The association between AB blood group and neonatal disease.
Numerous studies have examined the association between ABO blood groups and adult disease states, but very few have studied the neonatal population. The objective of this study was to determine the relationship between AB blood group and the occurrence of common neonatal disorders such as neutropenia at birth, sepsis, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and patent ductus arteriosus (PDA) compared to all other blood groups. We performed a retrospective review on 3,981 infants born at 22 0/7 to 42 6/7 weeks' gestational age and compared the relative risk of neonatal diseases in infants with AB blood group to that of infants with all other blood groups (A, B, and O). When compared to all other blood groups, AB infants demonstrated an increased risk for developing negative clinical outcomes. AB blood group was significantly associated with a 14-89% increased risk of neutropenia at birth, sepsis, RDS, and ROP. Risks for IVH and PDA were not significant. We hypothesize that the phenotypic expression of A and B antigens, rather than the antigens themselves, in the AB group may reveal an enhanced susceptibility to injury at the endothelial level resulting in an increased risk for disease development.


Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), inhibit activation of nuclear factor-kappaB by inhibiting both its nuclear localization and ability to bind DNA.
Triterpenoid saponins, which are present in leguminous plants and some marine animals, possess a broad range of biological actions. We have earlier reported the extraction of avicins, a family of triterpenoid saponins obtained from the Australian desert tree Acacia victoriae (Leguminosae: Mimosoideae) that inhibit tumor cell growth and induce apoptosis, in part, by perturbing mitochondrial function. These saponins have also been found to prevent chemical-induced carcinogenesis in mice. This study examines the effect of a triterpene mixture (F094) and a single molecular species (avicin G) isolated from the mixture on tumor necrosis factor (TNF)-induced activation of nuclear transcription factor-kappaB (NF-kappaB) in Jurkat cells (human T cell leukemia). Both F094 and avicin G were found to be potent inhibitors of TNF-induced NF-kappaB. Treatment of Jurkat cells with avicin G resulted in a much slower accumulation of the p65 subunit of NF-kappaB into the nucleus whereas the degradation of IkappaBalpha was unaffected. Avicin G also impaired the binding of NF-kappaB to DNA in in vitro binding assays. Treatment of cells with DTT totally reversed the avicin G-induced inhibition of NF-kappaB activity, suggesting that sulfhydryl groups critical for NF-kappaB activation were being affected. Avicin G treatment resulted in decreased expression of NF-kappaB-regulated proteins such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Thus, the avicins may prove important for reducing both oxidative and nitrosative cellular stress and thereby suppressing the development of malignancies and related diseases.


Preparation of activated carbon using low temperature carbonisation and physical activation of high ash raw bagasse for acid dye adsorption.
Activated carbons were prepared from bagasse through a low temperature (160 degrees C) chemical carbonisation treatment and gasification with carbon dioxide at 900 degrees C. The merit of low temperature chemical carbonisation in preparing chars for activation was assessed by comparing the physical and chemical properties of activated carbons developed by this technique to conventional methods involving the use of thermal and vacuum pyrolysis of bagasse. In addition, the adsorption properties (acid blue dye) of these bagasse activated carbons were also compared with a commercial activated carbon. The results suggest that despite the high ash content of the precursor, high surface areas (614-1433 m2 g(-1)) and microporous (median pore size from 0.45 to 1.2 nm) activated carbons can be generated through chemical carbonisation and gasification. The micropore area of the activated carbon developed from chars prepared by the low temperature chemical carbonisation provides favourable adsorption sites to acid blue dye (391 mg g(-1) of carbon). The alkalinity of the carbon surface and total surface area were shown to have complementary effects in promoting the adsorption of acid blue dye. Adsorption of the anionic coloured component of the acid dye was shown to be promoted in carbon exhibiting alkaline or positively charged surfaces. This study demonstrates that activated carbons with high acid dye adsorption capacities can be prepared from high ash bagasse based on low temperature chemical carbonisation and gasification.


p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice.
Radiation therapy, which is used for the treatment of some cancers, can cause delayed heart damage. In the heart, p53 influences myocardial injury that occurs after multiple types of stress. Here, we demonstrated that p53 functioned in endothelial cells to protect mice from myocardial injury after whole-heart irradiation. Mice with an endothelial cell-specific deletion of p53 succumbed to heart failure after whole-heart irradiation as a result of myocardial necrosis, systolic dysfunction, and cardiac hypertrophy. Moreover, the onset of cardiac dysfunction was preceded by alterations in myocardial vascular permeability and density, which resulted in cardiac ischemia and myocardial hypoxia. Mechanistic studies with primary cardiac endothelial cells irradiated in vitro indicated that p53 signaling caused mitotic arrest and protected cardiac endothelial cells from cell death resulting from abnormal mitosis or mitotic catastrophe. Furthermore, mice lacking the cyclin-dependent kinase inhibitor p21, which is a transcriptional target of p53, were also sensitized to myocardial injury after whole-heart irradiation. Together, our results demonstrate that the p53-p21 axis functions to prevent radiation-induced myocardial injury in mice.


Ocular irrigant alternatives in pediatric emergency medicine.
Minimizing pain and discomfort is an important consideration in pediatric ocular decontamination. The pH of an irrigant solution plays a significant role in its tolerability, because a solution with a pH that is too low or too high may cause edema and discomfort to the conjunctiva. We reviewed several available ocular irrigation solutions with respect to their chemical composition, pH, and cost efficiency. Currently, the irrigation solution of first choice for most ocular decontaminations in the pediatric emergency department (ED) is 0.9 % saline solution or normal saline (NS), which has a pH range between 4.5 and 6.0. Alternative ocular irrigant solutions available include Lactated Ringers solution (LR), which has a pH range between 6.2 and 7.5, buffered NS with pH adjusted to 7.4 with sodium bicarbonate, and Balanced Salt Solution Plus (BSS Plus), which has a pH of 7.4. Of these alternative solutions, all except BSS Plus are comparable in cost efficiency to NS. The use of more pH neutral solutions such as LR, NS with bicarbonate buffer, or BSS Plus may decrease ocular pain and irritation associated with copious irrigation, and may improve tolerance of ocular decontamination by a child.


Tactical Combat Casualty Care Training, Knowledge, and Utilization in the US Army.
Tactical Combat Casualty Care (TCCC) is the execution of prehospital trauma skills in the combat environment. TCCC was recognized by the 2018 Department of Defense Instruction on Medical Readiness Training as a critical wartime task. This study examines the training, understanding, and utilization of TCCC principles and guidelines among US Army medical providers and examines provider confidence of medics in performing TCCC skills. A cross-sectional survey, developed by members of the Committee on TCCC, was distributed to all US Army Physicians and Physician Assistants via anonymous electronic communication. A total of 613 completed surveys were included in the analyses. Logistic regression analyses were conducted on: TCCC test score of 80% or higher, confidence with medic utilization of TCCC, and medic utilization of ketamine in accordance with TCCC. <60% of respondents expressed confidence in the ability of the medics to perform all TCCC skills. Supervising providers who that believed 80 to 100% of their medics had completed TCCC training had more confidence in their medic's TCCC abilities. With TCCC, a recognized lifesaver on the battlefield, continued training and utilization of TCCC concepts are paramount for deploying personnel.


Growth Hormone-Releaser Diet Attenuates Cognitive Dysfunction in Klotho Mutant Mice via Insulin-Like Growth Factor-1 Receptor Activation in a Genetic Aging Model.
It has been recognized that a defect in klotho gene expression accelerates the degeneration of multiple age-sensitive traits. Accumulating evidence indicates that aging is associated with declines in cognitive function and the activity of growth hormone (GH)/insulin-like growth factor-1 (IGF-1). In this study, we examined whether a GH-releaser diet could be effective in protecting against cognitive impairment in klotho mutant mice. The GH-releaser diet significantly induced the expression of IGF-1 and IGF-1 receptors in the hippocampus of klotho mutant mice. Klotho mutant mice showed significant memory impairments as compared with wild-type mice. In addition, the klotho mutation significantly decreased the expression of cell survival/antiapoptotic factors, including phospho-Akt (p-Akt)/phospho-glycogen synthase kinase3β (p-GSK3β), phospho-extracellular signal-related kinase (p-ERK), and Bcl-2, but significantly increased those of cell death/proapoptotic factors, such as phospho-c-jun N-terminal kinase (p-JNK), Bax, and cleaved caspase-3 in the hippocampus. Treatment with GH-releaser diet significantly attenuated both decreases in the expression of cell survival/antiapoptotic factors and increases in the expression of cell death/proapoptotic factors in the hippocampus of klotho mutant mice. In addition, klotho mutation-induced oxidative stress was significantly attenuated by the GH-releaser diet. Consequently, a GH-releaser diet significantly improved memory function in the klotho mutant mice. GH-releaser diet-mediated actions were significantly reversed by JB-1, an IGF-1 receptor antagonist. The results suggest that a GH-releaser diet attenuates oxidative stress, proapoptotic changes and consequent dysfunction in klotho mutant mice by promoting IGF-1 expression and IGF-1 receptor activation.


Ethnic differences in uterine corpus cancer incidence and mortality in New Mexico's American Indians, hispanics and non-Hispanic whites.
Although ethnic and radical differences in uterine corpus cancer incidence and mortality have been reported worldwide, few published data have addressed the epidemiology of uterine cancer among US American Indians and Hispanics. We reviewed uterine corpus cancer incidence and survival data from New Mexico's population-based cancer registry collected from 1969 to 1992, and examined State vital records data for uterine cancer deaths collected from 1958 to 1992, focusing on ethnic differences in occurrence and outcomes of uterine malignancies. Non-Hispanic white women had age-adjusted incidence rates that were substantially higher (20.8 per 100,000) than rates for Hispanics (10.3) and American Indians (6.0) over the 24-year period. Uterine cancer mortality rates were also higher for non-Hispanic whites and Hispanics than for American Indian women, although mortality rates were substantially lower than incidence rates. Five-year survival for uterine cancer was comparable among all groups for all stages combined (87.3% for non-Hispanic whites, 81.4% for Hispanics, and 84.6% for American Indians). Our population-based data show ethnic differences in uterine corpus cancer incidence rates for non-Hispanic white women that were double those for Hispanics, and triple those for American Indian women. Ethnic differences in survival were comparable. Aetiologic studies are warranted to investigate the dramatic ethnic differences in occurrence of uterine cancer.


