Hepatocyte growth factor is involved in the morphogenesis of tooth germ in murine molars.
The patterns of gene expression for hepatocyte growth factor (HGF) and its receptor, c-Met, were revealed in the tooth germ of rat mandibular molars using RT-PCR. In situ hybridization demonstrated that the HGF gene was expressed only in the cells of the dental papilla of the tooth germ in vivo. The characteristic temporospatial distribution of HGF and c-Met during germ development was revealed using immunohistochemical studies in vivo. In order to demonstrate the functional role played by HGF in tooth development, HGF translation arrest by antisense phosphorothioate oligodeoxynucleotide (ODN) was carried out in vitro. In the control experiment, explants of tooth germs from embryonic 14 day mice were cultured in a modification of Trowell's system under serum-free and chemically defined conditions for two weeks. Other explants were cultured with 15mer antisense or sense ODN targeted to the HGF mRNA. Both the control and the sense-treated explants showed normal histological structure, as observed in vivo. On the other hand, antisense-treated explants exhibited an abnormal structure in which the enamel organs were surrounded by a thin layer of dentin and dental papilla, appearing 'inside-out' compared to the control and sense-treated explants, although the cytodifferentiation of ameloblasts and odontoblasts was not inhibited. The explants treated with recombinant human HGF combined with antisense ODN showed normal development, indicating that exogenous HGF rescued the explants from the abnormal structure caused by antisense ODN. The findings of a BrdU incorporation experiment suggested that the imbalance between the proliferation activity of the inner enamel epithelium and that of the dental papilla caused by HGF translation arrest results in the abnormal structure of the tooth germ. These results indicate that HGF is involved in the morphogenesis of the murine molar.


Modulation of Murine Olivary Connexin 36 Gap Junctions by PKA and CaMKII.
The inferior olive (IO) is a nucleus located in the brainstem and it is part of the olivo-cerebellar loop. This circuit plays a fundamental role in generation and acquisition of coherent motor patterns and it relies on synchronous activation of groups of Purkinje cells (PC) in the cerebellar cortex. IO neurons integrate their intrinsic oscillatory activity with excitatory inputs coming from the somatosensory system and inhibitory feedback coming from the cerebellar nuclei. Alongside these chemical synaptic inputs, IO neurons are coupled to one another via connexin 36 (Cx36) containing gap junctions (GJs) that create a functional syncytium between neurons. Communication between olivary neurons is regulated by these GJs and their correct functioning contributes to coherent oscillations in the IO and proper motor learning. Here, we explore the cellular pathways that can regulate the coupling between olivary neurons. We combined in vitro electrophysiology and immunohistochemistry (IHC) on mouse acute brain slices to unravel the pathways that regulate olivary coupling. We found that enhancing the activity of the protein kinase A (PKA) pathway and blocking the Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathway can both down-regulate the size of the coupled network. However, these two kinases follow different mechanisms of action. Our results suggest that activation of the PKA pathway reduces the opening probability of the Cx36 GJs, whereas inhibition of the CaMKII pathway reduces the number of Cx36 GJs. The low densities of Cx36 proteins and electrical synapses in βCaMKII knock-out mice point towards an essential role for this protein kinase in regulating the density of GJs in the IO. Thus, the level of olivary coupling is a dynamic process and regulated by a variety of enzymes modulating GJs expression, docking and activity.


Expression characteristics of CS-ACS1, CS-ACS2 and CS-ACS3, three members of the 1-aminocyclopropane-1-carboxylate synthase gene family in cucumber (Cucumis sativus L.) fruit under carbon dioxide stress.
We investigated the expression pattern of three 1-aminocyclopropane-1-carboxylate (ACC) synthase genes, CS-ACS1, CS-ACS2 and CS-ACS3 in cucumber (Cucumis sativus L.) fruit under CO2 stress. CO2 stress-induced ethylene production paralleled the accumulation of only CS-ACS1 transcripts which disappeared upon withdrawal of CO2. Cycloheximide inhibited the CO2 stress-induced ethylene production but superinduced the accumulation of CS-ACS1 transcript. At higher concentrations, cycloheximide also induced the accumulation of CS-ACS2 and CS-ACS3 transcripts. In the presence of CO2 and cycloheximide, the accumulation of CS-ACS2 transcript occurred within 1 h, disappeared after 3 h and increased greatly upon withdrawal of CO2. Inhibitors of protein kinase and types 1 and 2A protein phosphatases which inhibited and stimulated, respectively, CO2 stress-induced ethylene production had little effect on the expression of these genes. The results presented here identify CS-ACS1 as the main ACC synthase gene responsible for the increased ethylene biosynthesis in cucumber fruit under CO2 stress and suggest that this gene is a primary response gene and its expression is under negative control since it is expressed by treatment with cycloheximide. The results further suggest that the regulation of CO2 stress-induced ethylene biosynthesis by reversible protein phosphorylation does not result from enhanced ACC synthase transcription.


Pistachio nuts: composition and potential health benefits.
The pistachio is a nutrient-dense nut with a heart-healthy fatty-acid profile as well as protein, dietary fiber, potassium, magnesium, vitamin K, γ-tocopherol, and a number of phytochemicals. The pistachio's unique green and purple kernel color is a result of its lutein and anthocyanin content. Among nuts, pistachios contain the highest levels of potassium, γ-tocopherol, vitamin K, phytosterols, and xanthophyll carotenoids. Five published randomized cardiovascular trials have shown that pistachios promote heart-healthy blood lipid profiles. Exploratory clinical studies suggest that pistachios help maintain healthy antioxidant and anti-inflammatory activity, glycemic control, and endothelial function. When consumed in moderation, pistachios may help control body weight because of their satiety and satiation effects and their reduced net metabolizable energy content. One study with subjects in a weight-loss program demonstrated lower body mass index and triglyceride levels in individuals who consumed pistachios compared with those who consumed an isocaloric pretzel snack. Emerging research suggests that the addition of pistachios to high-glycemic meals may lower the overall postprandial glycemic response. This review examines the nutrients and phytochemicals in pistachios as well as the potential health effects of these nuts.


A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia.
A large double-blind, vehicle-controlled study of 143 patients with chronic postherpetic neuralgia (PHN) was performed to evaluate the degree of efficacy of topically applied capsaicin 0.075% cream. In addition, the safety and efficacy of long-term application of topical capsaicin in PHN was assessed by following patients in an open-label study for up to 2 years. In the double-blind phase, 143 patients with PHN of 6 months' duration or longer were enrolled. Since epidemiologic studies of patients who receive no treatment have shown that only 10% to 25% of those with PHN after 1 month will still have pain at 1 year, two separate efficacy analyses were performed: one with all evaluable patients (n = 131) and the other with 93 patients whose PHN lasted for longer than 12 months prior to study startup. All efficacy variables, including the physician's global evaluation of reduction in PHN pain, changes in pain severity on the categoric scale, visual analogue scale for pain severity, visual analogue scale for pain relief, and functional capacity scale, showed significant improvement at nearly all time points throughout the study for both patient groups, based on duration of PHN pain. In contrast, the group receiving vehicle cream remained essentially unchanged. Data from the long-term, open-label phase (up to 2 years, n = 77), which immediately followed the 6-week blinded phase, showed that the clinical benefit in patients treated for a short (6-week) period with topical capsaicin could be maintained or amplified in most patients (86%) during prolonged therapy. There were no serious adverse effects observed or reported throughout the trial; in fact, the only side effect associated with capsaicin treatment was the burning or stinging at local sites of application (in 9% of patients) during exposures of up to 2 years (long-term phase). On the basis of these data, we conclude that capsaicin 0.075% cream is a safe and effective treatment for the pain of postherpetic neuralgia and should be considered for initial management of patients with this condition.


A greener and efficient access to substituted four- and six-membered sulfur-bearing heterocycles.
The regioselective functionalization of four- and six-membered cyclic sulfones was investigated using a lithiation/electrophile trapping strategy. The protocol features an interesting eco-compatibility profile because of the use of 2-MeTHF as a solvent (more eco-friendly than other organic solvents) and n-hexyllithium as a lithiating agent safer than other alkyllithium compounds. Several derivatives were prepared with different stereochemistry and substitution patterns. A number of selected derivatives, spanning a range of 5 log P units, were characterized for their lipophilicity through RP-HPLC. A good linear correlation, with a slope close to 1.0, was observed between the experimentally determined RP-HPLC lipophilicity parameters (log k'w) and calculated log P (clog P) values, whereas a systematic difference in absolute values between the chromatographic parameters and in silico lipophilicity descriptors can be attributed mainly to silanophilic interactions between the H-bond acceptor SO2 group and free silanol groups on silica-based C18 columns, which results in increased retention times.


Cryptococcus neoformans serotype A glucuronoxylomannan-protein conjugate vaccines: synthesis, characterization, and immunogenicity.
We synthesized Cryptococcus neoformans serotype A glucuronoxylomannan (GXM) conjugate vaccines under conditions suitable for human use to prevent disseminated cryptococcosis. The purified, sonicated GXM was derivatized with adipic acid dihydrazide through either hydroxyl or carboxyl groups and then covalently bound to tetanus toxoid (TT) or Pseudomonas aeruginosa exoprotein A (rEPA). The immunogenicity of these conjugates was evaluated in BALB/c and general purpose mice by subcutaneous injection in saline. The conjugates elicited higher GXM antibody responses than GXM alone. Booster immunoglobulin G (IgG) and IgM responses were elicited by all conjugates in BALB/c mice. The conjugates prepared through hydroxyl activation (GXM-TT2 and GXM-rEPA) were more immunogenic than the one prepared through carboxyl activation (GXM-TT1). GXM antibody response was enhanced by the administration of monophosphoryl lipid A 2 days following the injection of GXM-TT2 (P less than 0.03). The conjugates also elicited IgG antibodies to the carrier proteins. Gel diffusion tests using conjugate-induced hyperimmune sera and chemically modified GXMs suggested that the specificity of GXM-TT1-induced antibodies was conferred by the O-acetyl groups. Hyperimmune sera generated by GXM-TT2 precipitated with the chemically unmodified and the de-O-acetylated GXMs but not with the carboxyl-reduced and de-O-acetylated GXM. GXM-TT2-induced hyperimmune serum also precipitated with the capsular polysaccharides of C. neoformans serotypes D, B, and C. The conjugate vaccines prepared through hydroxyl activation of the GXM are sufficiently immunogenic and appear to be suitable for clinical evaluation.


