6.19, P<0.00001 and (TC)/dominant model: MD=2.07, P=0.008). No association between the SLCO1B1 c.388A>G polymorphism and ADRs or efficacy was observed (P>0.05). SLCO1B1 c.521T>C polymorphism is a valuable biomarker for the evaluation of atorvastatin safety and efficacy.


Trends in Mean Nutrient Intakes of US Infants, Toddlers, and Young Children from 3 Feeding Infants and Toddlers Studies (FITS).
Many updates to young child feeding recommendations have been published over the past decade, but concurrent intake trends have not been assessed. The aim of this study was to evaluate adequacy and trends in energy and nutrient intakes of US infants and children aged 0-47.9 mo through use of Feeding Infants and Toddlers Study (FITS) data from 2002, 2008, and 2016. FITS are cross-sectional surveys of parents/caregivers of infants and young children (FITS 2002, n = 2962; FITS 2008, n = 3276; FITS 2016, n = 3235). Dietary intakes were assessed by telephone with trained interviewers using the Nutrition Data System for Research. Mean ± SE nutrient intakes were calculated. Diet adequacy was assessed with the nutrient adequacy ratio (NAR) for 17 nutrients and the corresponding mean adequacy ratio. Energy and macronutrient intakes were generally stable across surveys, but significant decreases for saturated fat and total sugars and an increase in fiber were observed among 6-11.9-mo-olds and 12-23.9-mo-olds (P-trend < 0.0001). Mean sodium intakes exceeded Adequate Intakes (AI) for all ages, whereas fiber intakes were universally below the AI. Nutrients with the lowest NAR values were vitamin D (range 0.41-0.67/1.00) and vitamin E (range 0.60-0.79/1.00 for 2008 and 2016). For iron, infants aged 6-11.9 mo had the lowest NAR values at 0.77-0.88/1.00, compared to 0.85-0.89/1.00 for 12-47.9-mo-olds. Potassium was low from 12 to 47.9 mo (NAR range 0.55-0.63/1.00 across survey years). The nutrients with the greatest decline in mean intakes were iron and vitamins D and E among 6-11.9-mo-olds, and vitamin D and potassium among 12-23.9-mo-olds in 2016 compared to 2002. The diets of US infants and young children were generally adequate for most micronutrients and stable over time, but sodium intakes were too high, and nutrient gaps still existed, especially for vitamins D, E, and fiber across ages and for iron among infants.


G-Quadruplexes in the Archaea Domain.
The importance of unusual DNA structures in the regulation of basic cellular processes is an emerging field of research. Amongst local non-B DNA structures, G-quadruplexes (G4s) have gained in popularity during the last decade, and their presence and functional relevance at the DNA and RNA level has been demonstrated in a number of viral, bacterial, and eukaryotic genomes, including humans. Here, we performed the first systematic search of G4-forming sequences in all archaeal genomes available in the NCBI database. In this article, we investigate the presence and locations of G-quadruplex forming sequences using the G4Hunter algorithm. G-quadruplex-prone sequences were identified in all archaeal species, with highly significant differences in frequency, from 0.037 to 15.31 potential quadruplex sequences per kb. While G4 forming sequences were extremely abundant in Hadesarchaea archeon (strikingly, more than 50% of the Hadesarchaea archaeon isolate WYZ-LMO6 genome is a potential part of a G4-motif), they were very rare in the Parvarchaeota phylum. The presence of G-quadruplex forming sequences does not follow a random distribution with an over-representation in non-coding RNA, suggesting possible roles for ncRNA regulation. These data illustrate the unique and non-random localization of G-quadruplexes in Archaea.


Treatment of pulmonary embolism.
Most clinically important pulmonary emboli are associated with thrombosis of the proximal deep veins of the leg. Anticoagulant therapy is highly successful in reducing death and recurrence from pulmonary embolism and is the treatment of choice in the majority of these patients. Thrombolytic therapy is usually reserved for selected patients with clinically serious or massive pulmonary embolism. Vena caval interruption is limited to patients who have an absolute contraindication to anticoagulant therapy or who develop recurrent pulmonary embolism despite adequate anticoagulant therapy. Pulmonary embolectomy has a high mortality and should therefore be restricted to the most desperate cases.


PGC-1 alpha serine 570 phosphorylation and GCN5-mediated acetylation by angiotensin II drive catalase down-regulation and vascular hypertrophy.
Angiotensin II (Ang II) is a pleuripotential hormone that is important in the pathophysiology of multiple conditions including aging, cardiovascular and renal diseases, and insulin resistance. Reactive oxygen species (ROS) are important mediators of Ang II-induced signaling generally and have a well defined role in vascular hypertrophy, which is inhibited by overexpression of catalase, inferring a specific role of H(2)O(2). The molecular mechanisms are understood incompletely. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a key regulator of energy metabolism and ROS-scavenging enzymes including catalase. We show that Ang II stimulates Akt-dependent PGC-1 alpha serine 570 phosphorylation, which is required for the binding of the histone acetyltransferase GCN5 (general control nonderepressible 5) to PGC-1 alpha and for its lysine acetylation. These sequential post-translational modifications suppress PGC-1 alpha activity and prevent its binding to the catalase promoter through the forkhead box O1 transcription factor, thus decreasing catalase expression. We demonstrate that overexpression of the phosphorylation-defective mutant PGC-1 alpha (S570A) prevents Ang II-induced increases in H(2)O(2) levels and hypertrophy ([(3)H]leucine incorporation). Knockdown of PGC-1 alpha by small interfering RNA promotes basal and Ang II-stimulated ROS and hypertrophy, which is reversed by polyethylene glycol-conjugated catalase. Thus, endogenous PGC-1 alpha is a negative regulator of vascular hypertrophy by up-regulating catalase expression and thus reducing ROS levels. We provide novel mechanistic insights by which Ang II may mediate its ROS-dependent pathophysiologic effects on multiple cardiometabolic diseases.