Epidemiology of pancreatic adenocarcinoma.
Pancreatic ductal adenocarcinoma is one of the most lethal cancers worldwide. The highest incidence rates her found are in North America and in Western Europe while lower rates in Asian Africa, with age standard incidence rates of 7.2 and 2.8 per 100,000 populations. Unfortunately the vast majority of individuals with pancreatic cancer present with symptoms, and once symptoms develop the chance for surgery is only about 20%. Additionally he incidence rate and mortality from pancreatic ductal adenocarcinoma in the United States shows a very close association suggesting that her earlier detection and treatment does little to change the outcome from this disease. Multiple of environmental and genetic risk factors have been implicated in the development of pancreatic ductal adenocarcinoma. We have reviewed those risk factors we believe are most important the development of this lethal disease. It is hoped that in the future, identification of biomarkers unique in the development of pancreatic ductal adenocarcinoma will be identified leading to earlier detection and a greater frequency of potential cure of this disease.


Role of canine circovirus in dogs with acute haemorrhagic diarrhoea.
Canine circovirus (CanineCV) has been detected in some dogs with severe haemorrhagic diarrhoea, but its pathogenic role is unclear. This study evaluated a suspected association between the presence of CanineCV and acute haemorrhagic diarrhoea syndrome (AHDS) in dogs. The prevalence of CanineCV in dogs with AHDS was compared with that in healthy dogs and those infected with canine parvovirus (CPV). Additionally, time to recovery and mortality rate were compared between CanineCV-positive and CanineCV-negative dogs. Faecal samples of dogs with AHDS (n=55), healthy dogs (n=66) and dogs infected with CPV (n=54) were examined by two real-time TaqMan PCR assays targeting the replicase and capsid genes of CanineCV. CanineCV was detected in faecal samples of two dogs with AHDS, three healthy controls and seven dogs infected with CPV. Among the three groups, there was no significant difference in prevalence of CanineCV. CPV-infected animals that were coinfected with CanineCV had a significantly higher mortality rate compared with those negative for CanineCV. CanineCV does not appear to be the primary causative agent of AHDS in dogs, but might play a role as a negative co-factor in disease outcome in dogs with CPV infection.


Melanoma incidence increases in the elderly of Catalonia but not in the younger population: effect of prevention or consequence of immigration?
All cases of MM diagnosed in 23 hospitals in Catalonia, from 2000 to 2007 were recorded and melanoma incidence calculated and adjusted for the European standard population via the direct method. The age standardised rate/100,000 inhabitants varied from 6.74 in 2000 to 8.64 in 2007 for all melanomas and from 4.79 to 5.80 for invasive MMs; the Breslow thickness was stable during the period. The increase in invasive melanoma incidence in the elderly was remarkable, the crude rate/100,000 inhabitants increasing from 11.04 (2000) to 15.49 (2007) in the 60-64 year population, while remaining more stable in the 30-34 year range, from 3.97 in 2000 to 4.55 in 2007, and with a tendency to decrease from 5.1 in 2000 to 2.5 in 2007 for the age range of 25-29 years. These lower age ranges are much more affected by immigration. Despite the large immigrant population (nearly one million immigrants arrived in Catalonia during the study period from countries with a low melanoma incidence), melanoma incidence in our region has risen considerably and this trend is likely to persist in the near future.


Evidence of an association between non-Hodgkin's lymphoma and skin cancer.
To investigate a possible link between exposure to ultraviolet light and the almost epidemic increase in non-Hodgkin's lymphoma worldwide. Because ultraviolet light is known to cause skin cancers, the association between non-Hodgkin's lymphoma and skin cancer was studied. Secondary occurrence of either malignant melanoma or squamous cell skin cancer in cohorts of patients with a first diagnosis of either non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, and vice versa, were studied. Expected numbers of subsequent cancers were calculated by sex, age, and period specific national incidence rates multiplied by the person years under observation in the cohorts. Denmark (1943-89) and Sweden (1958-89). Four population based cohorts identified in the nationwide cancer registries (34,641 people with non-Hodgkin's lymphoma, 17,400 with chronic lymphocytic leukaemia, 34,989 with malignant melanoma, 25,980 with squamous cell skin cancer). A total of 562,085 person years were accrued for the analysis. The ratios of observed to expected cancers (the standardised incidence ratio) served as a measure of the relative risk. The relative risk for developing squamous cell skin cancer was 5.5 (95% confidence interval 4.6 to 6.6) among patients with non-Hodgkin's lymphoma and 8.6 (7.2 to 10.3) among patients with chronic lymphocytic leukaemia. The relative risks remained high over more than 15 years of follow up. Relative risks for malignant melanoma were 2.4 (1.8 to 3.2) for patients with non-Hodgkin's lymphoma and 3.1 (2.1 to 4.4) for patients with chronic lymphocytic leukaemia. After squamous cell skin cancer had been diagnosed there was a twofold excess risk for non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. By contrast, in each of the cohorts the general cancer risks excluding skin and lymphoproliferative malignancies were close to the expected. The occurrence of non-Hodgkin's lymphoma and skin cancer are strongly associated; this supports the hypothesis that the secular increase in exposure to ultraviolet light may have contributed to the increasing incidence of non-Hodgkin's lymphoma in recent decades.


Restriction Site-Associated DNA Sequencing (RAD-seq) Reveals an Extraordinary Number of Transitions among Gecko Sex-Determining Systems.
Sex chromosomes have evolved many times in animals and studying these replicate evolutionary "experiments" can help broaden our understanding of the general forces driving the origin and evolution of sex chromosomes. However this plan of study has been hindered by the inability to identify the sex chromosome systems in the large number of species with cryptic, homomorphic sex chromosomes. Restriction site-associated DNA sequencing (RAD-seq) is a critical enabling technology that can identify the sex chromosome systems in many species where traditional cytogenetic methods have failed. Using newly generated RAD-seq data from 12 gecko species, along with data from the literature, we reinterpret the evolution of sex-determining systems in lizards and snakes and test the hypothesis that sex chromosomes can routinely act as evolutionary traps. We uncovered between 17 and 25 transitions among gecko sex-determining systems. This is approximately one-half to two-thirds of the total number of transitions observed among all lizards and snakes. We find support for the hypothesis that sex chromosome systems can readily become trap-like and show that adding even a small number of species from understudied clades can greatly enhance hypothesis testing in a model-based phylogenetic framework. RAD-seq will undoubtedly prove useful in evaluating other species for male or female heterogamety, particularly the majority of fish, amphibian, and reptile species that lack visibly heteromorphic sex chromosomes, and will significantly accelerate the pace of biological discovery.


Neurobiological and clinical effects of the antidepressant tianeptine.
The precise neurobiological processes involved in depression are not clear, but it is recognized that numerous factors are involved, including changes in neurotransmitter systems and brain plasticity. Neuroplasticity refers to the ability of the brain to adapt functionally and structurally to stimuli. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, learning, memory and emotions are altered in depression. The mechanisms underlying alterations in neuroplasticity are believed to relate to changes in neurotransmitters, hormones and growth factors. Structural changes in the hippocampus that have been proposed to be associated with depression include dendritic atrophy, reduced levels of cerebral metabolites, decreased adult neurogenesis (generation of new nerve cells) and reduced volume. Increased dendritic branching occurs in the basolateral nucleus of the amygdala. Reduced neuronal size and glial cell density occur in the prefrontal cortex. Clinically, tianeptine is an antidepressant effective in reducing symptoms of depression in mild to moderate-to-severe major depression, including over the long term. Tianeptine is also effective in alleviating the symptoms of depression-associated anxiety. It is generally well tolerated, with little sedation or cognitive impairment. The efficacy profile of tianeptine could be explained by its neurobiological properties observed in animal models. Tianeptine prevents or reverses stress-associated structural and cellular changes in the brain and normalizes disrupted glutamatergic neurotransmission. In particular, in the hippocampus, it prevents stress-induced dendritic atrophy, improves neurogenesis, reduces apoptosis and normalizes metabolite levels and hippocampal volume. Tianeptine also has beneficial effects in the amygdala and cortex and can reverse the effects of stress on neuronal and synaptic functioning. The neurobiological properties of tianeptine may provide an explanation not only for its antidepressant activity, but also for its anxiolytic effects in depressed patients and its lack of adverse effects on cognitive function and memory.


Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development.
Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling and selected 22 patients with MPT to perform genomic analysis (CytoScan HD Array, Affymetrix) aiming to identify new alterations related to a high risk of developing MPT. Twenty patients had a positive family history of cancer and 11 met phenotypic criteria for HCPS. Genetic testing for each of the genes associated with these syndromes revealed negative results for pathogenic mutations. Seventeen rare germline copy number variations (CNVs) covering 40 genes were identified in 11 patients, including an EPCAM/MSH2 deletion in one Lynch syndrome patient. An enrichment analysis revealed a significant number of genes (where the CNVs are mapped) associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. An interaction network analysis highlighted the importance of TP53 pathway in cancer emergence. A high number of germline copy-neutral loss of heterozygosity (cnLOH) was identified in nine cases, particularly in two patients. Eighteen genes were covered by both rare CNVs and cnLOH, including 14 related to tumorigenesis and seven genes (ABCC1, KDM4C, KIAA0430, MYH11, NDE1, PIWIL2, and ULK2) specifically associated with cellular growth and proliferation. Overall, we identified 14 cases with rare CNVs and/or cnLOH that may contribute to the risk of MPT development. CNVs may explain the risk of hereditary cancer syndromes in MPT patients. CNVs affecting genes related to cancer are candidates to be involved in MPT risk. EPCAM/MSH2 deletions should be investigated in patients suspected to have LS. Gene enrichment related to the TP53 network is associated with MPT development. cnLOH and CNVs contribute to the risk of MPT development.