A Quantitative General Population Job Exposure Matrix for Occupational Noise Exposure.
Occupational noise exposure is a known risk factor for hearing loss and also adverse cardiovascular effects have been suggested. A job exposure matrix (JEM) would enable studies of noise and health on a large scale. The objective of this study was to create a quantitative JEM for occupational noise exposure assessment of the general working population. Between 2001-2003 and 2009-2010, we recruited workers from companies within the 10 industries with the highest reporting of noise-induced hearing loss according to the Danish Working Environment Authority and in addition workers of financial services and children day care to optimize the range in exposure levels. We obtained 1343 personal occupational noise dosimeter measurements among 1140 workers representing 100 different jobs according to the Danish version of the International Standard Classification of Occupations 1988 (DISCO 88). Four experts used 35 of these jobs as benchmarks and rated noise levels for the remaining 337 jobs within DISCO 88. To estimate noise levels for all 372 jobs, we included expert ratings together with sex, age, occupational class, and calendar year as fixed effects, while job and worker were included as random effects in a linear mixed regression model. The fixed effects explained 40% of the total variance: 72% of the between-jobs variance, -6% of the between-workers variance and 4% of the within-worker variance. Modelled noise levels showed a monotonic increase with increasing expert score and a 20 dB difference between the highest and lowest exposed jobs. Based on the JEM estimates, metal wheel-grinders were among the highest and finance and sales professionals among the lowest exposed. This JEM of occupational noise exposure can be used to prioritize preventive efforts of occupational noise exposure and to provide quantitative estimates of contemporary exposure levels in epidemiological studies of health effects potentially associated with noise exposure.


Impact of adalimumab on work participation in rheumatoid arthritis: comparison of an open-label extension study and a registry-based control group.
Rheumatoid arthritis (RA) causes considerable disability and often results in loss of work capacity and productivity. This study evaluated the impact of adalimumab, a tumour necrosis factor antagonist with demonstrated efficacy in RA, on long-term employment. Data from an open-label extension study (DE033) of 486 RA patients receiving adalimumab monotherapy who previously did not respond to at least one disease-modifying antirheumatic drug (DMARD) and had baseline work status information were compared with data from 747 RA patients receiving DMARD treatment in a Norway-based longitudinal registry. Primary outcomes included the time patients continued working at least part time and the likelihood of stopping work. Secondary outcomes included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) responses and disease remission. Outcomes were compared 6, 12 and 24 months after enrolment. During a 24-month period, the 158 patients who received adalimumab and were working at baseline worked 7.32 months longer (95% CI 4.8 to 9.1) than did the 180 patients treated with DMARDs, controlling for differences in baseline characteristics. Regardless of baseline work status, patients receiving adalimumab worked 2.0 months longer (95% CI 1.3 to 2.6) and were significantly less likely to stop working than those receiving DMARDs (HR 0.36 (95% CI -0.30 to 0.42) for all patients and 0.36 (95% CI 0.15 to 0.85) for patients working at baseline, respectively). The patients who received adalimumab were also considerably more likely to achieve ACR responses and disease remission than DMARD-treated patients. Patients who achieved EULAR good response and remission were less likely to stop working, but this relationship was only seen in patients receiving DMARDs. Patients with RA who received adalimumab experienced considerably longer periods of work and continuous employment, and greater rates of clinical responses, than patients receiving DMARDs. The mechanism by which adalimumab decreases likelihood of stopping work seems to be different from that of DMARD treatment and independent of clinical responses.


BHIVA position statement on HIV, the law and the work of the clinical team.
The purpose of this statement is to outline issues at the interface between HIV transmission and the law and provide guidance to healthcare professionals (HCPs) working in the field of HIV medicine. The guidance is to support work in the UK, and it is important to note that the law in England and Wales differs from that in Scotland and Northern Ireland. Approaches are suggested to deal with these issues consistently, within legal and General Medical Council (GMC) regulatory frameworks and in the context of the public health agenda. The guidance specifically addresses sexual transmission.


The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression.
Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may-at least partly-be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites-and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo-in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.


Poorly differentiated thyroid carcinomas: how much poorly differentiated is needed?
Poorly differentiated (PD) carcinomas of the thyroid are conceptually situated between well-differentiated (papillary or follicular) carcinomas and anaplastic thyroid carcinomas. Although the morphologic criteria for PD tumors are well defined, it is not clear how much of a PD area besides a well-differentiated component in a given tumor is required to allow such a diagnosis. We identified 42 patients suffering from thyroid carcinoma with an adverse clinical outcome. Fifty patients with follicular carcinoma were added as controls. We analyzed poorly differentiated areas by applying the Turin criteria of PD carcinomas. These criteria consisted of the presence of a solid/trabecular/insular growth pattern, lack of nuclear features of papillary carcinoma, and presence of 1 of the following features: (1) convoluted nuclei, (2) tumor necrosis, (3) 3 or more mitoses per 10 high-power fields. Using a cutoff value of 10% of PD areas per examined tumor surface, we identified a total of 35 PD carcinomas. Despite using a threshold of 10% of the tumor area as poorly differentiated, the survival data in a Kaplan-Meier analysis were significantly worse than those in the control group (P<0.001) and did not differ from tumors with a PD area >50%. In a multivariate analysis that included age, sex, tumor stage, and PD area >10% against survival data, the only consistent significant factor was PD differentiation (P<0.001). As even slight amounts of PD areas (≥ 10%) in a thyroid carcinoma affect the prognosis significantly, the presence of such areas may be worth reporting in thyroid carcinomas.


A comparison of pectoral fin contact behaviour for three distinct dolphin populations.
Tactile exchanges involving the pectoral fin have been documented in a variety of dolphin species. Several functions (e.g., social, hygienic) have been offered as possible explanations for when and why dolphins exchange pectoral fin contacts. In this study, we compared pectoral fin contact between dolphin dyads from three distinct dolphin populations: two groups of wild dolphins; Atlantic spotted dolphins (Stenella frontalis) from The Bahamas and Indo-Pacific bottlenose dolphins (Tursiops aduncus) from around Mikura Island, Japan; and one group of captive bottlenose dolphins (Tursiops truncatus) residing at the Roatan Institute for Marine Sciences, Anthony's Key Resort. A number of similarities were observed between the captive and wild groups, including; rates of pectoral fin contact, which dolphin initiated contact, posture preference, and same-sex rubbing partner preference. Unlike their wild counterparts, however, dolphins in the captive study group engaged in petting and rubbing at equal rates, females were more likely to contact males, males assumed the various rubbing roles more frequently than females, and calves and juveniles were more likely to be involved in pectoral fin contact exchanges. These results suggest that some aspects of pectoral fin contact behaviour might be common to many dolphin species, whereas other aspects could be species specific, or could be the result of differing environmental and social conditions.


Diagnosis and management of isolated C1 fractures: A systematic review.
Atlas fractures are a common craniocervical injury, often resulting from trauma. However, diagnosis and management of atlas fractures continues to be the subject of controversy. We aimed to characterize the factors related to diagnosis of atlas fractures, delineate important considerations in selecting the optimal management for a patient with an atlas fracture, and compare outcomes of surgical and conservative management. We performed a systematic review using PubMed, Embase, and Scopus to identify articles that analyzed diagnosis and management of isolated atlas fractures published between 2013 and 2020. Titles and abstracts were screened. Studies meeting prespecified inclusion criteria were reviewed in full. Of 305 resultant articles, 13 were included. C1:C2 ratio and lateral mass displacement (LMD) were used to predict transverse atlantal ligament (TAL) injury. Surgery promoted high fusion rates overall. Stable atlas fractures achieved high fusion rates with conservative management, while spinal fusion promoted greater fusion rates than halo vest immobilization management for unstable fractures. Visual Analog Scale scores, range of motion, and/or LMD improved after surgery. LMD increased for unilateral sagittal split fractures with TAL injury after conservative treatment. Stable atlas fractures can be sufficiently treated conservatively. Unstable atlas fractures can be managed both conservatively and surgically, while surgery is associated with favorable outcomes for unstable isolated atlas fractures. Future studies are necessary to further guide risk stratification and treatment approaches in management of the patients with isolated atlas fractures.


Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations - a PEARRL review.
Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial-and-error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection. Advances in mechanistic understanding have been made possible by the use of analytical tools such as spectroscopy, microscopy and mathematical and molecular modelling, which have been reviewed herein. Using these techniques, PI selection can be guided by molecular rationale. However, more work is required to see widespread application of such an approach for PI selection. Precipitation inhibitors are becoming increasingly important in enabling formulations. Trial-and-error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.