FastPop: a rapid principal component derived method to infer intercontinental ancestry using genetic data.
Identifying subpopulations within a study and inferring intercontinental ancestry of the samples are important steps in genome wide association studies. Two software packages are widely used in analysis of substructure: Structure and Eigenstrat. Structure assigns each individual to a population by using a Bayesian method with multiple tuning parameters. It requires considerable computational time when dealing with thousands of samples and lacks the ability to create scores that could be used as covariates. Eigenstrat uses a principal component analysis method to model all sources of sampling variation. However, it does not readily provide information directly relevant to ancestral origin; the eigenvectors generated by Eigenstrat are sample specific and thus cannot be generalized to other individuals. We developed FastPop, an efficient R package that fills the gap between Structure and Eigenstrat. It can: 1, generate PCA scores that identify ancestral origins and can be used for multiple studies; 2, infer ancestry information for data arising from two or more intercontinental origins. We demonstrate the use of FastPop using 2318 SNP markers selected from the genome based on high variability among European, Asian and West African (African) populations. We conducted an analysis of 505 Hapmap samples with European, African or Asian ancestry along with 19661 additional samples of unknown ancestry. The results from FastPop are highly consistent with those obtained by Structure across the 19661 samples we studied. The correlations of the results between FastPop and Structure are 0.99, 0.97 and 0.99 for European, African and Asian ancestry scores, respectively. Compared with Structure, FastPop is more efficient as it finished ancestry inference for 19661 samples in 16 min compared with 21-24 h required by Structure. FastPop also provided scores based on SNP weights so the scores of reference population can be applied to other studies provided the same set of markers are used. We also present application of the method for studying four continental populations (European, Asian, African, and Native American). We developed an algorithm that can infer ancestries on data involving two or more intercontinental origins. It is efficient for analyzing large datasets. Additionally the PCA derived scores can be applied to multiple data sets to ensure the same ancestry analysis is applied to all studies.


The cortical timeline for deciding on reach motor goals.
Flexible sensorimotor planning is the basis for goal-directed behavior. We investigated the integration of visuospatial information with context-specific transformation rules during reach planning. We were especially interested in the relative timing of motor-goal decisions in monkey dorsal premotor cortex (PMd) and parietal reach region (PRR). We used a rule-based mapping task with different cueing conditions to compare task-dependent motor-goal latencies. The task allowed us a separation of cue-related from motor-related activity, and a separation of activity related to motor planning from activity related to motor initiation or execution. The results show that selectivity for the visuospatial goal of a pending movement occurred earlier in PMd than PRR whenever the task required spatial remapping. Such remapping was needed if the spatial representation of a cue or of a default motor plan had to be transformed into a spatially incongruent representation of the motor goal. In contrast, we did not find frontoparietal latency differences if the spatial representation of the cue or the default plan was spatially congruent with the motor goal. The fact that frontoparietal latency differences occurred only in conditions with spatial remapping was independent of the subjects' partial a priori knowledge about the pending goal. Importantly, frontoparietal latency differences existed for motor-goal representations during movement planning, without immediate motor execution. We interpret our findings as being in support of the hypothesis that latency differences reflect a dynamic reorganization of network activity in PRR, and suggest that the reorganization is contingent on frontoparietal projections from PMd.


Tracheal intubation of patients in non-standard positions requires training.
In extreme emergency situations, patients may need to undergo endotracheal intubation, while in a non-supine position. This manuscript offers several options to the anesthesiologist to cope with tracheal intubations in non-standard positions. The authors stress that there is a need for adequate training in an anaesthesia skills lab, whereby classic direct laryngoscopy and indirect videolaryngoscopy should be practiced on manikins, before our trainees actually practice anesthesia on patients in operating theatres. This manuscript is also a plea for developing an algorithm for emergency airway management in the non-supine position.


A novel mechanism for the control of circadian clock period by light.
The free-running period expressed by circadian clocks in constant environmental conditions is history dependent, and one effect of entrainment of circadian clocks by light cycles is to cause long-lasting changes in the free-running period that are termed aftereffects. It has been suggested that aftereffects are a consequence of the particular phase relationships among constituent oscillators of the circadian system that are established by the entrainment. In a test of this hypothesis, it is shown that aftereffects of entrainment of the free-running rhythm of nerve impulse activity from the eye of Bulla gouldiana are completely unaffected by treatment with 12-, 24-, or 48-h pulses of the translation inhibitor cycloheximide or with 24-h pulses of the transcription inhibitor DRB (5,6-dichlorobenzimidazole riboside). These treatments reset the phase of circadian oscillators generally and those in the eye of B. gouldiana specifically. The absence of any effect of the treatments indicates that aftereffects are independent of oscillator phase. These results suggest that history-dependent changes in period result from a novel, long-lasting, and previously unrecognized mechanism of action of light on the circadian pacemaking system. Furthermore, the data indicate that aftereffects can persist in the absence of translation, transcription, or the continued cycling of the circadian system.


Host-graft relationships of isolated bovine chromaffin cells in rat periaqueductal grey.
The transplantation of chromaffin cells from the adrenal medulla into pain modulatory regions of the CNS has previously been shown to reduce pain sensitivity, most likely via local release of neuroactive substances from the transplanted cells. The ready availability of bovine adrenal glands, as well as the high levels of opioid peptides produced by their chromaffin cells, make these glands a potentially valuable donor source for antinociception studies. However, the success of these xenografts depends on their ability to survive and integrate within the host CNS. The aim of the present study was to assess host-graft relationships of bovine chromaffin cells transplanted to the rat CNS. We have found that isolated bovine chromaffin cells survive for at least three months in the rat periaqueductal grey, with no evidence of immunological response following a short-term course of immunosuppressant treatment. In the early stages following transplantation, only minor pathology is found at the injection site, which apparently recovers completely at later stages. The host-graft borders are not well demarcated, in contrast to solid tissue grafts. Neuronal processes of host origin, forming numerous synapses with the transplanted bovine chromaffin cells, are apparent by three weeks following transplantation. Migration also occurs from the graft into the host parenchyma, as evidenced by individual chromaffin cells found near host parenchymal blood vessels. The clusters of chromaffin cells found in the graft itself are generally not very vascular, in contrast to solid tissue grafts. The chromaffin cell clusters are surrounded by blood vessels of the non-fenestrated CNS type at the host-graft border. It is likely that the small size of the graft does not require extensive angiogenesis. The lack of fenestrated peripheral-type endothelial capillaries, normally seen in adrenal medullary tissue grafts, may contribute to the survival of these xenografts in the rat brain.