Development of an intervention system for linkage-to-care and follow-up for hepatitis B and C virus carriers.
Poor connections in the cascade of viral hepatitis care have been discussed around the world. In 2011 in Japan, 500,000 to 1.25 million hepatitis B and C virus carriers needed to consult with hepatologists, so linkage-to-care (LTC) needs to be promoted. Therefore, in this study, to improve LTC and care-seeking behaviors, we attempted to establish a community-based intervention system and evaluate its effectiveness by analyzing behavior modifications. In a model city, Okazaki (population: 387,887 as of 2019), LTC was encouraged among HBV and HCV carriers by annually mailed brochures, and their care-seeking behaviors were followed up through questionnaires for 8 years (2012-2019). Their behavior modifications and demographic characteristics were analyzed anonymously in cooperation with community health workers, hepatologists, and researchers. Through regional HBsAg and anti-HCV screening, 333 HBV and 208 HCV carriers were identified. Before the intervention, only 34.7% (25/72) of HBV- and 34.3% (24/70) of HCV-positive individuals had consulted with hepatologists. However, in 2019, after the intervention, these proportions increased to 79.8% (91/114) and 91.2% (52/57), respectively. Access to outpatient care and treatment uptake also continuously improved. However, individuals over 70 years of age were significantly less likely to engage in care-seeking behaviors (p < 0.05), and significantly fewer HCV-positive females received treatment (p = 0.03). A paper-based reiterative intervention encouraging LTC and follow-up successfully improved the care-seeking behaviors of hepatitis virus-positive individuals and enabled their behavior modifications to be monitored. Further trials are required to advance the system by age- and gender-specific interventions.


The influence of low dose finasteride, a type II 5α-reductase inhibitor, on circulating neuroactive steroids.
Finasteride is a 5α-reductase inhibitor that has received clinical approval for the treatment of human benign prostatic hyperplasia and androgenetic alopecia. The treatment is practically without side effects, although some occasional cases of depression syndrome have been reported. 5α-Reductase is an enzyme responsible for the reduction of testosterone, progesterone or deoxycorticosterone to their 5α-reduced derivatives possessing anticonvulsant, antidepressant, and anxiolytic activity. Therefore, the formation of GABAergic neuroactive steroids is likely to be impacted by finasteride. The objective of the study was to show how the treatment of premature androgenetic alopecia with low doses (1 mg/day) of finasteride influences the broad spectrum of steroids with potential neuroactivity. A group of 12 men with premature androgenetic alopecia participated in the present study. The steroid hormone profile was determined for all individuals. Finasteride was administered for 4 months at a daily dose of 1 mg. After the treatment, the same hormonal profile was determined again. 5α-Reduced steroids, e.g., 5α-dihydrotestosterone, androsterone, epiandrosterone, 5α-androstene-3α,17β-diol, allopregnanolone, isopregnaolone, and some 5-ene steroids, such as dehydroepiandrosterone and pregnenolone, decreased gradually during treatment. The decrease of 5α-reduced steroids, especially of allopregnanediol, dihydrotestosterone, and pregnenolone, is probably one of the factors responsible for the increased occurrence of depression in men treated with finasteride, even at low doses.


Safety and tolerability of a body wash and moisturizer when applied to infants and toddlers with a history of atopic dermatitis: results from an open-label study.
Improving skin barrier function and moisturizing without irritation are important components of managing patients with atopic dermatitis. This study evaluated the safety and tolerability of a body wash and moisturizer regimen for infants and toddlers with atopic dermatitis. This was an open-label study involving 56 children (3-36 months old) with a history of atopic dermatitis. The skin care regimen (Cetaphil Restoraderm Skin Restoring Body Wash and Cetaphil Restoraderm Skin Restoring Moisturizer; Galderma Laboratories, L.P.) was used at least once daily, but no more than twice daily, for 4 weeks. The primary variable of interest was the worst postbaseline scores for local tolerability (expressed as success or failure) using a 4-point scale for each component (erythema, edema, scaling and dryness, rash, and signs of discomfort upon application). Assessments of moisture content of the stratum corneum and transepidermal water loss were also performed. Fifty-three children completed the study. The percentage of subjects with no erythema increased from 33.9% to 50.0% by Week 4. The percentage of subjects with no scaling or dryness increased from 58.9% to 85.2% at Week 4. A statistically significant increase in corneometry from baseline (p < 0.001) and a statistically significant decrease in transepidermal water loss (p = .009) were observed. The body wash and moisturizer regimen was safe and well tolerated and improved hydration and skin barrier function in infants and toddlers as young as 3 months of age with a history of atopic dermatitis.


DNA-functionalized hydrogels for confined membrane-free in vitro transcription/translation.
We microfluidically fabricate bio-orthogonal DNA-functionalized porous hydrogels from hyaluronic acid that are employed in in vitro transcription/translation (IVTT) of a green fluorescent protein. By co-encapsulating individual hydrogel particles and the IVTT machinery in water-in-oil microdroplets, we study protein expression in a defined reaction volume. Our approach enables precise control over protein expression rates by gene dosage. We show that gene transcription and translation are confined to the membrane-free hydrogel matrix, which contributes to the design of membrane-free protocells.


The C terminus of p53 family proteins is a cell fate determinant.
The p53 tumor suppressor is the most commonly mutated gene in human cancers. The ability of p53 to induce cell cycle arrest, apoptosis, DNA repair, and other p53-dependent activities is well known; however, the mechanism by which p53 induces a specific activity over another is unclear. Here, we showed that stringent regulation of and by p53 family isoforms facilitates differential target gene expression and thus determines cell fate. Through the use of engineered deletion mutants, we found that activation domain 2 is required for induction of the proapoptotic target gene insulin-like growth factor binding protein 3 (IGFBP3) by p53 and that the basic domain inhibits induction of this gene by p53. Thus, for the first time we provide evidence that the basic domain of p53 is inhibitory in vivo as has been determined in vitro. We also showed that the in vivo inhibitory activity of the basic domain depends upon activation domain 1, such that combined deletion of activation domain 1 and the basic domain was required to alleviate the inhibition by the basic domain. Importantly, deletion of the inhibitory functional domains, namely N-terminal activation domain 1 and the C-terminal basic domain, is paralleled in nature. We found that the IGFBP3 promoter was activated by p53(DeltaNDeltaBD), which mimics a naturally occurring N- and C-terminally truncated human p53 isoform, and by p53AS, a C-terminally truncated murine p53 isoform generated through alternative splicing, but not by full-length human or murine p53. In addition, we found that the C termini of p63 and p73 inhibit the induction of IGFBP3, such that C-terminally truncated p63 and p73 isoforms induce the expression of IGFBP3, whereas full-length ones cannot. We also demonstrated that IGFBP3 is an important effector of the apoptosis induced by N- and C-terminally truncated p53, such that knockdown of IGFBP3 by using an IGFBP3 neutralizing antibody or IGFBP3 small interfering RNA partially rescues the cell death induced by N- and C-terminally truncated p53. In addition, we identified that histone deacetylase activity, not p53 DNA binding ability, governs the regulation of IGFBP3 by full-length p53 family proteins, as inhibition of histone deacetylases restores the induction of IGFBP3 by exogenous full-length p53, p63, and p73 proteins. Furthermore, we found that activation of p53 or inhibition of histone deacetylases alone was not sufficient to induce IGFBP3; however, combined treatment endowed endogenous p53 with this activity. To better understand the significance of this regulation, we performed a microarray study and identified several target genes differentially regulated by full-length p53 and p53 lacking the N-terminal activation domain 1 and the C-terminal basic domain. Taken together, our data suggest a novel mechanism by which p53 family proteins differentially regulate gene expression and provide an insight for designing a combined therapy for cancer treatment.


Toxicity of tryptophan manganese(i) carbonyl (Trypto-CORM), against Neisseria gonorrhoeae.
The potential for carbon monoxide-releasing molecules (CO-RMs) as antimicrobials represents an exciting prospective in the fight against antibiotic resistance. Trypto-CORM, a tryptophan-containing manganese(i) carbonyl, is toxic against E. coli following photo-activation. Here, we demonstrate that Trypto-CORM is toxic against Neisseria gonorrhoeae in the absence of photoactivation. Trypto-CORM toxicity was reversed by the high CO affinity globin leg-haemoglobin (Leg-Hb), indicating that the toxicity is due to CO release. Release of CO from Trypto-CORM in the dark was also detected with Leg-Hb (but not myoglobin) in vitro. N. gonorrhoeae is more sensitive to CO-based toxicity than other model bacterial pathogens, and may serve as a viable candidate for antimicrobial therapy using CO-RMs.


Clinical interpretation of negative mediated interaction.
Recently, using a counterfactual framework, a causal mediation analysis has been formalized to decompose the total effect of a time-fixed exposure on an outcome into four components that can be loosely defined as being components due to mediation only, interaction only, mediated interaction and neither. The interpretation of the estimated effect sizes is challenging when these components of the total effect are of the opposite sign compared with each other. Particularly, a negative mediated interaction might be intuitively difficult to conceptualize and, so far, lacks an easy-to-understand biological or mechanical interpretation. In this paper, we focus on negative mediated interaction, and propose an interpretation using biological examples. For negative mediated interaction to be present, the effect of interaction on the outcome and the effect of the exposure on the mediator should be in opposite directions. In this article, we give examples of biological and biochemical processes that may exhibit negative mediated interaction, such as drug treatment in clinical practice, allosteric effects of enzymes, different adaptations in the cardiovascular system and its effect on brain health, and antibiotic drug-drug interactions. We aim to make researchers realize that negative-effect estimates might reflect relevant biological processes in the mechanism under study.


Optical properties of micrometer size water droplets studied by cavity ringdown spectroscopy.
Optical extinction by homogeneous, pure water droplets of 30 to 70 microm diameter produced by a vibrating orifice aerosol generator has been studied by pulsed cavity ringdown (CRD) spectroscopy at lambda=560 nm under ambient conditions. Experimental sensitivity of better than 1% achieved in measurements of CRD times enabled detection of changes in laser light losses per pass due to changes in the number and size of particles within the laser beam volume. By systematically changing the droplet size in the cavity while recording the CRD time, a periodic modulation in the value of the loss per pass was observed. The modulation is caused by the oscillatory nature of the extinction efficiency, which was subsequently inferred and compared with the results of theoretical calculations based on Mie theory.