Sex Differences in Coronary Artery and Thoracic Aorta Calcification and Their Association With Cardiovascular Mortality in Heavy Smokers.
The aim of this study was to investigate sex differences in the prevalence, extent, and association of coronary artery calcium (CAC) and thoracic aorta calcium (TAC) scores with cardiovascular mortality in a population eligible for lung screening. CAC and TAC scores derived from chest computed tomography (CT) might be useful biomarkers for individualized cardiovascular disease prevention and could be especially relevant in high-risk populations such as heavy smokers. Therefore, it is important to know the prevalence of arterial calcifications in male and female heavy smokers, and if there are differences in the predictive value calcifications carry. We performed a nested case-control study with 5,718 participants of the CT arm of the NLST (National Lung Screening Trial). Prevalence and extent of CAC and TAC were resampled to the full cohort to provide unbiased estimates of the typical calcium burden of male and female heavy smokers. Weighted Cox proportional hazards regression was used to assess differences in the association of CAC and TAC scores with all-cause and cardiovascular mortality. CAC was substantially more common and more severe in men (prevalence: 81% vs. 60%; median volume: 104 mm³ vs. 12 mm³). Women had CAC comparable to that of men who were 10 years younger. TAC was equally common in men and women, with a tendency to be more pronounced in women (prevalence: 92% vs. 93%; median volume: 388 mm³ vs. 404 mm³). Both types of calcification were associated with increased cardiovascular and all-cause mortality. TAC scores improved the prediction of coronary heart disease mortality over CAC in men, but not in women. In both sexes, TAC, but not CAC, was associated with cardiovascular mortality other than coronary heart disease. CAC develops later in women, whereas TAC develops equally in both sexes. CAC is strongly associated with coronary heart disease, whereas TAC is especially associated with extracardiac vascular mortality in either sex.


Pulmonary cavitation: an under-recognized late complication of severe COVID-19 lung disease.
Pulmonary radiological findings of the novel coronavirus disease 2019 (COVID-19) have been well documented and range from scattered ground-glass infiltrates in milder cases to confluent ground-glass change, dense consolidation, and crazy paving in the critically ill. However, lung cavitation has not been commonly described in these patients. The objective of this study was to assess the incidence of pulmonary cavitation in patients with COVID-19 and describe its characteristics and evolution. We conducted a retrospective review of all patients admitted to our institution with COVID-19 and reviewed electronic medical records and imaging to identify patients who developed pulmonary cavitation. Twelve out of 689 (1.7%) patients admitted to our institution with COVID-19 developed pulmonary cavitation, comprising 3.3% (n = 12/359) of patients who developed COVID-19 pneumonia, and 11% (n = 12/110) of those admitted to the intensive care unit. We describe the imaging characteristics of the cavitation and present the clinical, pharmacological, laboratory, and microbiological parameters for these patients. In this cohort six patients have died, and six discharged home. Cavitary lung disease in patients with severe COVID-19 disease is not uncommon, and is associated with a high level of morbidity and mortality.


The effects of hypovolemia on multiple organ injury following intestinal reperfusion.
This study examines the relationship between hypovolemia and remote organ injury following intestinal reperfusion. Sprague-Dawley rats underwent intestinal ischemia (120 min) and reperfusion (90 min, IIR) or sham operation (CTL). The animals received normal saline (NS) at 0, 30, or 40 ml/kg/h intravenously. Lung and intestinal injury was quantitated using an edema index, and liver injury was assessed by measuring bile flow rates. The infusion of 40 ml/kg/h of NS attenuated the intestinal edema index of IIR animals nearly 50% (p < .05). Despite this improvement, this parameter remained nearly 10-fold greater than that of CTL (p < .05). The lung edema index was 70% greater in IIR animals receiving 30 and 40 ml/kg/h of NS than those not receiving NS. The infusion of 40 ml/kg/h of NS restored bile flow rates in IIR animals to that of CTL. These data suggest that hypovolemia may contribute to the intestinal and hepatic injury in this model. The lung injury is independent of hypovolemia.


Polymorphism in Brucella strains detected by studying distribution of two short repetitive DNA elements.
Thirty-four Brucella reference or field strains representing all the species and biovars were studied by repetitive element sequence-based PCR, a PCR using primers complementary to two enterobacterial short repetitive sequences: repetitive extragenic palindromic and enterobacterial repetitive intergenic consensus sequences. All the stains showed a positive amplification, suggesting that the Brucella genome contains such sequences. Repetitive extragenic palindromic PCR was less discriminating than enterobacterial repetitive intergenic consensus PCR in terms of distinguishing strains, but a combination of the two methods was able to distinguish all the isolates, except for some strains belonging to biovars 3 and 9 of Brucella abortus. Repetitive element sequence-based PCR appears to be a simple and useful method for the study of brucellosis epidemiology.


[Survey on the threshold for platelet transfusions].
We carried out a survey on platelet transfusions performed in nine general hospitals. We evaluated 303 adults who received a total of 24455 units over 1864 platelet transfusions. The underlying diseases were hematologic disorders with chemotherapy (59.7%), hematologic disorders without chemotherapy (15.5%), hematopoietic stem cell transplantation (18.5%), and others (2.0%). The patient platelet count before transfusion (platelet trigger value) was measured in only 77.1%. The platelet trigger value differed greatly between the hospitals, with an average of 2.2 x 10(4)/microl, a minimum of 1.3 x 10(4)/microl, and maximum of 3.2 x 10(4)/microl. Only 55.3% of the platelet transfusions carried out complied with the Platelet Transfusion Guideline published by the Ministry of Health, Labour and Welfare. The hospitals surveyed could be divided into those who gave mainly around 10 units and those who gave over 10 units. The total dose of platelets transfused was more in the hospitals that used mainly 15 or more unit-PCs than in the hospitals that used mainly 10 unit-PCs. These results indicate that platelet transfusion may be greatly reduced by complying with the 2 x 10(4)/microl of platelet transfusion threshold and by selecting less than 10 units of PC per transfusion.


A qualitative exploration of asthma self-management beliefs and practices in Puerto Rican families.
Puerto Rican children suffer higher asthma morbidity than children of any other racial/ethnic group in the U.S. This study was intended to describe asthma self-management behaviors in Puerto Rican youth. Key informant interviews (n=5) and focus groups (n=4) were conducted. Informants were community pediatricians and community-based organization employees. The focus groups included Puerto Rican parents of children with asthma, children with asthma in grades 4-8, and adolescents with asthma in grades 9-12 (32 participants total). Data were audio-recorded, transcribed, and translated. Two separate analysts performed theme extraction using naturalistic inquiry. Children were assuming asthma self-management responsibilities at very young ages. The adolescents felt they needed more parental assistance with their asthma. Asthma management techniques that involved manipulation of the environment or emotions were the most popular. Fear of asthma, need for more general education and smoking cessation resources, and community supports for asthma were discussed. These findings have important implications for future interventions.


Prevalence of Sickle Cell Trait and Reliability of Self-Reported Status among Expectant Parents in Nigeria: Implications for Targeted Newborn Screening.
Sickle cell disease (SCD) is a life-threatening, autosomal recessive blood disorder prevalent in sub-Saharan Africa. We identified the prevalence of sickle cell trait (SCT) among pregnant women and their male partners in Enugu State, Nigeria, and determined the accuracy of self-reported sickle cell status and its reliability for identifying high-risk newborns for targeted screening. We conducted a nested cohort study of expectant parents enrolled in the Healthy Beginning Initiative (HBI). The HBI is a cluster-randomized trial of a congregation-based approach designed to increase HIV testing. Participants completed a survey regarding self-awareness of their sickle cell genotype and consented to genotype screening by cellulose acetate electrophoresis. SCT prevalence (HbAS) was 22% (746/3,371). Only 50% of participants provided an accurate self-report. Self-report accuracy was significantly different (p < 0.0001) between individuals who reported having SCT or SCD (61% accuracy) versus those who reported not having SCT or SCD (86% accuracy). Demographic variables including gender, age, household size, employment, education, and home location were significantly associated with providing an accurate self-report. Low numbers of accurate parental self-reports, coupled with a high SCT prevalence in Nigeria, could limit the efficacy of targeted newborn screening. However, our data indicate that it is feasible to integrate sickle cell screening for pregnant women with existing, community-based health care programs developed by the President's Emergency Plan for AIDS Relief (PEPFAR), such as the HBI. Expanding screening programs could enable the development of targeted newborn screening based on maternal genotype that could identify all newborns with SCD in resource-limited settings.


Strongly interacting fermions and phases of the Casimir effect.
With the intent of exploring how the interplay between boundary effects and chiral symmetry breaking may alter the thermodynamical behavior of a system of strongly interacting fermions, we study the Casimir effect for the setup of two parallel layers using a four-fermion effective field theory at zero density. This system reveals a number of interesting features. While for infinitely large separation (no boundaries), chiral symmetry is broken or restored via a second order phase transition, in the opposite case of small (and, in general, finite) separation the transition becomes first order, rendering effects of finite size, for the present setup, similar to those of a chemical potential. Appropriately moving on the separation-temperature plane, it is possible to generate a peculiar behavior in the temperature dependence of the thermodynamic potential and of the condensate, compensating thermal with geometrical variations. A behavior similar to what we find here has been predicted to occur in bilayer graphene. Chiral symmetry breaking induces different phases (massless and massive) in the Casimir force separated by critical lines.


Polygenic threshold model with sex dimorphism in clubfoot inheritance: the Carter effect.
Idiopathic clubfoot is approximately twice as common in males than in females. The reason for this discrepancy is unclear but may represent an inherent difference in the susceptibility to the deformity. If this difference is due to genetic factors it is predicted that in order to inherit clubfoot, females need to have a greater number of susceptibility genes than males. Females would also be more likely to transmit the disease to their children and have siblings with clubfoot. This phenomenon is known as the Carter effect, and the presence of such an effect supports a multifactorial threshold model of inheritance. Ninety-seven multiplex families with more than one individual with idiopathic clubfoot were studied. The study included 1093 individuals: 291 with clubfoot and 802 unaffected relatives. Rates of transmission by the thirty-seven affected fathers and twenty-six affected mothers were calculated, and the prevalence among siblings was determined in the nuclear families of affected persons. Within these multiplex families, the prevalence of clubfoot was lowest in daughters of affected fathers (eight of twenty-four) and highest in sons of affected mothers (eleven of thirteen). Affected mothers transmitted clubfoot to 59% of their children (nineteen of thirty-two children), whereas affected fathers transmitted idiopathic clubfoot to 37% of their children (twenty-six of seventy children) (p = 0.04). Siblings of an affected female also had a significantly higher prevalence of clubfoot than siblings of an affected male (46% [fifty-four of 117] compared with 34% [sixty-seven of 197]; p = 0.03). This study demonstrates the presence of the Carter effect in idiopathic clubfoot. This effect can be explained by a polygenic inheritance of clubfoot, with females requiring a greater genetic load to be affected.