Long-term MRI cell tracking after intraventricular delivery in a patient with global cerebral ischemia and prospects for magnetic navigation of stem cells within the CSF.
The purpose of the study was to evaluate the long-term clinical tracking of magnetically labeled stem cells after intracerebroventricular transplantation as well as to investigate in vitro feasibility for magnetic guidance of cell therapy within large fluid compartments. After approval by our Institutional Review Board, an 18-month-old patient, diagnosed as being in a vegetative state due to global cerebral ischemia, underwent cell transplantation to the frontal horn of the lateral ventricle, with umbilical cord blood-derived stem cells labeled with superparamagnetic iron oxide (SPIO) contrast agent. The patient was followed over 33 months with clinical examinations and MRI. To evaluate the forces governing the distribution of cells within the fluid compartment of the ventricular system in vivo, a gravity-driven sedimentation assay and a magnetic field-driven cell attraction assay were developed in vitro. Twenty-four hours post-transplantation, MR imaging (MRI) was able to detect hypointense cells in the occipital horn of the lateral ventricle. The signal gradually decreased over 4 months and became undetectable at 33 months. In vitro, no significant difference in cell sedimentation between SPIO-labeled and unlabeled cells was observed (p = NS). An external magnet was effective in attracting cells over distances comparable to the size of human lateral ventricles. MR imaging of SPIO-labeled cells allows monitoring of cells within lateral ventricles. While the initial biodistribution is governed by gravity-driven sedimentation, an external magnetic field may possibly be applied to further direct the distribution of labeled cells within large fluid compartments such as the ventricular system.


Helicobacter pylori infection--current status in Singapore.
Helicobacter pylori infection is a common infection in Singapore affecting about 31% of the population. The seroprevalence of H. pylori infection increases with age from 3% in children below 5 years to 71% in adults above 65 years. Amongst the races, Chinese and Indians had similar rates of seropositivity (34.3% and 33.6%) while in Malays it was significantly lower (13.7%; P < 0.05). H. pylori infection is associated with peptic ulcer disease (both duodenal and gastric ulcer) as well as gastric cancer [adenocarcinoma, early gastric cancer and mucosa-associated lymphoma of T cell type (MALT) lymphoma]. Its role in non-ulcer dyspepsia is controversial. H. pylori was found in 31% of non-ulcer dyspepsia patients in Singapore compared with 28% in normal healthy controls. Gastric emptying test using indigestible solids shows that gastroparesis per se, H. pylori in the presence of gastroparesis (but not H. pylori alone) are related to dyspeptic symptom. H. pylori plays a synergistic role with non-steroidal anti-inflammatory drugs (NSAIDs) in causing bleeding in gastric ulcer but not in duodenal ulcer. Invasive and non-invasive methods are available for diagnosis of H. pylori and should be used to establish the aetiology of gastro-duodenal disease. Currently two groups of therapeutic regimes with eradication rates of 90% are available: bismuth containing regimes and proton-pump inhibitors based regimes. Triple therapy for one week (using three drugs effective against H. pylori) is currently the treatment of choice.


Penalized survival models for the analysis of alternating recurrent event data.
Recurrent event data are widely encountered in clinical and observational studies. Most methods for recurrent events treat the outcome as a point process and, as such, neglect any associated event duration. This generally leads to a less informative and potentially biased analysis. We propose a joint model for the recurrent event rate (of incidence) and duration. The two processes are linked through a bivariate normal frailty. For example, when the event is hospitalization, we can treat the time to admission and length-of-stay as two alternating recurrent events. In our method, the regression parameters are estimated through a penalized partial likelihood, and the variance-covariance matrix of the frailty is estimated through a recursive estimating formula. Moreover, we develop a likelihood ratio test to assess the dependence between the incidence and duration processes. Simulation results demonstrate that our method provides accurate parameter estimation, with a relatively fast computation time. We illustrate the methods through an analysis of hospitalizations among end-stage renal disease patients.


Simultaneous recording of cervical and ocular vestibular-evoked myogenic potentials.
To increase clinical application of vestibular-evoked myogenic potentials (VEMPs) by reducing the testing time by evaluating whether a simultaneous recording of ocular and cervical VEMPs can be achieved without a loss in diagnostic sensitivity and specificity. Simultaneous recording of ocular and cervical VEMPs on each side during monaural stimulation, bilateral simultaneous recording of ocular VEMPs and cervical VEMPs during binaural stimulation, and conventional sequential recording of ocular and cervical VEMPs on each side using air-conducted sound (500 Hz, 5-millisecond tone burst) were compared in 40 healthy participants (HPs) and 20 patients with acute vestibular neuritis. Either simultaneous recording during monaural and binaural stimulation effectively reduced the recording time by ≈55% of that for conventional sequential recordings in both the HP and patient groups. The simultaneous recording with monaural stimulation resulted in latencies and thresholds of both VEMPs and the amplitude of cervical VEMPs similar to those found during the conventional recordings but larger ocular VEMP amplitudes (156%) in both groups. In contrast, compared to the conventional recording, simultaneous recording of each VEMP during binaural stimulation showed reduced amplitudes (31%) and increased thresholds for cervical VEMPs in both groups. The results of simultaneous recording of cervical and ocular VEMPs during monaural stimulation were comparable to those obtained from the conventional recording while reducing the time to record both VEMPs on each side. NCT03049683.