Importance of Dietary Sources of Iron in Infants and Toddlers: Lessons from the FITS Study.
Iron deficiency (ID) affects 13.5% of 1-2 years old children in the US and may have a negative impact on neurodevelopment and behavior. Iron-fortified infant cereal is the primary non-heme iron source among infants aged 6-11.9 months. The objective of this study was to compare iron intakes of infant cereal users with non-users. Data from the Feeding Infants and Toddlers Study 2008 were used for this analysis. Based on a 24-h recall, children between the ages of 4-17.9 months were classified as 'cereal users' if they consumed any amount or type of infant cereal and 'non-users' if they did not. Infant cereal was the top source of dietary iron among infants aged 6-11.9 months. The majority of infants (74.6%) aged 6-8.9 months consumed infant cereal, but this declined to 51.5% between 9-11.9 months and 14.8% among 12-17.9 months old toddlers. Infant cereal users consumed significantly more iron than non-users across all age groups. Infants and toddlers who consume infant cereal have higher iron intakes compared to non-users. Given the high prevalence of ID, the appropriate use of infant cereals in a balanced diet should be encouraged to reduce the incidence of ID and ID anemia.


Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input.
Peripheral nerve injuries caused by trauma are associated with increased sensory neuron excitability and debilitating chronic pain symptoms. Axotomy-induced alterations in the function of ion channels are thought to largely underlie the pathophysiology of these phenotypes. Here, we characterise the mRNA distribution of Kv2 family members in rat dorsal root ganglia (DRG) and describe a link between Kv2 function and modulation of sensory neuron excitability. Kv2.1 and Kv2.2 were amply expressed in cells of all sizes, being particularly abundant in medium-large neurons also immunoreactive for neurofilament-200. Peripheral axotomy led to a rapid, robust and long-lasting transcriptional Kv2 downregulation in the DRG, correlated with the onset of mechanical and thermal hypersensitivity. The consequences of Kv2 loss-of-function were subsequently investigated in myelinated neurons using intracellular recordings on ex vivo DRG preparations. In naïve neurons, pharmacological Kv2.1/Kv2.2 inhibition by stromatoxin-1 (ScTx) resulted in shortening of action potential (AP) after-hyperpolarization (AHP). In contrast, ScTx application on axotomized neurons did not alter AHP duration, consistent with the injury-induced Kv2 downregulation. In accordance with a shortened AHP, ScTx treatment also reduced the refractory period and improved AP conduction to the cell soma during high frequency stimulation. These results suggest that Kv2 downregulation following traumatic nerve lesion facilitates greater fidelity of repetitive firing during prolonged input and thus normal Kv2 function is postulated to limit neuronal excitability. In summary, we have profiled Kv2 expression in sensory neurons and provide evidence for the contribution of Kv2 dysfunction in the generation of hyperexcitable phenotypes encountered in chronic pain states.


Prenatal stress and its association with amygdala-related structural covariance patterns in youth.
Prenatal stress influences brain development and mood disorder vulnerability. Brain structural covariance network (SCN) properties based on inter-regional volumetric correlations may reflect developmentally-mediated shared plasticity among regions. Childhood trauma is associated with amygdala-centric SCN reorganization patterns, however, the impact of prenatal stress on SCN properties remains unknown. The study included participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) with archival prenatal stress data and structural MRI acquired in young adulthood (age 23-24). SCNs were constructed based on Freesurfer-extracted volumes of 7 subcortical and 34 cortical regions. We compared amygdala degree centrality, a measure of hubness, between those exposed to high vs. low (median split) prenatal stress, defined by maternal reports of stressful life events during the first (n = 93, 57% female) and second (n = 125, 54% female) half of pregnancy. Group differences were tested across network density thresholds (5-40%) using 10,000 permutations, with sex and intracranial volume as covariates, followed by sex-specific analyses. Finally, we sought to replicate our results in an independent all-male sample (n = 450, age 18-20) from the Avon Longitudinal Study of Parents and Children (ALSPAC). The high-stress during the first half of pregnancy ELSPAC group showed lower amygdala degree particularly in men, who demonstrated this difference at 10 consecutive thresholds, with no significant differences in global network properties. At the lowest significant density threshold, amygdala volume was positively correlated with hippocampus, putamen, rostral anterior and posterior cingulate, transverse temporal, and pericalcarine cortex in the low-stress (p(FDR) < 0.027), but not the high-stress (p(FDR) > 0.882) group. Although amygdala degree was nominally lower across thresholds in the high-stress ALSPAC group, these results were not significant. Unlike childhood trauma, prenatal stress may shift SCN towards a less amygdala-centric SCN pattern, particularly in men. These findings did not replicate in an all-male ALSPAC sample, possibly due to the sample's younger age and lower prenatal stress exposure.


Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.
There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts. However, the functional significance of these transcripts has been particularly controversial. Although there are some well-characterized examples, most (>95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise. Here we report a new approach to identifying large non-coding RNAs using chromatin-state maps to discover discrete transcriptional units intervening known protein-coding loci. Our approach identified approximately 1,600 large multi-exonic RNAs across four mouse cell types. In sharp contrast to previous collections, these large intervening non-coding RNAs (lincRNAs) show strong purifying selection in their genomic loci, exonic sequences and promoter regions, with greater than 95% showing clear evolutionary conservation. We also developed a functional genomics approach that assigns putative functions to each lincRNA, demonstrating a diverse range of roles for lincRNAs in processes from embryonic stem cell pluripotency to cell proliferation. We obtained independent functional validation for the predictions for over 100 lincRNAs, using cell-based assays. In particular, we demonstrate that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFkappaB, Sox2, Oct4 (also known as Pou5f1) and Nanog. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes.


Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel.
Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10-/- mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10-/- mice had a dysfunctional kidney epithelial sodium channel and became normotensive when administered amiloride, a selective inhibitor of this sodium channel. These studies (a) establish a physiological role for the arachidonate monooxygenases in renal sodium reabsorption and blood pressure regulation, (b) demonstrate that a dysfunctional Cyp4a10 gene causes alterations in the gating activity of the kidney epithelial sodium channel, and (c) identify a conceptually novel approach for studies of the molecular basis of human hypertension. It is expected that these results could lead to new strategies for the early diagnosis and clinical management of this devastating disease.


First things first: Importance of eosinophil count in diagnosing occult parasites.
Tropical pulmonary eosinophilia (TPE) is a rare allergic manifestation to the filarial nematode. A 38-year old male and a 15-year old female presented with cough and breathlessness. Their complete blood count showed eosinophilia. This finding was overshadowed by the radiological findings suggestive of tuberculosis. The diagnosis of TPE was confirmed by filarial antigen detection test and both the patients were successfully treated with diethylcarbamazine. TPE presents with cough and breathlessness and can be often confused with tuberculosis, especially in endemic settings. An important clue in differentiating the two entities is the presence of eosinophilia in the former.


Testicular development in an SRY-negative 46,XX individual harboring a distal Xp deletion.
A case of a true hermaphrodite presenting with a karyotype of 46,X,del(X)(p21.1-->pter) is described. The testis-determining gene, SRY, was not detected in DNA prepared from either peripheral blood lymphocytes or from a gonad biopsy. The patient also presented with a series of discrete somatic abnormalities, including abnormal skin and retinal pigmentation, and mental retardation. The extent of the Xp deletion was mapped by Southern blotting. X chromosome replication studies of lymphoblast cells prepared from the patient indicated that the deleted X chromosome was inactivated in all cells examined. It is suggested that the phenotype of the patient is caused by the unmasking of a recessive allele(s) on the grossly intact X chromosome. The relationship between the Xp deletion, the intersex phenotype, and the possible role of an Xp locus involved in human sex determination is discussed.


[Reasons for the application of medical ozone in the treatment of chronic purulent mesotympanitis].
Ozone-oxygen mixture (ozone concentration 600 microg/l) was used in irrigations of the tympanic cavity in 52 patients with chronic purulent mesotympanitis (CPM). The course of the treatment consisted of 5-7 procedures. 18 CPM controls received standard treatment without the irrigations. The course of the ozone-oxygen irrigations produced good results: ear discharge and tympanic mucosa inflammation stopped in 81% of the irrigated patients, levels of myeloperoxidase which marks inflammation reduced significantly, bactericidal effects of the mixture were observed for all the detected pathogens, antibiotic sensitivity of the bacteria rose. Fast antiinflammatory result of ozone therapy was due not only to its bactericidal effect but also via its antihypoxic and immunomodulating mechanisms.


Holt Oram syndrome: a registry-based study in Europe.
Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. The study was based on data collected during 1990-2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS. A total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births. HOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes.


Dual transcriptome of the immediate neutrophil and Candida albicans interplay.
Neutrophils are traditionally considered transcriptionally inactive. Compared to other immune cells, little is known about their transcriptional profile during interaction with pathogens. We analyzed the meta-transcriptome of the neutrophil-Candida albicans interplay and the transcriptome of C. albicans challenged with neutrophil extracellular traps (NETs) by RNA-Seq, considering yeast and hypha individually in each approach. The neutrophil response to C. albicans yeast and hyphae was dominated by a morphotype-independent core response. However, 11 % of all differentially expressed genes were regulated in a specific manner when neutrophils encountered the hyphal form of C. albicans. While involving genes for transcriptional regulators, receptors, and cytokines, the neutrophil core response lacked typical antimicrobial effectors genes. Genes of the NOD-like receptor pathway, including NLRP3, were enriched. Neutrophil- and NET-provoked responses in C. albicans differed. At the same time, the Candida transcriptome upon neutrophil encounter and upon NET challenge included genes from various metabolic processes and indicate a mutual role of the regulators Tup1p, Efg1p, Hap43p, and Cap1p. Upon challenge with neutrophils and NETs, the overall Candida response was partially morphotype-specific. Yet again, actual oppositional regulation in yeasts and hyphae was only detected for the arginine metabolism in neutrophil-infecting C. albicans. Taken together, our study provides a comprehensive and quantitative transcript profile of the neutrophil-C. albicans interaction. By considering the two major appearances of both, neutrophils and C. albicans, our study reveals yet undescribed insights into this medically relevant encounter. Hence, our findings will facilitate future research and potentially inspire novel therapy developments.