A genotyping study of human immunodeficiency virus type-1 drug resistance in a small Brazilian municipality.
In Brazil, surveillance studies on antiretroviral drug resistance among drug-naïve and treatment-experienced patients have focused primarily on patients living in large urban centers. As the epidemic spreads towards small municipalities and the innermost parts of the country, it will be essential to monitor the prevalence of antiretroviral drug resistance in these areas. We report the first survey on the prevalence of antiretroviral drug resistance in a small Brazilian municipality. Between July 1999 and March 2005, 72 adult human immunodeficiency virus type-1(HIV-1)-infected patients received care at the Municipal HIV/AIDS Program of the small, southeastern municipality of Miracema, state of Rio de Janeiro. A genotyping study of antiretroviral drug resistance was performed in 54 patients. Among 27 samples from treatment-experienced patients, 9 (33.3%) harbored strains with reduced drug susceptibility. Among these, 6 had reduced susceptibility to reverse transcriptase (RT) inhibitors and 3 to both RT and protease inhibitors. No primary antiretroviral drug resistance was recorded among 27 drug-naïve subjects. The relatively low prevalence of resistance mutations in the Miracema cohort argues against the concern that resource-poor settings should not implement widespread accessibility to standard of care antiretroviral combinations due to the possibility of sub-optimal adherence leading to the emergence and spread of drug-resistant strains.


Docetaxel in combination with doxorubicin and cyclophosphamide as adjuvant treatment for early node-positive breast cancer: a cost-effectiveness and cost-utility analysis.
To estimate the cost effectiveness of TAC (docetaxel, doxorubicin, and cyclophosphamide) compared with FAC (fluorouracil, doxorubicin, and cyclophosphamide) when administered as adjuvant therapy to women with node-positive early breast cancer in the United Kingdom (UK), both with and without primary prophylaxis with granulocyte colony-stimulating factor (G-CSF). A standard health economic Markov model estimated the cost and outcome for node-positive early breast cancer patients, from initiation of adjuvant chemotherapy to death. Patient-level data were used from the Breast Cancer International Research Group (BCIRG) 001 trial for estimates of the effect of chemotherapy on toxicity and outcome, and an observational data set collected from a UK university hospital provided estimates of resource use and outcome for patients with relapsed disease. Over a 10-year analysis timeframe, the incremental cost per life-year saved associated with the use of TAC rather than FAC was estimated as pound 15,418 (95% CI, pound 13,734 to pound 17,997) and the incremental cost per quality-adjusted life-year gained (IC/QALY) was pound 18,188 (95% CI, pound 14,161 to pound 32,422). The addition of primary G-CSF (lenograstim or filgrastim) to the TAC regimen resulted in an IC/QALY of pound 20,432. The results were most sensitive to the quality-of-life (QOL) score for patients in remission postchemotherapy. However, even if QOL was assumed to be as poor as for patients with metastatic disease, the IC/QALY estimate rose only to pound 32,430. The use of adjuvant TAC rather than FAC for node-positive early breast cancer patients is cost effective, despite the increased drug and toxicity treatment costs, and when primary G-CSF prophylaxis is given to all patients.


Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1).
In this study we report the cloning of four human OCT1 (hOCT1/SLC22A1) isoforms: a long form, hOCT1G/L554, and three shorter forms (hOCT1G/L506, hOCT1G483 and hOCT1G353). All four variants could be identified in the human glioma cell line SK-MG-1, whereas only two isoforms (hOCT1G/L554 and hOCT1G/L506) were found in human liver cDNA. The hOCT1G/L554 represents the full length hOCT1 since the sequence of this clone is more than 99% identical to previously cloned hOCT1 cDNAs. Elucidation of the gene structure of human OCT1 demonstrated that the other isolated isoforms are alternatively spliced variants. The hOCT1 gene consists of 7 exons and 6 introns. When stably expressed in human embryonic kidney (HEK293) cells, only the full length hOCT1 cDNA mediated decynium-22 (D22)-sensitive uptake of tritiated 1-methyl-4-phenylpyridinium ([3H]-MPP+).


Neuroplasticity and Clinical Practice: Building Brain Power for Health.
The focus of this review is on driving neuroplasticity in a positive direction using evidence-based interventions that also have the potential to improve general health. One goal is to provide an overview of the many ways new neuroscience can inform treatment protocols to empower and motivate clients to make the lifestyle choices that could help build brain power and could increase adherence to healthy lifestyle changes that have also been associated with simultaneously enhancing vigorous longevity, health, happiness, and wellness. Another goal is to explore the use of a focus in clinical practice on helping clients appreciate this new evidence and use evolving neuroscience in establishing individualized goals, designing strategies for achieving them and increasing treatment compliance. The timing is urgent for such interventions with goals of enhancing brain health across the lifespan and improving statistics on dementia worldwide.


Expression and Ion Transport Activity of Rice OsHKT1;1 Variants.
OsHKT1;1 in rice, belongs to the high-affinity K+ Transporter family, has been found to be involved in salt tolerance. OsHKT1;1 in japonica rice (Nipponbare) produces mRNA variants, but their functions remain elusive. In salt tolerant rice, Pokkali, eight OsHKT1;1 variants (V1-V8) were identified in addition to the full-length OsHKT1;1 (FL) cDNA. Absolute quantification by qPCR revealed that accumulation of OsHKT1;1-FL mRNA is minor in contrast to that of OsHKT1;1-V1, -V2, -V4, and -V7 mRNAs, all of which are predominant in shoots, while only V1 and V7 mRNAs are predominant in roots. Two electrode voltage clamp (TEVC) experiments using Xenopus laevis oocytes revealed that oocytes-expressing OsHKT1;1-FL from Pokkali exhibited inward-rectified currents in the presence of 96 mM Na+ as reported previously. Further TEVC analyses indicated that six of eight OsHKT1;1 variants elicited currents in a Na+ or a K+ bath solution. OsHKT1;1-V6 exhibited a similar inward rectification to the FL protein. Contrastingly, however, the rests mediated bidirectional currents in both Na+ and K+ bath solutions. These data suggest possibilities that novel mechanisms regulating the transport activity of OsHKT1;1 might exist, and that OsHKT1;1 variants might also carry out distinct physiological roles either independently or in combination with OsHKT1;1-FL.


Mechanical stress is communicated between different cell types to elicit matrix remodeling.
Tissue remodeling often reflects alterations in local mechanical conditions and manifests as an integrated response among the different cell types that share, and thus cooperatively manage, an extracellular matrix. Here we examine how two different cell types, one that undergoes the stress and the other that primarily remodels the matrix, might communicate a mechanical stress by using airway cells as a representative in vitro system. Normal stress is imposed on bronchial epithelial cells in the presence of unstimulated lung fibroblasts. We show that (i) mechanical stress can be communicated from stressed to unstressed cells to elicit a remodeling response, and (ii) the integrated response of two cell types to mechanical stress mimics key features of airway remodeling seen in asthma: namely, an increase in production of fibronectin, collagen types III and V, and matrix metalloproteinase type 9 (MMP-9) (relative to tissue inhibitor of metalloproteinase-1, TIMP-1). These observations provide a paradigm to use in understanding the management of mechanical forces on the tissue level.


In-house-made capillary electrophoresis instruments coupled with contactless conductivity detection as a simple and inexpensive solution for water analysis: a case study in Vietnam.
A simple and inexpensive method for the determination of various ionic species in different water matrices is discussed in this study. The approach is based on the employment of in-house-made capillary electrophoresis (CE) instruments with capacitively coupled contactless conductivity detection (C(4)D), which can be realized even when only a modest financial budget and limited expertise are available. Advantageous features and considerations of these instruments are detailed following their pilot deployment in Vietnam. Different categories of ionic species, namely major inorganic cations (K(+), Na(+), Ca(2+), Mg(2+), and NH4(+)) and major inorganic anions (Cl(-), NO3(-), NO2(-), SO4(2-), and phosphate), in different water matrices in Vietnam were determined using these in-house fabricated instruments. Inorganic trivalent arsenic (As(iii)), which is the most abundant form of arsenic in reducing groundwater, was determined by CE-C(4)D. The effect of some interfering ions in groundwater on the analytical performance was investigated and is highlighted. The results from in-house-made CE-C(4)D-instruments were cross-checked with those obtained using the standard methods (AAS, AES, UV and IC), with correlation coefficients r(2) ≥ 0.9 and deviations from the referenced results less than 15%.


Erythropoietin in amyotrophic lateral sclerosis: a pilot, randomized, double-blind, placebo-controlled study of safety and tolerability.
Preclinical studies demonstrated that erythropoietin is neuroprotective in different models of peripheral and central nervous system diseases. We investigated safety and tolerability of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). We performed a phase II double-blind, randomized, placebo-controlled study. After screening, 23 patients were randomly assigned to rhEPO or placebo arm. Patients were examined during a six-month lead-in period, and then they received fortnightly either 40,000 units of rhEPO or placebo for 24 months. Primary outcomes were adverse events, safety, and death or tracheotomy. Treatment was safe and well tolerated. One patient in the rhEPO arm dropped out for a superficial phlebitis. Median values of haematocrit, haemoglobin, red cells, and reticulocytes were non-significantly higher in rhEPO than placebo arm. Haemoglobin did not increase >1 g/dl between subsequent doses. Anti-rhEPO antibodies were not detected. Survival and slope of ALSFRS-R curves did not significantly differ between treatment groups. RhEPO treatment was safe and well tolerated in ALS patients. Our results suggest that larger studies are warranted to confirm safety of treatment and to investigate different dose schedule and efficacy.