Inferring selection intensity and allele age from multilocus haplotype structure.
It is a challenging task to infer selection intensity and allele age from population genetic data. Here we present a method that can efficiently estimate selection intensity and allele age from the multilocus haplotype structure in the vicinity of a segregating mutant under positive selection. We use a structured-coalescent approach to model the effect of directional selection on the gene genealogies of neutral markers linked to the selected mutant. The frequency trajectory of the selected allele follows the Wright-Fisher model. Given the position of the selected mutant, we propose a simplified multilocus haplotype model that can efficiently model the dynamics of the ancestral haplotypes under the joint influence of selection and recombination. This model approximates the ancestral genealogies of the sample, which reduces the number of states from an exponential function of the number of single-nucleotide polymorphism loci to a quadratic function. That allows parameter inference from data covering DNA regions as large as several hundred kilo-bases. Importance sampling algorithms are adopted to evaluate the probability of a sample by exploring the space of both allele frequency trajectories of the selected mutation and gene genealogies of the linked sites. We demonstrate by simulation that the method can accurately estimate selection intensity for moderate and strong positive selection. We apply the method to a data set of the G6PD gene in an African population and obtain an estimate of 0.0456 (95% confidence interval 0.0144-0.0769) for the selection intensity. The proposed method is novel in jointly modeling the multilocus haplotype pattern caused by recombination and mutation, allowing the analysis of haplotype data in recombining regions. Moreover, the method is applicable to data from populations under exponential growth and a variety of other demographic histories.


Sleep/wake patterns of breast-fed infants in the first 2 years of life.
Published norms for infant sleep/wake patterns during the first 2 years of life include an increase in length of maximum sleep bout from four to five to eight to ten hours by 4 months but little decrease in total sleep in 24 hours from 13 to 15 hours. Thirty-two breast-fed infants were followed for 2 years and data collected on 24-hour patterns of nursing and sleep. Infants who were breast-fed into the second year did not develop sleep/wake patterns in conformance with the norms. Instead of having long unbroken night sleep, they continued to sleep in short bouts with frequent wakings. Their total sleep in 24 hours was less than that of weaned infants. This pattern was most pronounced in infants who both nursed and shared a bed with the mother, common practices in many nonwestern cultures. The sleep/wake development accepted as the physiologic norm may be attributable to the early weaning and separated sleeping practiced in western culture. As prolonged breast-feeding becomes more popular in our society, the norms of sleep/wake patterns in infancy will have to be revised.


Antibiotic prophylaxis for clean neck surgery.
The frequency of surgical site infections (SSIs) after clean neck surgery is low and antibiotic prophylaxis is not recommended. This retrospective study investigated the effect of perioperative prophylactic antimicrobial therapy on the development of infections. A total of 807 consecutive patients undergoing clean neck surgery were included in the study. Antimicrobial prophylaxis with intravenous cefuroxime was administered in 518 cases. Although patients who received prophylaxis had a lower rate of SSIs than those who did not receive antibiotics, this was not statistically significant (0.4% vs 1.4% respectively, p=0.19). Older age was the only variable associated with the development of SSIs (p=0.014).


Chronic superantigen exposure induces systemic inflammation, elevated bloodstream endotoxin, and abnormal glucose tolerance in rabbits: possible role in diabetes.
Excessive weight and obesity are associated with the development of diabetes mellitus type 2 (DMII) in humans. They also pose high risks of Staphylococcus aureus colonization and overt infections. S. aureus causes a wide range of severe illnesses in both healthy and immunocompromised individuals. Among S. aureus virulence factors, superantigens are essential for pathogenicity. In this study, we show that rabbits that are chronically exposed to S. aureus superantigen toxic shock syndrome toxin-1 (TSST-1) experience impaired glucose tolerance, systemic inflammation, and elevated endotoxin levels in the bloodstream, all of which are common findings in DMII. Additionally, such DMII-associated findings are also seen through effects of TSST-1 on isolated adipocytes. Collectively, our findings suggest that chronic exposure to S. aureus superantigens facilitates the development of DMII, which may lead to therapeutic targeting of S. aureus and its superantigens. Obesity has a strong correlation with type 2 diabetes, in which fatty tissue, containing adipocytes, contributes to the development of the illness through altered metabolism and chronic inflammation. The human microbiome changes in persons with obesity and type 2 diabetes, including increases in Staphylococcus aureus colonization and overt infections. While the microbiome is essential for human wellness, there is little understanding of the role of microbes in obesity or the development of diabetes. Here, we demonstrate that the S. aureus superantigen toxic shock syndrome toxin-1 (TSST-1), an essential exotoxin in pathogenesis, induces inflammation, lipolysis, and insulin resistance in adipocytes both in vitro and in vivo. Chronic stimulation of rabbits with TSST-1 results in impaired systemic glucose tolerance, the hallmark finding in type 2 diabetes in humans, suggesting a role of S. aureus and its superantigens in the progression to type 2 diabetes.


Delphi consensus on strategies in the management of opioid-induced constipation in cancer patients.
Opioid-induced constipation (OIC) is a frequent and bothersome adverse event related with opioid therapy in cancer patients. Despite the high prevalence, medical management of OIC is often uncertain. The current project aimed to investigate expert opinion on OIC management and provide practical recommendations to improve the clinical approach of OIC in cancer patient. A modified Delphi method was conducted involving 46 different physicians experts in OIC. Using a structured questionnaire of 67 items this project intended to seek consensus on aspects related to diagnosis, treatment, and quality of life of cancer patients suffering with OIC. After two rounds, a consensus was reached in 91% of the items proposed, all in agreement. Agreement was obtained on OIC definition (95.7%). Objective and patient-reported outcomes included in that definition should be assessed routinely in clinical practice. Responsive to symptom changes and easy-to-use assessment tools were recommended (87.2%). Successful diagnosis of OIC requires increase clinicians awareness of OIC and proactivity to discuss symptoms with their patients (100%). Successful management of OIC requires individualization of the treatment (100%), regular revaluation once is established, and keeping it for the duration of opioid treatment (91.5%). Oral Peripherally Acting μ-Opioid Receptor Agonists (PAMORAs), were considered good alternatives for the treatment of OIC in cancer patients (97.9%). This drugs and laxatives can be co-prescribed if OIC coexist with functional constipation. The panelists, based on their expert clinical practice, presented a set of recommendations for the management of OIC in cancer patients.