The use of culture-independent tools to characterize bacteria in endo-tracheal aspirates from pre-term infants at risk of bronchopulmonary dysplasia.
Although premature infants are increasingly surviving the neonatal period, up to one-third develop bronchopulmonary dysplasia (BPD). Despite evidence that bacterial colonization of the neonatal respiratory tract by certain bacteria may be a risk factor in BPD development, little is known about the role these bacteria play. The aim of this study was to investigate the use of culture-independent molecular profiling methodologies to identify potential etiological agents in neonatal airway secretions. This study used terminal restriction fragment length polymorphism (T-RFLP) and clone sequence analyses to characterize bacterial species in endo-tracheal (ET) aspirates from eight intubated pre-term infants. A wide range of different bacteria was identified in the samples. Forty-seven T-RF band lengths were resolved in the sample set, with a range of 0-15 separate species in each patient. Clone sequence analyses confirmed the identity of individual species detected by T-RFLP. We speculate that the identification of known opportunistic pathogens including S. aureus, Enterobacter sp., Moraxella catarrhalis, Pseudomonas aeruginosa and Streptococcus sp., within the airways of pre-term infants, might be causally related to the subsequent development of BPD. Further, we suggest that culture-independent techniques, such as T-RFLP, hold important potential for the characterization of neonatal conditions, such as BPD.


Deaths: final data for 2006.
This report presents final 2006 data on U.S. deaths, death rates, life expectancy, infant and maternal mortality, and trends by selected characteristics such as age, sex, Hispanic origin, race, marital status, educational attainment, injury at work, state of residence, and cause of death. It also presents more detailed information than previously presented about the mortality experience of the American Indian or Alaska Native and the Asian or Pacific Islander populations. Information reported on death certificates, which are completed by funeral directors, attending physicians, medical examiners, and coroners, is presented in descriptive tabulations. The original records are filed in state registration offices. Statistical information is compiled in a national database through the Vital Statistics Cooperative Program of the Centers for Disease Control and Prevention's National Center for Health Statistics. Causes of death are processed in accordance with the International Classification of Diseases, Tenth Revision (ICD-10). In 2006, a total of 2,426,264 deaths were reported in the United States. The age-adjusted death rate was 776.5 deaths per 100,000 standard population, a decrease of 2.8 percent from the 2005 rate and a record low historical figure. Life expectancy at birth rose 0.3 years, from a revised 2005 value of 77.4 years to a record 77.7 years in 2006. Age-specific death rates increased for those aged 25-34 years but decreased for most other age groups: 5-14 years, 35-44 years, 45-54 years, 55-64 years, 65-74 years, 75-84 years, and 85 years and over. The 15 leading causes of death in 2006 remained the same as in 2005. Heart disease and cancer continued to be the leading and second-leading causes of death, together accounting for almost half of all deaths. The infant mortality rate in 2006 was 6.69 deaths per 1,000 live births. Mortality patterns in 2006, such as the decline in the age-adjusted death rate to a record historical low, were generally consistent with long-term trends. Life expectancy increased in 2006 from 2005.


A Novobiocin Derivative, XN4, Inhibits the Proliferation of Chronic Myeloid Leukemia Cells by Inducing Oxidative DNA Damage.
XN4 might induce DNA damage and apoptotic cell death through reactive oxygen species (ROS). The inhibition of proliferation of K562 and K562/G01 cells was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide). The mRNA levels of NADPH oxidase 1-5 (Nox1-5) genes were evaluated by qRT-PCR. The levels of extracellular reactive oxygen species (ROS), DNA damage, apoptosis, and cell cycle progression were examined by flow cytometry (FCM). Protein levels were analyzed by immunoblotting. XN4 significantly inhibited the proliferation of K562 and K562/G01 cells, with IC50 values of 3.75±0.07 µM and 2.63±0.43 µM, respectively. XN4 significantly increased the levels of Nox4 and Nox5 mRNA, stimulating the generation of intracellular ROS, inducing DNA damage and activating ATM-γ-H2AX signaling, which increased the number of cells in the S and G2/M phase of the cell cycle. Subsequently, XN4 induced apoptotic cell death by activating caspase-3 and PARP. Moreover, the above effects were all reversed by the ROS scavenger N-acetylcysteine (NAC). Additionally, XN4 can induce apoptosis in progenitor/stem cells isolated from CML patients' bone marrow. In conclusion, XN4-induced DNA damage and cell apoptosis in CML cells is mediated by the generation of ROS.


Efficacy of early cognitive-linguistic treatment and communicative treatment in aphasia after stroke: a randomised controlled trial (RATS-2).
The two main approaches in aphasia treatment are cognitive-linguistic treatment (CLT), aimed at restoring the linguistic levels affected, semantics, phonology or syntax, and communicative treatment, aimed at optimising information transfer by training compensatory strategies and use of residual language skills. The hypothesis that CLT is more effective than communicative treatment in the early stages after stroke was tested in this study. In this multicentre, randomised, parallel group trial with blinded outcome assessment, 80 patients with aphasia after stroke were included within 3 weeks post-stroke. Patients received 6 months of CLT, comprising semantic and/or phonological training, or communicative treatment for at least 2 h per week. They were assessed before treatment and at 3 and 6 months with the Amsterdam-Nijmegen Everyday Language Test (ANELT-A, primary outcome) and semantic and phonological tests (secondary outcomes). The intervention effect was evaluated by means of analysis of covariance, with adjustment for baseline scores. There was no difference between the mean ANELT-A score of the CLT group (n=38) and the communicative treatment group (n=42), at 3 months (adjusted difference 1.5, 95% CI -2.6 to 5.6) or at 6 months (adjusted difference 1.6, 95% CI -2.3 to 5.6) post-stroke. On two of six specific semantic and phonological tests, the mean scores differed significantly, both in favour of CLT. This study does not confirm the hypothesis that patients with aphasia after stroke benefit more from CLT, aimed at activation of the underlying semantic and phonologic processes, than from general, non-specific communicative treatment (ISRCTN67723958 Current Controlled Trials).


Post-traumatic stress disorder: medicine and politics.
Regrettably, exposure to trauma is common worldwide, and can have serious adverse psychological results. The introduction of the notion of post-traumatic stress disorder has led to increasing medicalisation of the problem. This awareness has helped popular acceptance of the reality of post-traumatic psychiatric sequelae, which has boosted research into the pathogenesis of the disorder, leading to improved pharmacological and psychological management. The subjective experience of trauma and subsequent expression of symptoms vary considerably over space and time, and we emphasise that not all psychological distress or psychiatric disorders after trauma should be termed post-traumatic stress disorder. There are limits to the medicalisation of distress and there is value in focusing on adaptive coping during and after traumas. Striking a balance between a focus on heroism and resilience versus victimhood and pathological change is a crucial and constant issue after trauma for both clinicians and society. In this Review we discuss the advantages and disadvantages of medicalising trauma response, using examples from South Africa, the Armed Services, and post-disaster, to draw attention to our argument.


Retinoic acid signaling spatially restricts osteoblasts and controls ray-interray organization during zebrafish fin regeneration.
The zebrafish caudal fin consists of repeated units of bony rays separated by soft interray tissue, an organization that must be faithfully re-established during fin regeneration. How and why regenerating rays respect ray-interray boundaries, thus extending only the existing bone, has remained unresolved. Here, we demonstrate that a retinoic acid (RA)-degrading niche is established by Cyp26a1 in the proximal basal epidermal layer that orchestrates ray-interray organization by spatially restricting osteoblasts. Disruption of this niche causes preosteoblasts to ignore ray-interray boundaries and to invade neighboring interrays where they form ectopic bone. Concomitantly, non-osteoblastic blastema cells and regenerating blood vessels spread into the interrays, resulting in overall disruption of ray-interray organization and irreversible inhibition of fin regeneration. The cyp26a1-expressing niche plays another important role during subsequent regenerative outgrowth, where it facilitates the Shha-promoted proliferation of osteoblasts. Finally, we show that the previously observed distal shift of ray bifurcations in regenerating fins upon RA treatment or amputation close to the bifurcation can be explained by inappropriate preosteoblast alignment and does not necessarily require putative changes in proximodistal information. Our findings uncover a mechanism regulating preosteoblast alignment and maintenance of ray-interray boundaries during fin regeneration.


Magnesium protects against bile duct ligation-induced liver injury in male Wistar rats.
The aim of this study was to investigate the effects of magnesium sulfate (MgSO4) on cholestasis-induced hepatic injury after bile duct ligation (BDL) in male Wistar rats. In this study, the effects of 28-day, oral administration of MgSO4 (at doses of 0.01, 0.05, 0.1, and 0.2 g/kg bw) were evaluated in normal and BDL-induced cholestatic rats. The BDL group showed significant increases in serum levels of ALP, ALT, AST, GGT and significant decreases in hepatic SOD and catalase activities. BDL rats also had significant decreases in the serum levels of albumin, bilirubin, total cholesterol, triglycerides, and LDL. Administration of MgSO4 significantly attenuated these changes to nearly normal levels. Administrations of MgSO4 did not change these parameters in normal rats. Histopathological studies further confirmed the protective effects of MgSO4 on cholestasis-induced hepatic injury in the BDL rat model. Taken together, the results of this study suggest that MgSO4 treatment may be beneficial in cholestasis-induced hepatotoxicity.