Hematological and molecular response evaluation of CML patients on imatinib.
The BCR-ABL tyrosine kinase is a well-validated therapeutic target in Chronic Myeloid Leukemia (CML). Imatinib mesylate (formerly STI-571), a tyrosine kinase inhibitor is highly effective at the hematological, cytogenetic and molecular level in CML. To evaluate hematological and molecular response in CML patients on Imatinib and also the side effects of the therapy if any. Sixteen patients were diagnosed as having chronic phase CML at Kasturba Medical College Hospital, Attavar, Mangalore during the period of two years from January 2004 to January 2006 and were given Imatinib at 400 mg/day orally. They were followed closely over a period of 1 year using the following parameters: (1) monthly clinical examination, (2) monthly peripheral blood smear examination, (3) real time reverse transcriptase quantitative polymerase chain reaction (RT Q-PCR) for BCR-ABL at the end of every 6 months. The findings were evaluated after one year for hematological and molecular response achieved. Fifteen (93.75%) patients achieved complete hematological response within three months of therapy. Six (37.5%) patients achieved complete molecular response(CMR) within six months of therapy as measured by real time RT Q-PCR. None of the patients who did not achieve CMR within first six months of therapy achieved it after one year of therapy. No patient lost the initial response. The median BCR--ABL/ABL value at the end of the six months was 11% and at the end of the one year was 3.38%. Imatinib mesylate is highly effective in the treatment of chronic phase CML and so should be considered as the drug of first choice in CML. Molecular response evaluation after six months can predict the subsequent molecular response and can also be usedas a surrogate monitor of the marrow cytogenetic response to imatinib therapy in CML.


GLP-1 amidation efficiency along the length of the intestine in mice, rats and pigs and in GLP-1 secreting cell lines.
XXX: Measurements of plasma concentrations of the incretin hormone GLP-1 are complex because of extensive molecular heterogeneity. This is partly due to a varying and incompletely known degree of C-terminal amidation. Given that virtually all GLP-1 assays rely on a C-terminal antibody, it is essential to know whether or not the molecule one wants to measure is amidated. We performed a detailed analysis of extractable GLP-1 from duodenum, proximal jejunum, distal ileum, caecum, proximal colon and distal colon of mice (n=9), rats (n=9) and pigs (n=8) and determined the degree of amidation and whether this varied with the six different locations. We also analyzed the amidation in 3 GLP-1 secreting cell lines (GLUTag, NCI-H716 and STC-1). To our surprise there were marked differences between the 3 species with respect to the concentration of GLP-1 in gut. In the mouse, concentrations increased continuously along the intestine all the way to the rectum, but were highest in the distal ileum and proximal colon of the rat. In the pig, very little or no GLP-1 was present before the distal ileum with similar levels from ileum to distal colon. In the mouse, GLP-1 was extensively amidated at all sampling sites, whereas rats and pigs on average had around 2.5 and 4 times higher levels of amidated compared to non-amidated GLP-1, although the ratio varied depending upon the location. GLUTag, NCI-H716 and STC-1 cells all exhibited partial amidation with 2-4 times higher levels of amidated compared to non-amidated GLP-1.


Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective.
Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.


Executive n-back tasks for the neuropsychological assessment of working memory.
Working memory (WM) has been defined as a cerebral function which allows us to maintain and manipulate information "online". One of the most widely used paradigms to assess WM is the n-back test. Despite its extensive application, some authors have questioned its capacity to assess the manipulation of WM load. The present study introduces a new version of the n-back test to carry out this assessment. We use functional near-infrared spectroscopy (fNIRS) to evaluate prefrontal cortex (PFC) activation. The modified n-back requires monitoring of sequentially presented stimuli (in this case the days of the week). The target response relates to a stimulus which appears previously, from 0 to 2 items back, on the computer screen. Our data reveals that while modified and unmodified n-back activate the same regions of the left PFC, our modified 2-back version shows significantly higher activation in the left dorsolateral PFC (DLPFC) and the left frontal opercula. These results suggest that increased complexity in verbal WM tasks entail greater executive control, which would lead to an increase in cerebral blood flow to the areas associated with verbal WM. Therefore, an increase in the manipulation of WM load in verbal tasks reflects greater physiological activity in the left DLPFC and the left frontal opercula. The modified n-back test may also be incorporated into the armamentarium of valid instruments for the neuropsychological assessment of the maintenance and manipulation of verbal information in tasks requiring working memory.


Active tactile exploration using a brain-machine-brain interface.
Brain-machine interfaces use neuronal activity recorded from the brain to establish direct communication with external actuators, such as prosthetic arms. It is hoped that brain-machine interfaces can be used to restore the normal sensorimotor functions of the limbs, but so far they have lacked tactile sensation. Here we report the operation of a brain-machine-brain interface (BMBI) that both controls the exploratory reaching movements of an actuator and allows signalling of artificial tactile feedback through intracortical microstimulation (ICMS) of the primary somatosensory cortex. Monkeys performed an active exploration task in which an actuator (a computer cursor or a virtual-reality arm) was moved using a BMBI that derived motor commands from neuronal ensemble activity recorded in the primary motor cortex. ICMS feedback occurred whenever the actuator touched virtual objects. Temporal patterns of ICMS encoded the artificial tactile properties of each object. Neuronal recordings and ICMS epochs were temporally multiplexed to avoid interference. Two monkeys operated this BMBI to search for and distinguish one of three visually identical objects, using the virtual-reality arm to identify the unique artificial texture associated with each. These results suggest that clinical motor neuroprostheses might benefit from the addition of ICMS feedback to generate artificial somatic perceptions associated with mechanical, robotic or even virtual prostheses.


Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage.
Rebleeding is an important cause of death and disability in people with aneurysmal subarachnoid haemorrhage. Rebleeding is probably related to dissolution of the blood clot at the site of aneurysm rupture by natural fibrinolytic activity. This review is an update of a previously published Cochrane review. To assess the effects of antifibrinolytic treatment in people with aneurysmal subarachnoid haemorrhage. We searched the Cochrane Stroke Group Trials Register (February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1948 to December 2012), and EMBASE (1947 to December 2012). In an effort to identify further published, unpublished, and ongoing studies we searched reference lists and trial registers, performed forward tracking of relevant references and contacted drug companies. Randomised trials comparing oral or intravenous antifibrinolytic drugs (tranexamic acid, epsilon amino-caproic acid, or an equivalent) with control in people with subarachnoid haemorrhage of suspected or proven aneurysmal cause. Two review authors independently selected trials for inclusion and extracted the data. Three review authors assessed trial quality. For the primary outcome we converted the outcome scales between good and poor outcome for the analysis. We scored death from any cause and rates of rebleeding, cerebral ischaemia, and hydrocephalus per treatment group. We expressed effects as risk ratios (RR) with 95% confidence intervals (CI). We used random-effects models for all analyses. We included 10 trials involving 1904 participants. The risk of bias was low in six studies. Four studies were open label and were rated as high risk of performance bias. One of these studies was also rated as high risk for attrition bias. Four trials reported on poor outcome (death, vegetative state, or severe disability) with a pooled risk ratio (RR) of 1.02 (95% confidence interval (CI) 0.91 to 1.15). All trials reported on death from all causes with a pooled RR of 1.00 (95% CI 0.85 to 1.18). In a trial that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for cerebral ischaemia the RR for poor outcome was 0.85 (95% CI 0.64 to 1.14). Antifibrinolytic treatment reduced the risk of re-bleeding reported at the end of follow-up (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 participants), but there was heterogeneity (I² = 62%) between the trials. The pooled RR for reported cerebral ischaemia was 1.41 (95% CI 1.04 to 1.91, 83 per 1000 participants), again with heterogeneity between the trials (I² = 52%). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus in five trials (RR 1.11, 95% CI 0.90 to 1.36). The current evidence does not support the use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage, even in those who have concomitant treatment strategies to prevent cerebral ischaemia. Results on short-term treatment are promising, but not conclusive. Further randomised trials evaluating short-term antifibrinolytic treatment are needed to evaluate its effectiveness.


Molecular Basis for the Recognition of HIV Nef138-8 Epitope by a Pair of Human Public T Cell Receptors.
Cross-recognized public TCRs against HIV epitopes have been proposed to be important for the control of AIDS disease progression and HIV variants. The overlapping Nef138-8 and Nef138-10 peptides from the HIV Nef protein are HLA-A24-restricted immunodominant T cell epitopes, and an HIV mutant strain with a Y139F substitution in Nef protein can result in immune escape and is widespread in Japan. Here, we identified a pair of public TCRs specific to the HLA-A24-restricted Nef-138-8 epitope using PBMCs from White and Japanese patients, respectively, namely TD08 and H25-11. The gene use of the variable domain for TD08 and H25-11 is TRAV8-3, TRAJ10 for the α-chain and TRBV7-9, TRBD1*01, TRBJ2-5 for the β-chain. Both TCRs can recognize wild-type and Y2F-mutated Nef138-8 epitopes. We further determined three complex structures, including TD08/HLA-A24-Nef138-8, H25-11/HLA-A24-Nef138-8, and TD08/HLA-A24-Nef138-8 (2F). Then, we revealed the molecular basis of the public TCR binding to the peptide HLA, which mostly relies on the interaction between the TCR and HLA and can tolerate the mutation in the Nef138-8 peptide. These findings promote the molecular understanding of T cell immunity against HIV epitopes and provide an important basis for the engineering of TCRs to develop T cell-based immunotherapy against HIV infection.