Laparoscopic pneumodissection: results in initial 20 patients.
The efficiency of laparoscopic procedures has been hindered by a lack of instrumentation for blunt tissue dissection. We evaluated here the efficacy of a new 5-mm laparoscopic dissecting instrument, a pneumodissector. This instrument allows the surgeon to use short bursts of high-pressure carbon dioxide to bluntly dissect fatty tissue. In 20 patients undergoing a variety of laparoscopic procedures, a 5-mm laparoscopic pneumodissector was used. Subjective assessment of the efficacy of the instrument was recorded. In addition, acid-base changes were measured by blood gas determination, and serum chemistries were obtained before, during, and after the procedure. The pneumodissector enhanced dissection of the kidney, ureter, and major blood vessels and shortened the operative time for laparoscopic nephrectomy. Although statistically significant changes in acidbase values occurred with use of the pneumodissector, these changes were not clinically significant and were no different than what is normally seen during carbon dioxide pneumoperitoneum. Laparoscopic pneumodissection is a safe and efficacious technique for rapid blunt tissue dissection.


Mothers' prenatal distress accelerates adrenal pubertal development in daughters.
Human life history schedules vary, partly, because of adaptive, plastic responses to early-life conditions. Little is known about how prenatal conditions relate to puberty timing. We hypothesized that fetal exposure to adversity may induce an adaptive response in offspring maturational tempo. In a longitudinal study of 253 mother-child dyads followed for 15 years, we investigated if fetal exposure to maternal psychological distress related to children's adrenarche and gonadarche schedules, assessed by maternal and child report and by dehydroepiandrosterone sulfate (DHEA-S), testosterone, and estradiol levels. We found fetal exposure to elevated maternal prenatal psychological distress predicted earlier adrenarche and higher DHEA-S levels in girls, especially first-born girls, and that associations remained after covarying indices of postnatal adversity. No associations were observed for boys or for gonadarche in girls. Adrenarche orchestrates the social-behavioral transition from juvenility to adulthood; therefore, significant findings for adrenarche, but not gonadarche, suggest that prenatal maternal distress instigates an adaptive strategy in which daughters have earlier social-behavioral maturation. The stronger effect in first-borns suggests that, in adverse conditions, it is in the mother's adaptive interest for her daughter to hasten social maturation, but not necessarily sexual maturation, because it would prolong the duration of the daughter allomothering younger siblings. We postulate a novel evolutionary framework that human mothers may calibrate the timing of first-born daughters' maturation in a way that optimizes their own reproductive success.


[High-energy laser therapy of stomach ulcers].
Efficacy of local therapy with copper laser was tried in 105 patients with drug-resistant gastric ulcers. The exposure to yellow-green light each other day brought about scarring of the defects for 15.4 +/- 2.0 days, on the average. In the two-times a week regimen the healing was reached for 24.1 +/- 2.3 days. Separate use of yellow and green light proved highly effective, 42.5% of patients were in remission for 5 years. Frequency of the exacerbation before the treatment and duration of the remission were unrelated. Not a single case of malignant transformation of the ulcer was registered.


Greek nurses reach crisis point.
Nurses in Greece have been hit hard by job freezes and 40 per cent wage cuts, as the government attempts to stave off bankruptcy with austerity measures. Hospital wards are understaffed and short of medical supplies following a 50 per cent reduction in the country's health budget. A union representative reveals his fears for the future and a nurse in Athens explains that her family's income has shrunk so much that buying food is her priority.


Oxidized adrenodoxin acts as a competitive inhibitor of cytochrome P450scc in mitochondria from the human placenta.
The conversion of cholesterol to pregnenolone by cytochrome P450scc is the rate-determining step in placental progesterone synthesis. The limiting component for placental cytochrome P450scc activity is the concentration of adrenodoxin reductase in the mitochondria, where it permits cytochrome P450scc to work at only 16% of maximum velocity. Adrenodoxin reductase serves to reduce adrenodoxin as part of the electron transfer from NADPH to cytochrome P450scc. We therefore measured the proportion of adrenodoxin in the reduced form in intact mitochondria from the human placenta during active pregnenolone synthesis, using EPR. We found that the adrenodoxin pool was only 30% reduced, indicating that the adrenodoxin reductase concentration was insufficient to maintain the adrenodoxin in the fully reduced state. As both oxidized and reduced adrenodoxin can bind to cytochrome P450scc we tested the ability of oxidized adrenodoxin to act as a competitive inhibitor of pregnenolone synthesis. This was done in a fully reconstituted system comprising 0.3% Tween 20 and purified proteins, and in a partially reconstituted system comprising submitochondrial particles, purified adrenodoxin and adrenodoxin reductase. We found that oxidized adrenodoxin is an effective competitive inhibitor of placental cytochrome P450scc with a Ki value half that of the Km for reduced adrenodoxin. We conclude that the limiting concentration of adrenodoxin reductase present in placental mitochondria has a two-fold effect on cytochrome P450scc activity. It limits the amount of reduced adrenodoxin that is available to donate electrons to cytochrome P450scc and the oxidized adrenodoxin that remains, competitively inhibits the cytochrome.


Characterization of the human CD34+ hematopoietic progenitor cell compartment during the second trimester of pregnancy.
Characterization of the different sites of fetal hematopoiesis during the second trimester of pregnancy can provide important information for the timing of in utero stem cell transplantation (SCT), as an experimental treatment for congenital hematologic disorders. We analyzed the distribution of the different hematopoietic precursor cells in fetal blood, liver, bone marrow (BM), spleen and thymus from 66 fetuses between the ages of 13 to 23 weeks of gestation by flow cytometry and culture of hematopoietic progenitor cells (HPC) in semi-solid media. During the second trimester the percentages of CD34+ cells did not change and were 4.0% (1.0-12.0%) (median [min.-max.]) in blood, 16.5% (3.0-32.0%) in BM, 6.0% (2.0-16.0%) in liver, 5.0% (2.0-14.0%) in spleen, and 1.1% (0.9-3.0%) in the thymus. Each tissue contained all subsets of CD34+ cells at various levels. Within the CD34+ population, in BM the main sub-population was CD34+CD19+ (38% (11-67%)), in thymus CD34+ CD7+ (83% [45-98%]), and in blood and liver CD34+ CD33+ (57% (30-80%) and 48% (20-82%), respectively). In all tissues approximately 1 % of nucleated cells were non-committed CD34+ CD38- cells. The frequencies of both committed CD34+ cells and non-committed CD34+ CD38- cells were constant from 13 to 23 weeks in fetal blood, BM, liver and spleen. The frequencies of cultured HPC were high in fetal liver, low in fetal BM, and increasing in fetal blood. During the second trimester of gestation, all CD34+ subsets were present in each hematopoietic compartment at different levels. An exchange of stem cells between organs is likely, but no major shift of the hematopoietic stem cell compartment from the liver to other hematopoietic organs was found during the mid-trimester. No arguments for a specific time window for performing in utero SCT were found, but if engraftment of donor stem cells in the human fetus is influenced by competition of endogenous stem cells or fetal immune competence, in utero SCT should be performed as early as possible during fetal development.