A hybrid perturbed-chain SAFT density functional theory for representing fluid behavior in nanopores: mixtures.
The perturbed-chain statistical associating fluid theory (PC-SAFT) density functional theory developed in our previous work was extended to the description of inhomogeneous confined behavior in nanopores for mixtures. In the developed model, the modified fundamental measure theory and the weighted density approximation were used to represent the hard-sphere and dispersion free energy functionals, respectively, and the chain free energy functional from interfacial statistical associating fluid theory was used to account for the chain connectivity. The developed model was verified by comparing the model prediction with molecular simulation results, and the agreement reveals the reliability of the proposed model in representing the confined behaviors of chain mixtures in nanopores. The developed model was further used to predict the adsorption of methane-carbon dioxide mixtures on activated carbons, in which the parameters of methane and carbon dioxide were taken from the bulk PC-SAFT and those for solid surface were determined from the fitting to the pure-gas adsorption isotherms measured experimentally. The comparison of the model prediction with the available experimental data of mixed-gas adsorption isotherms shows that the model can reliably reproduce the confined behaviors of physically existing mixtures in nanopores.


scQCEA: a framework for annotation and quality control report of single-cell RNA-sequencing data.
Systematic description of library quality and sequencing performance of single-cell RNA sequencing (scRNA-seq) data is imperative for subsequent downstream modules, including re-pooling libraries. While several packages have been developed to visualise quality control (QC) metrics for scRNA-seq data, they do not include expression-based QC to discriminate between true variation and background noise. We present scQCEA (acronym of the single-cell RNA sequencing Quality Control and Enrichment Analysis), an R package to generate reports of process optimisation metrics for comparing sets of samples and visual evaluation of quality scores. scQCEA can import data from 10X or other single-cell platforms and includes functions for generating an interactive report of QC metrics for multi-omics data. In addition, scQCEA provides automated cell type annotation on scRNA-seq data using differential gene expression patterns for expression-based quality control. We provide a repository of reference gene sets, including 2348 marker genes, which are exclusively expressed in 95 human and mouse cell types. Using scRNA-seq data from 56 gene expressions and V(D)J T cell replicates, we show how scQCEA can be applied for the visual evaluation of quality scores for sets of samples. In addition, we use the summary of QC measures from 342 human and mouse shallow-sequenced gene expression profiles to specify optimal sequencing requirements to run a cell-type enrichment analysis function. The open-source R tool will allow examining biases and outliers over biological and technical measures, and objective selection of optimal cluster numbers before downstream analysis. scQCEA is available at https://isarnassiri.github.io/scQCEA/ as an R package. Full documentation, including an example, is provided on the package website.


Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein.
Deregulation of the evolutionarily conserved Notch signaling is highly correlated with oncogenesis. Intracellular activated Notch (ICN) is a protooncogene linked to the transcription activation of a number of cellular genes involved in cell cycle regulation, differentiation, and proliferation. Stability of ICN is tightly regulated by the Sel10-mediated ubiquitin-proteasome pathway. Sel10 can function as a negative regulator of Notch and exhibits activities of a tumor-suppressor protein. This article shows that the Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) directly interacts with Sel10 and forms a complex in KSHV-infected cells. This results in suppression of ICN ubiquitination and degradation. The carboxyl terminus of LANA interacts with the F-box and WD40 domains of Sel10 and competes with ICN for binding to Sel10. This elevated level of ICN is also critical for maintaining the enhanced proliferation of KSHV-infected tumor cells. These findings describe a mechanism by which the KSHV-encoded LANA protein regulates ubiquitination of ICN mediated by the F-box component of the E3 ligase Sel10, leading to proliferation of the virus-infected cells.


Integrated Histogenetic Analysis Reveals BAP1-Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary.
This case report presents a male patient with epithelioid mesothelioma that was initially misdiagnosed as cancer of unknown primary (CUP) and correctly identified using molecular panel sequencing. The patient had a prior history of colon and breast cancer. To assess the enlarged mediastinal lymph nodes, retrosternal lymphadenectomy was performed in 2016. The lymph nodes were histologically deemed unrelated to the known breast cancer by the reference pathologist, thus leading to the diagnosis of a CUP syndrome. When the patient presented to our center, targeted deep sequencing of both breast cancer and presumed CUP was performed to address the clonal relationship between both malignancies. A missense mutation in BAP1 was revealed in both samples, with coverage data indicating a germline event. The patient was subsequently counseled by a human geneticist and underwent genetic testing, which confirmed the germline nature of this mutation. Collectively, these data led to the diagnosis of BAP1 (BRCA1-associated protein-1) tumor predisposition syndrome (TPDS). With the knowledge of an underlying BAP1 mutation and its known frequent association with epithelioid mesothelioma, the histology was reassessed and the diagnosis was revised to epithelioid mesothelioma. At this point, peritoneal involvement of mesothelioma could be diagnosed and histologically confirmed. This case illustrates the potential of integrated histopathologic and molecular diagnostics in helping to decipher CUP syndromes and establish the correct diagnosis. Additionally, this case highlights typical features of BAP1 TPDS with its general susceptibility to cancers, with pleural and peritoneal mesotheliomas as most prevalent clinical entities and the typically more benign course of these epithelioid mesotheliomas compared with BAP1-unrelated cases of mesotheliomas.


Obesity and overweight associated with increased carotid diameter and decreased arterial function in young otherwise healthy men.
Obesity is linked to cardiovascular disease, stroke, increased mortality and vascular remodeling. Although increased arterial diameter is associated with multiple cardiovascular risk factors and obesity, it is unknown whether lumen enlargement is accompanied by unfavorable vascular changes in young and otherwise healthy obese individuals. The purpose of this study was to compare carotid and brachial artery diameter, blood pressure, arterial stiffness, and endothelial function in young, apparently healthy, normal-weight, overweight, and obese male subjects. One hundred sixty-five male subjects (27.39±0.59 years) were divided into 3 groups (normal weight, overweight, and obese) according to body mass index. Subjects underwent cardiovascular measurements to determine arterial diameter, function, and stiffness. After adjusting for age, the obese group had significantly greater brachial, carotid, and aortic pressures, brachial pulse wave velocity, carotid intima media thickness, and carotid arterial diameter compared with both the overweight and normal-weight groups. Obesity is associated with a much worse arterial profile, as an increased carotid lumen size was accompanied by higher blood pressure, greater arterial stiffness, and greater carotid intima media thickness in obese compared with overweight or normal-weight individuals. These data suggest that although obesity may be a factor in arterial remodeling, such remodeling is also accompanied by other hemodynamic and arterial changes consistent with reduced arterial function and increased cardiovascular risk.


Serological responses to Ehrlichia equi, Ehrlichia chaffeensis, and Borrelia burgdorferi in patients from New York State.
Serological testing at the New York State Department of Health for human granulocytic ehrlichiosis in the residents of Westchester County, N.Y., was performed with specimens from 176 patients by the indirect fluorescent-antibody (IFA) technique with Ehrlichia equi MRK-infected neutrophils. To understand whether human monocytotropic ehrlichiosis also occurs in this northeastern geographic region, specimens were also tested for antibodies to Ehrlichia chaffeensis Arkansas. Screening tests and immunoblots for Lyme disease (Borrelia burgdorferi infection) were also performed. Thirty-two patients had antibodies only to E. equi and 21 patients had antibodies to both E. equi and E. chaffeensis, whereas 12 patients had only E. chaffeensis antibodies by the IFA technique. The remaining patients did not have antibodies to either ehrlichia. Eighteen serum samples from 13 of these patients were coded and sent to the Ehrlichia Research Laboratory (Baltimore, Md.) for repeat analysis by the IFA test and for E. equi and E. chaffeensis immunoblots. Immunoblot analysis for E. equi in samples with positive IFA test results confirmed the results for eight of the nine specimens. Immunoblot analyses for E. chaffeensis were negative for all 18 serum samples. Borrelia-reactive antibodies were found in sera both from patients with granulocytic ehrlichiosis and from patients with monocytotropic ehrlichiosis from New York State. Our results suggest that E. equi antigen is an appropriate substrate for identifying human granulocytic ehrlichiosis. E. chaffeensis antigen lacks appropriate sensitivity to serve as a surrogate substrate for the detection of human granulocytic ehrlichiosis and should be used solely for the diagnosis of human monocytotropic ehrlichiosis. Heat shock proteins may, in some cases, cause cross-reactivity between B. burgdorferi and ehrlichiae.


Hypnosis for nausea and vomiting in cancer chemotherapy: a systematic review of the research evidence.
To systematically review the research evidence on the effectiveness of hypnosis for cancer chemotherapy-induced nausea and vomiting (CINV). A comprehensive search of major biomedical databases including MEDLINE, EMBASE, ClNAHL, PsycINFO and the Cochrane Library was conducted. Specialist complementary and alternative medicine databases were searched and efforts were made to identify unpublished and ongoing research. Citations were included from the databases' inception to March 2005. Randomized controlled trials (RCTs) were appraised and meta-analysis undertaken. Clinical commentaries were obtained. Six RCTs evaluating the effectiveness of hypnosis in CINV were found. In five of these studies the participants were children. Studies report positive results including statistically significant reductions in anticipatory and CINV. Meta-analysis revealed a large effect size of hypnotic treatment when compared with treatment as usual, and the effect was at least as large as that of cognitive-behavioural therapy. Meta-analysis has demonstrated that hypnosis could be a clinically valuable intervention for anticipatory and CINV in children with cancer. Further research into the effectiveness, acceptance and feasibility of hypnosis in CINV, particularly in adults, is suggested. Future studies should assess suggestibility and provide full details of the hypnotic intervention.


D-Alanylation of teichoic acids contributes to Lactobacillus plantarum-mediated Drosophila growth during chronic undernutrition.
The microbial environment influences animal physiology. However, the underlying molecular mechanisms of such functional interactions are largely undefined. Previously, we showed that during chronic undernutrition, strains of Lactobacillus plantarum, a major commensal partner of Drosophila, promote host juvenile growth and maturation partly through enhanced expression of intestinal peptidases. By screening a transposon insertion library of Lactobacillus plantarum in gnotobiotic Drosophila larvae, we identify a bacterial cell-wall-modifying machinery encoded by the pbpX2-dlt operon that is critical to enhance host digestive capabilities and promote animal growth and maturation. Deletion of this operon leads to bacterial cell wall alteration with a complete loss of D-alanylation of teichoic acids. We show that L. plantarum cell walls bearing D-alanylated teichoic acids are directly sensed by Drosophila enterocytes to ensure optimal intestinal peptidase expression and activity, juvenile growth and maturation during chronic undernutrition. We thus conclude that besides peptidoglycan, teichoic acid modifications participate in the host-commensal bacteria molecular dialogue occurring in the intestine.