Endoscopic ultrasound in pediatric population: a comprehensive review of the literature.
Endoscopic ultrasonography (EUS) with or without fine needle aspiration/biopsy (FNA/B) is a well-established diagnostic tool in adults for the evaluation and management of gastrointestinal (GI) tract disorders. Its use in children is still limited as well as literature in pediatric age is limited, although the application of EUS is now increasing. The present article aims to review the current literature about EUS indication, accuracy and safety in pediatric age. Electronic literature searches were conducted using Pubmed, Medline, Embase, and the Cochrane Central Register of Controlled Trials using the word pediatric endoscopic ultrasound, pediatric pancreaticobiliary AND/OR EUS, pediatric EUS technique. Main patients and procedures characteristics were analyzed. The primary endpoint was the indication of EUS. Secondary endpoints were the accuracy of the technique and the incidence of complications. Data were extracted from 19 articles. A total of 571 patients were investigated, with a median age of 12,7 years. A total of 634 EUS procedures were performed. The majority of EUS procedures investigated the pancreaticobiliary tract (77,7%). Most studies showed a high positive impact on management with a median value of 81,7%. No major complications were reported. Five studies reported minor complications with a median value of 2%. EUS is safe and has a significant role in the diagnosis of pancreaticobiliary and GI diseases even in children, with a high therapeutic success. An increasing EUS utilization by pediatric gastroenterologists is expected and offering dedicated EUS training to some selected pediatric gastroenterologists might be indicated.


Fast evolution of image manifolds and application to filtering and segmentation in 3D medical images.
In many instances, numerical integration of space-scale PDEs is the most time consuming operation of image processing. This is because the scale step is limited by conditional stability of explicit schemes. In this work, we introduce the unconditionally stable semi-implicit linearized difference scheme that is fashioned after additive operator split (AOS) [1], [2] for Beltrami and the subjective surface computation. The Beltrami flow [3], [4], [5] is one of the most effective denoising algorithms in image processing. For gray-level images, we show that the flow equation can be arranged in an advection-diffusion form, revealing the edge-enhancing properties of this flow. This also suggests the application of AOS method for faster convergence. The subjective surface [6] deals with constructing a perceptually meaningful interpretation from partial image data by mimicking the human visual system. However, initialization of the surface is critical for the final result and its main drawbacks are very slow convergence and the huge number of iterations required. In this paper, we first show that the governing equation for the subjective surface flow can be rearranged in an AOS implementation, providing a near real-time solution to the shape completion problem in 2D and 3D. Then, we devise a new initialization paradigm where we first "condition" the viewpoint surface using the Fast-Marching algorithm. We compare the original method with our new algorithm on several examples of real 3D medical images, thus revealing the improvement achieved.


Randomized controlled trial of motivational interviewing for reducing injection risk behaviours among people who inject drugs.
We tested the efficacy of a brief intervention based on motivational interviewing (MI) to reduce high-risk injection behaviours over a 6-month period among people who inject drugs (PWID). A single-site two-group parallel randomized controlled trial comparing MI with a brief educational intervention (EI). A study office located in downtown Montréal, Canada, close to the community-based harm reduction programmes where PWID were recruited. PWID who had shared drug injection equipment or shared drugs by backloading or frontloading in the month prior to recruitment were randomized to either the MI (112) or EI (109) groups. The MI aimed to (1) encourage PWID to voice their desires, needs and reasons to change behaviours; (2) boost motivation to change behaviours; and (3) when the person was ready, support the plan he or she chose to reduce injection risk behaviours. The EI consisted of an individual session about safe injection behaviours. The primary outcome was defined as having any of these risk behaviours at 6 months: having shared syringes, containers, filters or water to inject drugs in the previous month and backloading/frontloading; each behaviour was examined separately, as secondary outcomes. The probability of reporting a risk injection behaviour decreased in both the MI and the EI groups. At 6-month follow-up, participants who reported any risk behaviours were 50% [odds ratio (OR) = 0.50; confidence interval (CI) = 0.13-0.87] less likely to be in the MI group than in the EI group as well as those who reported sharing containers (OR = 0.50; CI = 0.09-0.90). PWID who reported sharing equipment excluding syringes were 53% less likely to be in the MI group (OR = 0.47; CI = 0.11-0.84). A brief motivational interviewing intervention was more effective than a brief educational intervention in reducing some high risk injecting behaviours up in the subsequent 6 months.


Localization of sucrose synthase in developing seed and siliques of Arabidopsis thaliana reveals diverse roles for SUS during development.
This study investigated the roles of sucrose synthase (SUS) in developing seeds and siliques of Arabidopsis thaliana. Enzyme activity assays showed that SUS activity was highest in developing whole siliques and young rosette leaves compared with other tissues including mature leaves, stems, and flowers. Surprisingly, quantitative PCR analyses revealed little correlation between SUS activity and transcript expression, which indicated the importance of examining the role of SUS at the protein level. Therefore, immunolocalization was performed over a developmental time course to determine the previously unreported cellular localization of SUS in Arabidopsis seed and silique tissues. At 3 d and 10 d after flowering (daf), SUS protein localized to the silique wall, seed coat, funiculus, and endosperm. By 13 daf, SUS protein was detected in the embryo and aleurone layer, but was absent from the seed coat and funiculus. Starch grains were also present in the seed coat at 3 and 10 daf, but were absent at 13 daf. Co-localization of SUS protein and starch grains in the seed coat at 3 and 10 daf indicates that SUS may be involved in temporary starch deposition during the early stages of seed development, whilst in the later stages SUS metabolizes sucrose in the embryo and cotyledon. Within the silique wall, SUS localized specifically to the companion cells, indicating that SUS activity may be required to provide energy for phloem transport activities in the silique wall. The results highlight the diverse roles that SUS may play during the development of silique and seed in Arabidopsis.


Multisystemic inflammatory syndrome in children associated with COVID-19: a single center experience in Turkey.
Multisystem inflammatory syndrome in children (MIS-C) associated with the coronavirus disease 2019 (COVID-19) is a new concern emerging as a severe presentation of COVID-19 in children. We aimed to describe the characteristics and short-term outcomes of children diagnosed with MIS-C. A retrospective study was conducted on 24 patients who were diagnosed with MIS-C between June 1, 2020 and December 1, 2020. A total of 24 (14 male and 10 female) patients were included in the study. The median age at the diagnosis was 111 (10-180) months. A total of 17 patients had a history of contact with a patient with COVID-19. Among the 24 patients, the most common findings were gastrointestinal involvement (n=20), followed by conjunctivitis (n=12), erythematous rash (n=11), and oral changes (n=10). Cardiovascular involvement was detected in 12 patients, of whom six had systolic dysfunction, four had mild coronary artery involvement, four had pericardial effusion, and three had mitral insufficiency. All patients received intravenous immunoglobulin, and 14 patients were treated with methylprednisolone in addition. Anti-interleukin-1 was given to two patients. The median duration of hospitalization was 8 (5-15) days. A total of 23 patients were discharged and evaluated on the median of 68.5 (52-140) days after discharge. The remaining one patient with dilated cardiomyopathy died after 2 months in the intensive care unit. Increasing the knowledge on MIS-C will provide clinicians with information on early recognition, evaluation, and management of these patients.


The Effect of Short- and Long-Term Aerobic Training Years on Systemic O2 Utilization, and Muscle and Prefrontal Cortex Tissue Oxygen Extraction in Young Women.
Buzza, G, Lovell, GP, Askew, CD, and Solomon, C. The effect of short- and long-term aerobic training years on systemic O2 utilization, and muscle and prefrontal cortex tissue oxygen extraction in young women. J Strength Cond Res 33(8): 2128-2137, 2019-This study aimed to determine if systemic O2 utilization (VO2) and tissue oxygen extraction (deoxyhemoglobin [HHb]) in the vastus lateralis (VL), gastrocnemius (GAST), and prefrontal cortex were different during exercise between short-term trained (STT, 6-24 months) and long-term trained (LTT, >5 years) young women while controlling for current training load. Thirteen STT and 13 LTT participants completed ramp incremental (RI) and square-wave constant load (SWCL) tests on a cycle ergometer. In LTT compared with STT: (a) VO2 was higher during the RI (p = 0.024) and SWCL (p = 0.001) tests; (b) HHb in the VL (p = 0.044) and GAST (p = 0.027) was higher in the RI test; and (c) there were significant group × intensity interactions for VO2 in the SWCL test. The additional years of aerobic training in LTT compared with STT (LTT 7.1 ± 1.9 vs. STT 1.5 ± 0.4 years) resulted in higher VO2 and HHb in the VL and GAST. These results indicate that in young women, independent of current training load, systemic VO2 and peripheral muscle O2 extraction during exercise continues to increase beyond 24 months of aerobic training.


Food for Thought: Opportunities to Improve Diversity, Inclusion, Representation, and Participation in Epidemiology.
DeVilbiss et al. (Am J Epidemiol. 2020;189(10):998-1010) have taken on the noble and worthy cause of improving diversity, inclusion, representation, and participation across the Society for Epidemiologic Research (SER) membership-a reflection/microcosm of society. The objective of this commentary is to underscore the importance of diversity and to offer initiative ideas, which should be centered around inequity stemming from the widespread historical and contemporary maldistribution of power (e.g., decision-making) and resources (e.g., funding) within institutions and organizations. Nonexhaustive strategies could include SER becoming an opportunity and information hub that helps to fill resource gaps. It is also recommended that SER leadership learn from existing associations and scientific initiatives to improve the culture of science in general by equitably incorporating policy, systems, and environmental interventions throughout the career spectrum. Examples include the provision of tools and incentives to address explicit or implicit biases, enhance mentoring skills, and remove predictable barriers (e.g., financial). Explicitly labeling diversity/inclusion efforts should be avoided, and the initiative should be evaluated based on impact rather than intent. Our fates are interconnected, and we can all help increase diversity, inclusion, representation, and participation to improve our science in hopes of equitably improving public health.