Ascorbate transport in pig coronary artery smooth muscle: Na(+) removal and oxidative stress increase loss of accumulated cellular ascorbate.
Pig deendothelialized coronary artery rings and smooth muscle cells cultured from them accumulated ascorbate from medium containing Na(+). The accumulated material was determined to be ascorbate using high-performance liquid chromatography. We further characterized ascorbate uptake in the cultured cells. The data fitted best with a Hill coefficient of 1 for ascorbate (K(asc) = 22 +/- 2 microM) and 2 for Na(+) (K(Na) = 84 +/- 10 mM). The anion transport inhibitors sulfinpyrazone and 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS) inhibited the uptake. Transferring cultured cells loaded with (14)C-ascorbate into an ascorbate-free solution resulted in a biphasic loss of radioactivity - an initial sulfinpyrazone-insensitive faster phase and a late sulfinpyrazone-sensitive slower phase. Transferring loaded cells into a Na(+)-free medium increased the loss in the initial phase in a sulfinpyrazone-sensitive manner, suggesting that the ascorbate transporter is bidirectional. Including peroxide or superoxide in the solution increased the loss of radioactivity. Thus, ascorbate accumulated in coronary artery smooth muscle cells by a Na(+)-dependent transporter was lost in an ascorbate-free solution, and the loss was increased by removing Na(+) from the medium or by oxidative stress.


[Osteo-bursal muscular pedicle surgical flap in aseptic femur head necrosis].
In 14 patients with aseptic necrosis of the whole or almost the whole support surface of the femoral head its affected part was dissected and the defect was replaced with osteo-bursal muscular pedicle graft, taken from the greater trochanter of the same name. Peculiarity of the technique resides in the fact that the bursa of the greater trochanter is used as an integrated block with the osteochondral graft of the greater trochanter and the musculotendinous pedicle, attached to its frontal edge, taken from the musculus gluteus medius. Clinico-roentgenologic observations of the operated patients during 4 years demonstrated that the anatomical structure of the femoral head and functions of the joint are restored.


Influence of the anion on the properties of ionic liquid mixtures: a molecular dynamics study.
Mixing of ionic liquids provides new opportunities for their tuning, enabling the applications of ionic liquid mixtures to expand. At the same time, the genesis of the fundamental properties of ionic liquid mixtures is still poorly understood. In this study we carried out a molecular dynamics simulation of binary mixtures of 1-buthyl-3-methylimidazolium hexafluorophosphate, 1-buthyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, and 1-buthyl-3-methylimidazolium tris(perfluoroethyl)trifluorophosphate ([C4mim][PF6] + [C4mim][NTf2], [C4mim][PF6] + [C4mim][FAP], [C4mim][FAP] + [C4mim][NTf2]) in a wide concentration range at 303.15 K and complemented it with quantum mechanical calculations. Three pure ionic liquids underwent the same kind of analysis for comparison purposes. We found that the addition of the [FAP]--anion to a mixture enhances the segregation of non-polar domains and weakens the hydrogen-bond network. The H-bonds in the studied mixtures are rather weak, as follows from QTAIM analysis, with the rarest occurrence for the [FAP]--anion. The competition of two anions in the mixtures for the most acidic hydrogen of the 1-butyl-3-methylimidazolium cation is reported. In most of the cases, the smaller anion ([PF6]- or [NTf2]-) with stronger charge concentration displaces the bigger one ([NTf2]- or [FAP]-) from the preferred coordination site. The existing nano-segregation in some mixtures notably slows down ion diffusion. Our results show that the differences in anion size, shape and nature are the main reasons for nano-segregation and the non-ideal behavior of ionic liquid mixtures.


Actual and Standardized Patient Evaluations of Medical Students' Skills.
Physicians must communicate effectively with patients. Actual patients (APs) rarely evaluate medical students' clinical skills; instead, standardized patients (SPs) provide proxy ratings. It is unclear how well SP ratings mirror AP experiences. The aim of this study was to compare AP and SP assessments of medical students' communication skills and professionalism. We hypothesized that their perspectives would be similar, but distinct, and offer insight about how to more reliably include the patient's voice in medical education. Using a mixed methods design, data were gathered from both APs and SPs using a modified SEGUE (Set the stage, Elicit information, Give information, Understand the patient's perspective, End the encounter) framework. Authors analyzed Likert-scale surveys using Spearman's rho (ρ) correlations, and qualitatively analyzed open-ended comments about students' interpersonal skills and professionalism. For APs, the domains of "trusted the student," "discussed treatment," and "reviewed next steps" were positively correlated with whether they would recommend the student to others (ρ.89, ρ.89, ρ.88, respectively, all P<.001). For SPs, feeling like they "trusted the student," "student appeared professionally competent," and "made personal connection" were most highly correlated with recommending the student to others (ρ.86, ρ.86, ρ.76, respectively, all P<.001). Feedback from APs provides unique perspectives, complementing those of SPs, and prompts insights into incorporating patients' voices and values into training. Students may benefit from learning experiences focused on sharing and clarifying information. Providing opportunities for deliberate practice and feedback during both AP and SP encounters may enhance mastery of these skills.