Mortality trends of stranded marine mammals on Cape Cod and southeastern Massachusetts, USA, 2000 to 2006.
To understand the cause of death of 405 marine mammals stranded on Cape Cod and southeastern Massachusetts between 2000 and 2006, a system for coding final diagnosis was developed and categorized as (1) disease, (2) human interaction, (3) mass-stranded with no significant findings, (4) single-stranded with no significant findings, (5) rock and/or sand ingestion, (6) predatory attack, (7) failure to thrive or dependent calf or pup, or (8) other. The cause of death for 91 animals could not be determined. For the 314 animals that could be assigned a cause of death, gross and histological pathology results and ancillary testing indicated that disease was the leading cause of mortality in the region, affecting 116/314 (37%) of cases. Human interaction, including harassment, entanglement, and vessel collision, fatally affected 31/314 (10%) of all animals. Human interaction accounted for 13/29 (45%) of all determined gray seal Halichoerus grypus mortalities. Mass strandings were most likely to occur in northeastern Cape Cod Bay; 97/106 (92%) of mass stranded animals necropsied presented with no significant pathological findings. Mass strandings were the leading cause of death in 3 of the 4 small cetacean species: 46/67 (69%) of Atlantic white-sided dolphin Lagenorhynchus acutus, 15/21 (71%) of long-finned pilot whale Globicephala melas, and 33/54 (61%) of short-beaked common dolphin Delphinus delphis. These baseline data are critical for understanding marine mammal population health and mortality trends, which in turn have significant conservation and management implications. They not only afford a better retrospective analysis of strandings, but ultimately have application for improving current and future response to live animal stranding.


Defects in subventricular zone pigmented epithelium-derived factor niche signaling in the senescence-accelerated mouse prone-8.
We studied potential changes in the subventricular zone (SVZ) stem cell niche of the senescence-accelerated mouse prone-8 (SAM-P8) aging model. Bromodeoxyuridine (BrdU) assays with longtime survival revealed a lower number of label-retaining stem cells in the SAM-P8 SVZ compared with the SAM-Resistant 1 (SAM-R1) control strain. We also found that in SAM-P8 niche signaling is attenuated and the stem cell pool is less responsive to the self-renewal niche factor pigmented epithelium-derived factor (PEDF). Protein analysis demonstrated stable amounts of the PEDF ligand in the SAM-P8 SVZ niche; however, SAM-P8 stem cells present a significant expression decrease of patatin-like phospholipase domain containing 2, a receptor for PEDF (PNPLA2-PEDF) receptor, but not of laminin receptor (LR), a receptor for PEDF (LR-PEDF) receptor. We observed changes in self-renewal related genes (hairy and enhancer of split 1 (Hes1), hairy and enhancer of split 1 (Hes5), Sox2] and report that although these genes are down-regulated in SAM-P8, differentiation genes (Pax6) are up-regulated and neurogenesis is increased. Finally, sheltering mammalian telomere complexes might be also involved given a down-regulation of telomeric repeat binding factor 1 (Terf1) expression was observed in SAM-P8 at young age periods. Differences between these 2 models, SAM-P8 and SAM-R1 controls, have been previously detected at more advanced ages. We now describe alterations in the PEDF signaling pathway and stem cell self-renewal at a very young age, which could be involved in the premature senescence observed in the SAM-P8 model.


Comparative Evaluation of Conventional Stool Testing and Multiplex Molecular Panel in Outpatients With Relapse of Inflammatory Bowel Disease.
Differentiating between enteric infection and relapse of inflammatory bowel disease (IBD) is a common clinical challenge. Few studies have evaluated the impact of multiplex gastrointestinal polymerase chain reaction (GI PCR) pathogen panels on clinical practice compared to stool culture. Our aim was to compare the impact of PCR stool testing to conventional stool testing in outpatients presenting with relapse of IBD. In a retrospective cohort study of outpatients with IBD presenting to NYU Langone Health with flare from September 2015 to April 2019, we compared patients who underwent stool testing with GI PCR to age-, sex-, and IBD-subtype-matched patients who underwent culture and ova and parasite exam (conventional testing). The primary outcome was IBD therapy escalation after testing. Secondary outcomes included rates of posttesting endoscopy, abdominal radiography, antibiotics, and IBD-related emergency department visits, hospitalizations, and abdominal surgeries. We identified 134 patients who underwent GI PCR matched to 134 patients who underwent conventional testing. Pathogens were more frequently identified on GI PCR (26 vs 5%; P < 0.01). We found that GI PCR was associated with less escalation in IBD therapy (16 vs 29%; P < 0.01) and fewer posttest endoscopies (10% vs 18%; P = 0.04), with no differences in IBD outcomes. On multivariate analysis, testing with GI PCR was associated with an odds ratio of 0.26 (95% confidence interval, 0.08-0.84; P = 0.02) for escalation of IBD therapies. Testing with GI PCR was associated with higher rates of pathogen detection and lower rates of IBD therapy escalation and endoscopy in the outpatient setting. These changes in management were not associated with a difference in IBD outcomes.


[Advanced achievements about neuroprotective mechanisms of paeoniflorin].
Paeoniflorin is one of the bioactive components of Paeonia lactiflora, a traditional Chinese herbal medicine. Some recent studies prove its distinguished neuroprotective effect. These neuroprotective mechanisms have become hot points and show closely correlated to activating adenosine A1 receptor, ameliorating the function of cholinergic nerve, regulating ion channel homeostasis, retarding oxidative stress and apoptosis of the neurocytes, promoting nerve growth, having an influence on astrocytes and being ableto penetrate though blood brain barrier. In this review, we present the neuroprotective mechanisms of paeoniflorin in the following eight aspects.


Patterns of Lynx Predation at the Interface between Protected Areas and Multi-Use Landscapes in Central Europe.
In Central Europe, protected areas are too small to ensure survival of populations of large carnivores. In the surrounding areas, these species are often persecuted due to competition with game hunters. Therefore, understanding how predation intensity varies spatio-temporally across areas with different levels of protection is fundamental. We investigated the predation patterns of Eurasian lynx (Lynx lynx) on roe deer (Capreolus capreolus) and red deer (Cervus elaphus) in both protected areas and multi-use landscapes of the Bohemian Forest Ecosystem. Based on 359 roe and red deer killed by 10 GPS-collared lynx, we calculated the species-specific annual kill rates and tested for effects of season and lynx age, sex and reproductive status. Because roe and red deer in the study area concentrate in unprotected lowlands during winter, we modeled spatial distribution of kills separately for summer and winter and calculated-the probability of a deer killed by lynx and-the expected number of kills for areas with different levels of protection. Significantly more roe deer (46.05-74.71/year/individual lynx) were killed than red deer (1.57-9.63/year/individual lynx), more deer were killed in winter than in summer, and lynx family groups had higher annual kill rates than adult male, single adult female and subadult female lynx. In winter the probability of a deer killed and the expected number of kills were higher outside the most protected part of the study area than inside; in summer, this probability did not differ between areas, and the expected number of kills was slightly larger inside than outside the most protected part of the study area. This indicates that the intensity of lynx predation in the unprotected part of the Bohemian Forest Ecosystem increases in winter, thus mitigation of conflicts in these areas should be included as a priority in the lynx conservation strategy.


Error sources in deferred heterodyne moire deflectometry: an analytical study.
Effects of aperture size and shape of the photodetector and effects of the structure of the grating lines on the performance of deferred electronic heterodyne moire deflectometry are theoretically investigated. Deferred deflectometry is used for measurements of nonsteady phase objects for which it is difficult to complete the analysis of the field in real time. It has been shown that scanning of a moire fringe pattern parallel to an unshifted fringe yields periodical variations in the heterodyne phase and amplitude, which cause severe errors in the measurements. Theory indicates that these variations may be minimized by using a detector with square aperture of size rho/p = 1.0,2.0,3.0 ... or a circular detector with size rho/p =1.25,2.25,3.25... To minimize errors in deflection angle measurements, the fringe inclination due to the phase object should not exceed 15 degrees for a square detector and 13 degrees for a rho/p = 3.25 circular detector. Ronchi gratings with structure factor 0.5 less, similar q less, similar 0.7 are recommended.


A Core Outcome Set for the Benefits and Adverse Events of Bariatric and Metabolic Surgery: The BARIACT Project.
Bariatric and metabolic surgery is used as a treatment for patients with severe and complex obesity. However, there is a need to improve outcome selection and reporting in bariatric surgery trials. A Core Outcome Set (COS), an agreed minimum set of outcomes reported in all studies of a specific condition, may achieve this. Here, we present the development of a COS for BARIAtric and metabolic surgery Clinical Trials-the BARIACT Study. Outcomes identified from systematic reviews and patient interviews informed a questionnaire survey. Patients and health professionals were surveyed three times and asked to rate the importance of each item on a 1-9 scale. Delphi methods provided anonymised feedback to participants. Items not meeting predefined criteria were discarded between rounds. Remaining items were discussed at consensus meetings, held separately with patients and professionals, where the COS was agreed. Data sources identified 2,990 outcomes, which were used to develop a 130-item questionnaire. Round 1 response rates were moderate but subsequently improved to above 75% for other rounds. After rounds 2 and 3, 81 and 14 items were discarded, respectively, leaving 35 items for discussion at consensus meetings. The final COS included nine items: "weight," "diabetes status," "cardiovascular risk," "overall quality of life (QOL)," "mortality," "technical complications of the specific operation," "any re-operation/re-intervention," "dysphagia/regurgitation," and "micronutrient status." The main limitation of this study was that it was based in the United Kingdom only. The COS is recommended to be used as a minimum in all trials of bariatric and metabolic surgery. Adoption of the COS will improve data synthesis and the value of research data. Future work will establish methods for the measurement of the outcomes in the COS.


Post-infectious encephalomyelitis: some aetiological mechanisms.
The possibility that acute disseminated encephalomyelitis (ADEM) and epidemic myalgic encephalomyelitis ('epidemic neuromyasthenia') may share a common pathogenesis is examined and many factors common to the two diseases are described. It is suggested that further study of ADEM may help our understanding of epidemic myalgic encephalomyelitis.