Structural and functional evidence that lipoprotein LpqN supports cell envelope biogenesis in Mycobacterium tuberculosis.
The mycobacterial cell envelope is crucial to host-pathogen interactions as a barrier against antibiotics and the host immune response. In addition, cell envelope lipids are mycobacterial virulence factors. Cell envelope lipid biosynthesis is the target of a number of frontline tuberculosis treatments and has been the focus of much research. However, the transport mechanisms by which these lipids reach the mycomembrane remain poorly understood. Many envelope lipids are exported from the cytoplasm to the periplasmic space via the mycobacterial membrane protein large (MmpL) family of proteins. In other bacteria, lipoproteins can contribute to outer membrane biogenesis through direct binding of substrates and/or protein-protein associations with extracytoplasmic biosynthetic enzymes. In this report, we investigate whether the lipoprotein LpqN plays a similar role in mycobacteria. Using a genetic two-hybrid approach, we demonstrate that LpqN interacts with periplasmic loop domains of the MmpL3 and MmpL11 transporters that export mycolic acid-containing cell envelope lipids. We observe that LpqN also interacts with secreted cell envelope biosynthetic enzymes such as Ag85A via pulldown assays. The X-ray crystal structures of LpqN and LpqN bound to dodecyl-trehalose suggest that LpqN directly binds trehalose monomycolate, the MmpL3 and Ag85A substrate. Finally, we observe altered lipid profiles of the ΔlpqN mutant during biofilm maturation, pointing toward a possible physiological role for the protein. The results of this study suggest that LpqN may act as a membrane fusion protein, connecting MmpL transporters with periplasmic proteins, and provide general insight into the role of lipoproteins in Mycobacterium tuberculosis cell envelope biogenesis.


Postcranial morphology of the middle Pleistocene humans from Sima de los Huesos, Spain.
Current knowledge of the evolution of the postcranial skeleton in the genus Homo is hampered by a geographically and chronologically scattered fossil record. Here we present a complete characterization of the postcranium of the middle Pleistocene paleodeme from the Sima de los Huesos (SH) and its paleobiological implications. The SH hominins show the following: (i) wide bodies, a plesiomorphic character in the genus Homo inherited from their early hominin ancestors; (ii) statures that can be found in modern human middle-latitude populations that first appeared 1.6-1.5 Mya; and (iii) large femoral heads in some individuals, a trait that first appeared during the middle Pleistocene in Africa and Europe. The intrapopulational size variation in SH shows that the level of dimorphism was similar to modern humans (MH), but the SH hominins were less encephalized than Neandertals. SH shares many postcranial anatomical features with Neandertals. Although most of these features appear to be either plesiomorphic retentions or are of uncertain phylogenetic polarity, a few represent Neandertal apomorphies. Nevertheless, the full suite of Neandertal-derived features is not yet present in the SH population. The postcranial evidence is consistent with the hypothesis based on the cranial morphology that the SH hominins are a sister group to the later Neandertals. Comparison of the SH postcranial skeleton to other hominins suggests that the evolution of the postcranium occurred in a mosaic mode, both at a general and at a detailed level.


An empirical data comparison of regulatory agency and malpractice legal problems for psychiatrists.
Our objective is to compare legal difficulties that psychiatrists encounter in regulatory agency and malpractice (insurance) settings. Data sources included a literature search of malpractice and medical board discipline from 1990 to 2009 (rates and types of discipline); publicly available insurance data (malpractice frequency and type); and data from the National Practitioner Data Bank (NPDB) (required reports of malpractice settlements and hospital discipline). Medical board discipline findings indicate that psychiatrists are at increased risk of disciplinary action compared with other specialties. NPDB data indicated relatively infrequent problems for psychiatrists. In malpractice, psychiatry accounted for a small percentage of overall claims and settlements. Overall, more years in practice and a lack of board certification increased the risk of legal difficulties. There are shared and separate risk factors in the malpractice and regulatory agency areas, but there is evidence that these 2 legal areas are distinct from each other.


Antenatal Assessment of the Prognosis of Congenital Diaphragmatic Hernia: Ethical Considerations and Impact for the Management.
Congenital diaphragmatic hernia (CDH) is associated with abnormal pulmonary development, which is responsible for pulmonary hypoplasia with structural and functional abnormalities in pulmonary circulation, leading to the failure of the cardiorespiratory adaptation at birth. Despite improvement in treatment options and advances in neonatal care, mortality remains high, at close to 15 to 30%. Several risk factors of mortality and morbidities have been validated in fetuses with CDH. Antenatal assessment of lung volume is a reliable way to predict the severity of CDH. The two most commonly used measurements are the observed/expected lung to head ratio (LHRo/e) and the total pulmonary volume (TPV) on MRI. The estimation of total pulmonary volume (TPVo/e) by means of prenatal MRI remains the gold standard. In addition to LHR and TPV measurements, the position of the liver (up, in the thorax or down, in the abdomen) also plays a role in the prognostic evaluation. This prenatal prognostic evaluation can be used to select fetuses for antenatal surgery, consisting of fetoscopic endoluminal tracheal occlusion (FETO). The antenatal criteria of severe CDH with an ascended liver (LHRo/e or TPVo/e < 25%) are undoubtedly associated with a high risk of death or significant morbidity. However, despite the possibility of estimating the risk in antenatal care, it is difficult to determine what is in the child's best interest, as there still are many uncertainties: (1) uncertainty about individual short-term prognosis; (2) uncertainty about long-term prognosis; and (3) uncertainty about the subsequent quality of life, especially when it is known that, with a similar degree of disability, a child's quality of life varies from poor to good depending on multiple factors, including family support. Nevertheless, as the LHR decreases, the foreseeable "burden" becomes increasingly significant, and the expected benefit is increasingly unlikely. The legal and moral principle of the proportionality of medical procedures, as well as the prohibition of "unreasonable obstinacy" in all investigations or treatments undertaken, is necessary in these situations. However, the scientific and rational basis for assessing the long-term individual prognosis is limited to statistical data that do not adequately reflect individual risk. The risk of self-fulfilling prophecies should be kept in mind. The information given to parents must take this uncertainty into account when deciding on the treatment plan after birth.


The effects of polyphenols and other bioactives on human health.
Although deficiencies in polyphenol intake do not result in specific deficiency diseases, adequate intake of polyphenols could confer health benefits, especially with regard to chronic diseases. Tea, cocoa, fruits, and berries, as well as vegetables, are rich in polyphenols. Flavan-3-ols from cocoa have been found to be associated with a reduced risk of stroke, myocardial infarction, and diabetes, as well as improvements in lipids, endothelial-dependent blood flow and blood pressure, insulin resistance, and systemic inflammation. The flavonoid quercetin and the stilbene resveratrol have also been associated with cardiometabolic health. Although polyphenols have been associated with improved cerebral blood flow, evidence of an impact on cognition is more limited. The ability of dietary polyphenols to produce clinical effects may be due, at least in part, to a bi-directional relationship with the gut microbiota. Polyphenols can impact the composition of the gut microbiota (which are independently associated with health benefits), and gut bacteria metabolize polyphenols into bioactive compounds that produce clinical benefits. Another critical interaction is that of polyphenols with other phytochemicals, which could be relevant to interpreting the health parameter effects of polyphenols assayed as purified extracts, whole foods, or whole food extracts.


Cancer immunotherapy μ-environment LabChip: taking advantage of optoelectronic tweezers.
A cancer immunotherapy μ-environment LabChip, equipped with titanium oxide phthalocyanine (TiOPc)-based optoelectronic tweezers (OET) to achieve direct cell-cell contact, can be used to study the interaction between immune cells and other cells for real-time analysis of NK cells' behavior. In microfluidic devices, it is difficult to solve dead zone problems and observe dynamic cell-cell interactions. We have created a stable and static culture μ-environment which can enhance NK cell activities. In addition, OET is used to solve dead zone problems by manipulating a single cell into four-leaf-clover-shaped (FLCS) microwells made of poly(ethylene glycol) diacrylate (PEG-DA) through optofluidic maskless lithography, causing direct cell-cell contact. Our design reconstructed an in vitro human immune system for the study of dynamic immunological response. When the NK cells came into contact with the target cells in the μ-environment LabChip, we observed that the target cells showed apoptotic characteristics (i.e. cell shrinkage and blebbing within 2 h and then die within 3 h). In addition, our μ-environment LabChip demonstrated higher NK cell activity compared with conventional analysis. We have created an innovative cancer immunotherapy μ-environment LabChip to provide a stable and static μ-environment for cell-cell interaction study. Furthermore, our μ-environment LabChip showed the potential to enhance NK cell activity and to study immunological interactions between immune cells and cancer cells dynamically.


Biological effectiveness of isolated short electron tracks: V79-4 cell inactivation following low dose-rate irradiation with Al(K) ultrasoft X-rays.
To investigate the biological effect of single, isolated, short electron tracks (<70 nm) relevant to practical human exposures to low-linear energy transfer radiation. An irradiation rig was constructed that allowed environmentally controlled, protracted irradiations with an individually prescribed dose to up to 20 samples over a period of days. Inactivation of V79-4 mammalian cells by Al(K) ultrasoft X-rays was studied at high and low dose-rates with a maximum exposure time of 42 h. A significant increase in clonogenic survival was observed at the higher doses when the exposure time was increased from <6 min to 21 h, with no further increase observed for 42-h exposures. Despite the short range of the low-energy electrons produced (<70 nm), significant cell inactivation was observed for these low dose-rate exposures. The results are consistent with the hypothesis that even individual tracks can be biologically effective.