Effect of deuterium oxide on the thermodynamic quantities associated with phase transitions of phosphatidylcholine bilayer membranes.
The bilayer phase transitions of three kinds of phospholipids, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and dihexadecylphosphatidylcholine (DHPC), in deuterium oxide (D(2)O) and hydrogen oxide (H(2)O) were observed by differential scanning calorimetry (DSC) under ambient pressure and light-transmittance measurements under high pressure. The DSC measurements showed that the substitution of H(2)O by D(2)O affected the pretransition temperatures and the main-transition enthalpies of all PC bilayers. The temperature-pressure phase diagrams for these PC bilayer membranes in both solvents were constructed by use of the data of light-transmittance measurements. Regarding the main transition of all PC bilayer membranes, there was no appreciable difference between the transition temperatures in D(2)O and H(2)O under high pressure. On the other hand, the phase transitions among the gel phases including the pretransition were significantly affected by the solvent substitution. The thermodynamic quantities of phase transitions for the PC bilayer membranes were evaluated and the differences in thermodynamic properties by the water substitution were considered from the difference of interfacial-free energy per molecule in the bilayer in both solvents. It was proved that the substitution of H(2)O by D(2)O causes shrinkage of the molecular area of phospholipid at bilayer interface due to the difference in bond strength between deuterium and hydrogen bonds and produces the great influence on the bilayer phase with the smaller area. Further, the induction of bilayer interdigitation in D(2)O turned out to need higher pressures than in H(2)O.


Registry of experimental digestive tract tumours in europe.
A survey was carried out throughout Europe to establish a Registry of Experimental Digestive Tumours, including cancers of the oesophagus, stomach, colon, rectum and pancreas, transplantable tumour lines in animal models, and human digestive tumours grafted into nude mice or immunosuppressed animals. Cell lines from human and animal digestive tract cancers are also included. This registry is to provide information and facilitate communication between interested research workers.


A randomized, double-blinded, placebo-controlled study of the effect of a combination of lemon verbena extract and fish oil omega-3 fatty acid on joint management.
The aim of this study was to test the efficacy of an antioxidant/anti-inflammatory supplement containing standardized lemon verbena (Aloysia triphylla, Lippia citriodora) extract and fish oil omega-3 fatty acid in a human pilot trial as an alternative treatment for joint management. First, antioxidant activity of the supplement was determined through an oxygen radical absorbance capacity (ORAC) assay. In a randomized, double-blinded placebo-controlled trial, 45 subjects with pain discomfort received the nutritional supplement or placebo for 9 weeks. Western Ontario MacMaster (WOMAC) and Lequesne's questionnaires, which are disease-specific measurements validated to measure joint dysfunction and pain, were administered and evaluated once per week in the placebo and intervention groups. Pain and stiffness symptoms, and joint function were determined once per week through recording their respective WOMAC and Lequesne's scores in the placebo and intervention groups. Statistically significant differences were determined at every measurement point between the two groups. Lemon verbena extract showed strong antioxidant properties as measured by the ORAC assay. The nutritional supplement containing standardized lemon verbena extract (14% verbascoside, w/w) and fish oil omega-3 fatty acid reduced symptoms of pain and stiffness significantly, and improved physical function as shown by WOMAC and Lequesne's scores after 9 weeks of treatment. WOMAC and Lequesne's total scores decreased 53% and 78%, respectively, at the end of the study compared to initial conditions. Onset of the effect was observed at the third and fourth weeks, when statistically significant differences were detected, compared to placebo. This pilot study reveals that supplementation with lemon verbena combined with omega-3 fatty acids may be considered for further investigation as a complementary and alternative treatment for improving joint status in subjects with joint discomfort.


Gold(III)-Catalyzed Glycosylation using Phenylpropiolate Glycosides: Phenylpropiolic Acid, An Easily Separable and Reusable Leaving Group.
An efficient and operationally simple gold(III)-catalyzed glycosylation protocol was developed using newly synthesized benchtop stable phenylpropiolate glycosyl (PPG) donors. Gold(III)-catalyzed activation of PPGs proceeds well with various carbohydrate and noncarbohydrate-based glycosyl acceptors and leads to their corresponding O/ N-glycosides in good to excellent yields with regeneration of reusable and easily separable phenylpropiolic acid. Differentially protected PPGs reacted well under the optimized reaction conditions. In particular, good anomeric selectivity was observed with mannosyl and rhamnosyl PPG donors. A preliminary mechanistic study reveals that the presence of a triple bond adjacent to the ester group is essential for activation, and PPG-based donor shows higher reactivity than analogous acetate and benzoate donors.


Bed side teaching: Student's perception and its correlation with academic performance.
To determine student's perception of bedside clinical teaching and to correlate it with their performance in assessment. This cross-sectional study of correlational survey was conducted at Services Institute of Medical Sciences in September 2019, involving students of final professional year who filled a proforma to rate their bedside teaching experience during clinical rotations using rating scale. Mean scores of items were determined with score < 3 reflecting dis-satisfaction. Mean scores were compared between high and low performing students using student's t test. Total of 160 students participated. Physical environment domain was assigned lowest scores by students (mean 2.94±0.74) followed by teaching task by teachers (3.04±0.72), group dynamics (3.16±0.81) and patient comfort and attitude towards patient (3.87±0.60). Teaching task by teacher had maximum stems with scores < 3 needing significant improvement. Students with low academic performance were more unsatisfied with group dynamics of bedside teaching (p value 0.009), especially lack of equal opportunities of participation for every member (p value <0.000) in clinical rotations. Small size group with adequate space for bedside training and faculty training can enhance learning experience of students. Ensuring active participation of each group member during bedside learning can improve academic performance of students.