Purchase of medications without prescription in Peru: a cross-sectional population-based study.
Background: Low availability of medicines in health services, self-medication, inadequate use of medicines, and inadequate dispensing practices in pharmacies are frequent problems in Peru. We aimed to evaluate how frequent the purchase of medications without medical prescription is in Peru, and which factors are associated with this practice. Methods: We conducted a secondary analysis of the 2016 ENSUSALUD national survey data. Purchase of medicines that require a prescription was measured as a dichotomous coded as bought one or more medicines that requires medical prescription or bought medicines that do not require a prescription. Crude and adjusted prevalence ratios (PR) and their 95% confidence intervals (95% CI) were calculated using Poisson regressions model with robust variance to assess the association of purchasing of medicines that require prescriptions with sociodemographic factors. Results: There were 3858 participants in the dataset. The prevalence of purchasing medications without prescriptions was 47.2%. History of having previously consumed the same medication (31.6%), and the delay in receiving an appointment at health facilities (26.9%) were the main reasons to buy medications without a prescription. Regarding the recommendation of the medication purchased, the advice of the pharmacy, and remembering a previous old prescription, were the most frequent reasons (38.3%, and 25.9%, respectively). On the multivariable analysis, users that buy medications without prescription were more likely to be of aged 24-45; reside in the Amazon and Highlands regions; and self-consumption of the purchase. Individuals with Seguro Integral de Salud (Comprehensive Health Insurance) were less likely to buy medications without prescription. Conclusions: There is a high prevalence of prescription requiring medication being bought without one from pharmacies in Peru. It is necessary to include the evaluation of consumer patterns to develop strategies with the aim to regulate the consumption of prescription drugs in the Peruvian population.


ABA is required for Leptosphaeria maculans resistance via ABI1- and ABI4-dependent signaling.
Abscisic acid (ABA) is a defense hormone with influence on callose-dependent and -independent resistance against Leptosphaeria maculans acting in the RLMcol pathway. ABA-deficient and -insensitive mutants in Ler-0 background (abal-3 and abil-1) displayed susceptibility to L. maculans, along with a significantly decreased level of callose depositions, whereas abi2-1 and abi3-1 remained resistant, together with the abi5-1 mutant of Ws-0 background. Suppressor mutants of abil-1 confirmed that the L. maculans-susceptible response was due to the dominant negative nature of the abil-1 mutant. Highly induced camalexin levels made ABA mutants in Col-0 background (aba2-1, aba3-1, and abi4-1) appear resistant, but displayed enhanced susceptibility as double mutants with pad3-1, impaired in camalexin biosynthesis. beta-Aminobutyric acid (BABA) pretreatment of Ler-0 contributed to an elevated level of endogenous ABA after L. maculans inoculation. Comparisons between (RLM1co1)pad3 and rlmlLerpad3 showed that ABA and BABA enhancement of callose deposition requires induction from RLM1col. ABII, but not ABI2, was found to be involved in a feedback mechanism that modulates RLM1co, expression. Genetic analysis showed further that this feedback occurs upstream of ABI4 and that components downstream of ABI4 modulate ABIJ activity. ABA and BABA treatments of the L. maculans-susceptible callose synthase mutant pmr4 showed that ABA also induces a callose-independent resistance. Similar treatments enhanced callose depositions and induced resistance to L. maculans in oilseed rape, and BABA-induced resistance was found to be independent of salicylic acid.


Movement behavior profiles and obesity: a latent profile analysis of 24-h time-use composition among Danish workers.
An element of obesity prevention is increasing total physical activity energy expenditure. However, this approach does not incorporate the balance of various movement behaviors-physical activity, sedentary behaviors and sleep-across domains of the day. We aimed to identify time-use profiles over work and leisure, termed 'movement behavior profiles' and to investigate their association with obesity. Eight-hundred-and-seven workers completed (a) thigh accelerometry and diaries to determine their 24-h composition of behaviors (sedentary and standing, light physical activity and moderate-to-vigorous physical activity at work and leisure, and time in bed) and (b) obesity measurements. Movement behavior profiles were determined using latent profile analyses of isometric log-ratios of the 24-h composition, and labeled according to animal movement behavior traits. Linear models were applied to determine the association between profiles and obesity. Four profiles were identified, labeled as "Chimpanzees" (n = 226), "Lions" (n = 179), "Ants" (n = 244), and "Koalas" (n = 158). "Chimpanzees" work time was evenly distributed between behaviors while their leisure time was predominantly active. Compared to Chimpanzees, "Lions" were more active at work and sedentary during leisure and spent more time in bed; "Ants" were more active at work and during leisure; "Koalas" were more sedentary at work and leisure and spent similar time in bed. With "Chimpanzees" as reference, "Lions" had least favorable obesity indicators: +2.0 (95% confidence interval [CI] 0.6, 3.4) %body fat, +4.3 cm (1.4, 7.3) waist circumference and +1.0 (2.0, 0.0) Body Mass Index (BMI), followed by "Koalas" +2.0 (0.4, 3.7) %body fat, +3.1 cm (0.1, 6.0) waist circumference, and +0.8 (-0.30, 1.94) BMI. No significant differences were found between "Chimpanzees" and "Ants". Movement behavior profiles across work and leisure time-use compositions are associated with obesity. Achieving adequate balance between work and leisure movement behaviors should be further investigated as a potential obesity prevention strategy.


Family history of suicide and personality.
The objective of this study was to analyze the impact of family history of suicidal behaviour on psychopathlogical features of inmates. A sample of 1,179 prisoners had a psychiatric interview including the Brown-Goodwin Assessment for Lifetime History of Aggression (BGLHA). Prisoners completed the Barratt Impulsivity Scale (BIS), Buss-Durkee Hostility Inventory (BDHI), and Eysenck Personality Questionnaire (EPQ). Prisoners with a family history of suicide were compared with prisoners without a family history of suicide on clinical and personality variables. Seventy of the 1,179 prisoners (5.9%) had a family history of suicide. Significantly more FHS positive prisoners had attempted suicide compared with FHS negative prisoners (36% vs. 12%, P < 0.0001). Significantly more FHS positive prisoners had a previous history of convictions, a history of juvenile convictions, and had exhibited aggressive behavior in jail. FHS positive prisoners had significantly higher aggression scores on the BGLHA, higher hostility scores on the BDHI, higher impulsivity scores on the BIS, and higher neuroticism scores on the EPQ. A family history of suicide may be a useful clinical indicator that a prisoner is at increased risk for suicidal behaviour and may have problems with impulsive-aggression.


ASA failure: does the combination ASA/clopidogrel confer better long-term vascular protection?
To assess whether adding clopidogrel to acetylsalicylic acid (ASA) has a long-term protective vascular effect in patients with lacunar stroke while taking ASA. Post hoc analysis of 838 patients with ASA failure and recent lacunar stroke from the Secondary Prevention of Small Subcortical Strokes Trial (SPS3) cohort randomly allocated to aspirin (325 mg/day) and clopidogrel (75 mg/day) or placebo. Primary efficacy outcome was stroke recurrence (ischemic and intracranial hemorrhage) and main safety outcome was major extracranial hemorrhage. Patients were followed for a mean period of 3.5 years. The ASA failure group had a significantly higher risk of vascular events including ischemic stroke when compared with the non-ASA failure group (n = 2,151) in SPS3 (p = 0.03). Mean age was 65.6 years and 65% were men. The risk of recurrent stroke was not reduced in the dual antiplatelet group, 3.1% per year, compared to the aspirin-only group, 3.3% per year (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.61-1.37). There was also no difference between groups for ischemic stroke (HR 0.90; 95% CI 0.59-1.38). The risk of gastrointestinal bleeding was higher in the dual antiplatelet group (HR 2.7; 95% CI 1.1-6.9); however, the risk of intracranial hemorrhage was not different. In patients with a recent lacunar stroke while taking ASA, the addition of clopidogrel did not result in reduction of vascular events vs continuing ASA only. This study provides Class I evidence that for patients with recent lacunar stroke while taking ASA, adding clopidogrel as compared to continuing ASA alone does not reduce the risk of recurrent stroke.


Multiple transcriptome mining coupled with tissue specific molecular cloning and mass spectrometry provide insights into agatoxin-like peptide conservation in decapod crustaceans.
Over the past decade, in silico genome and transcriptome mining has led to the identification of many new crustacean peptide families, including the agatoxin-like peptides (ALPs), a group named for their structural similarity to agatoxin, a spider venom component. Here, analysis of publicly accessible transcriptomes was used to expand our understanding of crustacean ALPs. Specifically, transcriptome mining was used to investigate the phylogenetic/structural conservation, tissue localization, and putative functions of ALPs in decapod species. Transcripts encoding putative ALP precursors were identified from one or more members of the Penaeoidea (penaeid shrimp), Sergestoidea (sergestid shrimps), Caridea (caridean shrimp), Astacidea (clawed lobsters and freshwater crayfish), Achelata (spiny/slipper lobsters), and Brachyura (true crabs), suggesting a broad, and perhaps ubiquitous, conservation of ALPs in decapods. Comparison of the predicted mature structures of decapod ALPs revealed high levels of amino acid conservation, including eight identically conserved cysteine residues that presumably allow for the formation of four identically positioned disulfide bridges. All decapod ALPs are predicted to have amidated carboxyl-terminals. Two isoforms of ALP appear to be present in most decapod species, one 44 amino acids long and the other 42 amino acids in length, both likely generated by alternative splicing of a single gene. In carideans, a gene or terminal exon duplication appears to have occurred, with alternative splicing producing four ALPs, two 44 and two 42 amino acid isoforms. The identification of ALP precursor-encoding transcripts in nervous system-specific transcriptomes (e.g., Homarus americanus brain, eyestalk ganglia, and cardiac ganglion assemblies, finding confirmed using RT-PCR) suggests that members of this peptide family may serve as locally-released and/or hormonally-delivered neuromodulators in decapods. Their detection in testis- and hepatopancreas-specific transcriptomes suggests that members of the ALP family may also play roles in male reproduction and innate immunity/detoxification.