Ex Vivo Renal Stone Characterization with Single-Source Dual-Energy Computed Tomography: A Multiparametric Approach.
We aimed to investigate a multiparametric approach using single-source dual-energy computed tomography (ssDECT) for the characterization of renal stones. ssDECT scans were performed at 80 and 140 kVp on 32 ex vivo kidney stones of 3-10 mm in a phantom. True composition was determined by infrared spectroscopy to be uric acid (UA; n = 14), struvite (n = 7), cystine (n = 7), or calcium oxalate monohydrate (n = 4). Measurements were obtained for up to 52 variables, including mean density at 11 monochromatic keV levels, effective Z, and multiple material basis pairs. The data were analyzed with five multiparametric algorithms. After omitting 8 stones smaller than 5 mm, the remaining 24-stone dataset was similarly analyzed. Both stone datasets were also analyzed with a subset of 14 commonly used variables in the same fashion. For the 32-stone dataset, the best method for distinguishing UA from non-UA stones was 97% accurate, and for distinguishing the non-UA subtypes was 72% accurate. For the 24-stone dataset, the best method for distinguishing UA from non-UA stones was 100% accurate, and for distinguishing the non-UA subtypes was 75% accurate. Multiparametric ssDECT methods can distinguish UA from non-UA stones of 5 mm or larger with 100% accuracy. The best model to distinguish the non-UA renal stone subtypes was 75% accurate. Further refinement of this multiparametric approach may increase the diagnostic accuracy of separating non-UA subtypes and assist in the development of a clinical paradigm for in vivo use.


A 100-Year Review: Regulation of nutrient partitioning to support lactation.
We have seen remarkable advances in animal productivity in the last 75 years, with annual milk yield per cow increasing over 4-fold and no evidence of nearing a plateau. Because of these gains in productive efficiency, there have been dramatic reductions in resource inputs and the carbon footprint per unit of milk produced. The primary source for the historic gains relates to animal variation in nutrient partitioning. The regulation of nutrient use for productive functions has the overall goal of maintaining the cow's well-being regardless of the physiological or environmental challenges. From a conceptual standpoint, it involves both acute homeostatic controls operating on a minute-by-minute basis and chronic homeorhetic controls operating on a long-term basis to provide orchestrated adaptations that coordinate tissues and body processes. This endocrine regulation is mediated by changes in circulating anabolic and catabolic hormones, hormone membrane receptors and intracellular signaling pathways. The coordination of tissues and physiological systems includes a plethora of hormones, but insulin and somatotropin are 2 key regulators of nutrient trafficking. Herein, we review the advances in our understanding of both conceptual and actual regulation of nutrient partitioning in support of milk synthesis and identify examples of the challenges and future opportunities in dairy science.


Quantitative texton sequences for legible bivariate maps.
Representing bivariate scalar maps is a common but difficult visualization problem. One solution has been to use two dimensional color schemes, but the results are often hard to interpret and inaccurately read. An alternative is to use a color sequence for one variable and a texture sequence for another. This has been used, for example, in geology, but much less studied than the two dimensional color scheme, although theory suggests that it should lead to easier perceptual separation of information relating to the two variables. To make a texture sequence more clearly readable the concept of the quantitative texton sequence (QTonS) is introduced. A QTonS is defined a sequence of small graphical elements, called textons, where each texton represents a different numerical value and sets of textons can be densely displayed to produce visually differentiable textures. An experiment was carried out to compare two bivariate color coding schemes with two schemes using QTonS for one bivariate map component and a color sequence for the other. Two different key designs were investigated (a key being a sequence of colors or textures used in obtaining quantitative values from a map). The first design used two separate keys, one for each dimension, in order to measure how accurately subjects could independently estimate the underlying scalar variables. The second key design was two dimensional and intended to measure the overall integral accuracy that could be obtained. The results show that the accuracy is substantially higher for the QTonS/color sequence schemes. A hypothesis that texture/color sequence combinations are better for independent judgments of mapped quantities was supported. A second experiment probed the limits of spatial resolution for QTonSs.


Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line.
Observed mutation rates in humans appear higher in male than female gametes and often increase with paternal age. This bias, usually attributed to the accumulation of replication errors or inefficient repair processes, has been difficult to study directly. Here, we describe a sensitive method to quantify substitutions at nucleotide 755 of the fibroblast growth factor receptor 2 (FGFR2) gene in sperm. Although substitution levels increase with age, we show that even high levels originate from infrequent mutational events. We propose that these FGFR2 mutations, although harmful to embryonic development, are paradoxically enriched because they confer a selective advantage to the spermatogonial cells in which they arise.


Perceptual Quality Assessment for Multi-Exposure Image Fusion.
Multi-exposure image fusion (MEF) is considered an effective quality enhancement technique widely adopted in consumer electronics, but little work has been dedicated to the perceptual quality assessment of multi-exposure fused images. In this paper, we first build an MEF database and carry out a subjective user study to evaluate the quality of images generated by different MEF algorithms. There are several useful findings. First, considerable agreement has been observed among human subjects on the quality of MEF images. Second, no single state-of-the-art MEF algorithm produces the best quality for all test images. Third, the existing objective quality models for general image fusion are very limited in predicting perceived quality of MEF images. Motivated by the lack of appropriate objective models, we propose a novel objective image quality assessment (IQA) algorithm for MEF images based on the principle of the structural similarity approach and a novel measure of patch structural consistency. Our experimental results on the subjective database show that the proposed model well correlates with subjective judgments and significantly outperforms the existing IQA models for general image fusion. Finally, we demonstrate the potential application of the proposed model by automatically tuning the parameters of MEF algorithms.


Neural dynamics of verbal working memory processing in children and adolescents.
Development of cognitive functions and the underlying neurophysiology is evident throughout childhood and adolescence, with higher order processes such as working memory (WM) being some of the last cognitive faculties to fully mature. Previous functional neuroimaging studies of the neurodevelopment of WM have largely focused on overall regional activity levels rather than the temporal dynamics of neural component recruitment. In this study, we used magnetoencephalography (MEG) to examine the neural dynamics of WM in a large cohort of children and adolescents who were performing a high-load, modified verbal Sternberg WM task. Consistent with previous studies in adults, our findings indicated left-lateralized activity throughout the task period, beginning in the occipital cortices and spreading anterior to include temporal and prefrontal cortices during later encoding and into maintenance. During maintenance, the occipital alpha increase that has been widely reported in adults was found to be relatively weak in this developmental sample, suggesting continuing development of this component of neural processing, which was supported by correlational analyses. Intriguingly, we also found sex-specific developmental effects in alpha responses in the right inferior frontal region during encoding and in parietal and occipital cortices during maintenance. These findings suggested a developmental divergence between males and females in the maturation of neural circuitry serving WM during the transition from childhood to adolescence.


Training load responses to football game profile-based training (GPBT) formats: effects of locomotive demands manipulation.
The aim of this study was to compare internal and external load profiles of different game profile-based training (GPBT) formats among elite young football players. Twenty-one participants (age: 18.7 ± 0.6 years) performed three sessions of three GPBT formats, which were matched for training volume but structured with different high-speed running and sprint demands: i) performed along linear paths (GPBT-L); ii) performed as repetitive actions of short distance including many multi-directional changes of direction (GPBT-S) and, iii) a combination of the other two protocols, that is linear high-speed runs and sprint efforts with a single change of direction (GPBT-M). External load outputs were collected using GPS units, physiological and perceptual responses were monitored with heart rate (HR) monitors, and ratings of perceived exertion (RPE), respectively. While no differences were found between formats for HR and RPE, distinct external load profiles were observed for high-speed running (HSD) and sprint distances (SD), (GPBT-L > GPBT-M > GBPT-S, all p < 0.05), and high-intensity acceleration and deceleration efforts (HIE), (GPBT-S > GPBT-M > GPBT-L, all p < 0.05). Moreover, the GPBT-S format was characterized by greater intra-session variability for HSD, SD, and HIE (CV% = 24.2%, 16.5% and 20.4%, respectively) and inter-session variability for HSD and SD (CV% = 10% and 15.7%, respectively) compared to the other two formats. Considering their load profiles and the associated reliability scores, football practitioners can implement GPBT formats interchangeably to elicit necessary internal load responses and selectively to prioritize specific external load outputs.


Effect of changing transit time on colonic microbial metabolism in man.
An investigation was made of the effect of changing mean transit time (MTT) by administration of drugs which affect colonic motility on faecal microbial mass in man. Senokot was used to accelerate and codeine and/or loperamide to prolong transit in subjects maintained on a constant high fibre diet. Doses of Senokot or codeine/loperamide were adjusted to halve or double transit time measured during a three week control period on diet alone. Stools were collected throughout and analysed for bacterial mass by a gravimetric procedure. Transit was measured by a continuous marker method. Senokot decreased mean transit time from 63.9 to 25.0 hours (n = 6), with increased stool weight from 148 to 285 g/day. Bacterial mass increased in all subjects from a mean of 16.5 to 20.3 g/day (dry weight) (p less than 0.025). Codeine/loperamide increased mean transit time from 47.1 to 87.6 hours (n = 5), with decreased stool weight from 182 to 119 g/day. Bacterial mass decreased in all but one subject from a mean of 18.9 to 16.1 g/day (NS). There was a significant correlation between transit time and bacterial mass in all three periods (r = 0.77, p less than 0.001). Changes in transit time are shown to alter microbial growth in the human colon and result in altered stool output, on a constant diet. Factors which affect transit may be as important as diet in determining large bowel function and hence susceptibility to disease.