Feasibility and acceptability of a volunteer-mediated diversional therapy program for older patients with cognitive impairment.
Understanding the perceptions of stakeholders is critical for determining acceptability and feasibility of volunteer-mediated programs. This study evaluated the feasibility and acceptability for staff, volunteers, patients and their carers, of a volunteer diversional therapy program for patients with cognitive impairment undergoing inpatient rehabilitation. Post-program structured interviews were conducted with the volunteers (n = 10), patients (n = 30) and their carers (n = 3); and nursing staff (n = 6) participated in a focus group. Thematic analysis identified five themes (values, attitudes, knowledge, purpose, support) in two dimensions (personal, team culture). Overall, patients, carers, staff and volunteers were satisfied with the volunteer program and perceived benefits for quality of care. Recommendations for improvements to the program related to staff engagement with the program and the volunteers' education and training. The volunteer diversional therapy pilot program for patients with cognitive impairment on a sub-acute ward was acceptable and feasible for patients, carers, staff and volunteers.


miR-140-3p regulation of TNF-α-induced CD38 expression in human airway smooth muscle cells.
CD38, a membrane protein expressed in airway smooth muscle (ASM) cells, plays a role in cellular Ca(2+) dynamics and ASM contractility. In human ASM (HASM) cells, TNF-α induces CD38 expression through activation of MAPKs, NF-κB, and AP-1, and its expression is differentially elevated in cells from asthmatic patients compared with cells from nonasthmatic subjects. The CD38 3'-untranslated region (UTR) has targets for miR-140-3p. We hypothesized that miR-140-3p regulates CD38 expression in HASM cells by altering CD38 mRNA stability. Basal and TNF-α-induced expression of miR-140-3p was determined in nonasthmatic ASM (NAASM) and asthmatic ASM (AASM) cells. NAASM and AASM cells were transfected with control, miR-140-3p mimic, or miR-140-3p antagomirs, and CD38 expression and CD38 mRNA stability were determined. Luciferase reporter assays were used to determine miR-140-3p binding to the CD38 3'-UTR. Activation of p38, ERK, and JNK MAPKs, NF-κB, and AP-1 was determined in miR-140-3p mimic-transfected NAASM. TNF-α attenuated miR-140-3p expression in NAASM and AASM cells, but at a greater magnitude in AASM cells. CD38 mRNA expression was attenuated by miR-140-3p mimic at comparable magnitude in NAASM and AASM cells. Mutated miR-140-3p target on the CD38 3'-UTR reversed the inhibition of luciferase activity by miR-140-3p mimic. CD38 mRNA stability was unaltered by miR-140-3p mimic in NAASM or AASM cells following arrest of transcription. TNF-α-induced activation of p38 MAPK and NF-κB was attenuated by miR-140-3p mimic. The findings indicate that miR-140-3p modulates CD38 expression in HASM cells through direct binding to the CD38 3'-UTR and indirect mechanisms involving activation of p38 MAPK and NF-κB. Furthermore, indirect mechanisms appear to play a major role in the regulation of CD38 expression.


Psychosocial and environmental determinants of child cognitive development in rural south africa and tanzania: findings from the mal-ed cohort.
Approximately 66% of children under the age of 5 in Sub-Saharan African countries do not reach their full cognitive potential, the highest percentage in the world. Because the majority of studies investigating child cognitive development have been conducted in high-income countries (HICs), there is limited knowledge regarding the determinants of child development in low- and middle-income countries (LMICs). This analysis includes 401 mother-child dyads from the South Africa and Tanzania sites of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal birth cohort study. We investigated the effect of psychosocial and environmental determinants on child cognitive development measured by the Wechsler Preschool Primary Scales of Intelligence (WPPSI) at 5 years of age using multivariable linear regression. Socioeconomic status was most strongly associated with child cognitive development (WPSSI Score Difference (SD):14.27, 95% CI:1.96, 26.59). Modest associations between the organization of the home environment and its opportunities for cognitive stimulation and child cognitive development were also found (SD: 3.08, 95% CI: 0.65, 5.52 and SD: 3.18, 95% CI: 0.59, 5.76, respectively). This study shows a stronger association with child cognitive development at 5 years of age for socioeconomic status compared to more proximal measures of psychosocial and environmental determinants. A better understanding of the role of these factors is needed to inform interventions aiming to alleviate the burden of compromised cognitive development for children in LMICs.


What neuroscience has already done for us.
Each of the components of the biopsychosocial model of mental illness is important for understanding mental illness. Biological and genetic abnormalities have been demonstrated in major mental illnesses. These are leading to changes in our understanding of these conditions, as well as our understanding of the link between life events and mental illness.


Signal transduction targets in androgen-independent prostate cancer.
Prostate cancer (PCa) first manifests as an androgen-dependent disease. Thus, androgen-deprivation therapy is a standard regimen for patients with metastatic PCa. Despite the initial success of androgen-deprivation therapy, PCa inevitably progresses from being androgen dependent (AD) to androgen independent (AI), and this marks the poor prognosis of this disease. Relapse of AIPCa becomes life threatening and accounts for the majority of mortality of PCa patients. Currently, no effective therapy is available for controlling AIPCa. Therefore, the challenge in providing a new intervention is to understand the fundamental changes that occur in AIPCa. Increasing evidence indicates that, under androgen-deprived milieu, several signal networks elicited by peptide growth factors dictate the AI phenotype of PCa. This review covers the latest studies investigating the potential involvement of autocrine growth factors in cell proliferation, survival, metastasis, and the reciprocal interaction with the androgen receptor pathway. In addition, loss of the negative feedback mechanism of the signal cascade further amplifies the effect of growth factors, and thus contributes significantly to the onset of AIPCa. The understanding of the signal target(s) in AIPCa should provide the new markers for prognosis and a new strategy for prevention and therapy.


[Peculiarities of anion actions on mitochondrial ATPase].
The effects of bicarbonate, sulfite and thiocyanate anions on the ATPase activity of mouse liver mitochondria were studied. The anions stimulated and inhibited the ATPase activity non-competitively with respect to ATP and Mg2+. The stimulatory and inhibitory effects of the anions were persistent, when the ratios of Mg2+ and ATP wee changed considerably. Thyocyanate inhibited the ATPase activity competitively to sulfite. The hydrolysis of ATP was sensitive to sulfite, bicarbonate and thiocyanate in the presence of calcium, cobalt, manganese and zinc. The correlation between the data obtained and the previously proposed mechanism of the anions effect of the ATPase activity is discussed.