Early changes in pulmonary functions after mitral valve replacement.
This study evaluates changes in pulmonary functions before and after mitral valve replacement (MVR). Twenty-five patients with rheumatic mitral lesions who had undergone MVR were divided into three groups, based on New York Heart Association (NYHA) class. They were evaluated for changes in pulmonary functions, preoperatively and postoperatively at 1 week, 1 month and 3 months to find any improvements after MVR. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), peak expiratory flow rates were universally found to be decreased preoperatively. Total lung capacity (TLC) and diffusion capacity (DLCO) were significantly reduced preoperatively in NYHA Class III and IV. The pulmonary functions further declined at 1 week after surgery. Except for FVC in NYHA Class IV (32.3% improvement, P < 0.05), the changes were statistically insignificant. Pulmonary functions deteriorate immediately after surgery and then recover gradually over a period of 3 months. However, they remain below the predicted values.


Heart rate recovery post 6-minute walking test in obstructive sleep apnea: cycle ergometry versus 6-minute walking test in OSA patients.
To examine the clinical usefulness of heart rate recovery (HRR) post 6-minute walking test (6MWT) as a simple marker of cardiovascular risk in obstructive sleep apnea (OSA) patients in comparison to HRR post cycle ergometry, the validated and more sophisticated protocol. Seventy-four participants underwent full overnight polysomnography, cycle ergometry and 6MWT. The HRR at 1, 2 and 3 min (HRR-1, HRR-2 and HRR-3) 6MWT was compared to HRR at 1, 2, and 3 min post cycle ergometry in normal subjects and in moderate and severe OSA patients before and after 6-month CPAP treatment. The HRR-1, HRR-2 and HRR-3 in 6MWT were significantly different between normal, moderate and severe OSA patients with higher rates achieved in normal. The higher the severity of OSA the lower the HRR was. There were also no differences found between work rate and distance walked during cycle ergometry or 6MWT, respectively, concerning normal, moderate and severe OSA patients. Heart rate recovery was further associated with minimum saturation of oxygen during sleep independently of the duration of apnea episodes of BMI and ESS. The treatment with CPAP had a beneficial effect on HRR both post-6MWT and post cycle ergometry. Autonomic nervous system dysfunction in OSA can be found even with submaximal exertion. Heart rate recovery post-6MWT, such as HRR post cycle ergometry, was significantly impaired in OSA patients in comparison to normals and was favorably influenced from CPAP treatment. Furthermore, it was found to be more sensitive compared with distance walked in 6MWT in discriminating severity of OSA. The HRR post-6MWT was found to be an easily measured and reliable marker of OSA severity both before and after CPAP treatment.


Vernalizing cold is registered digitally at FLC.
A fundamental property of many organisms is an ability to sense, evaluate, and respond to environmental signals. In some situations, generation of an appropriate response requires long-term information storage. A classic example is vernalization, where plants quantitatively sense long-term cold and epigenetically store this cold-exposure information to regulate flowering time. In Arabidopsis thaliana, stable epigenetic memory of cold is digital: following long-term cold exposure, cells respond autonomously in an all-or-nothing fashion, with the fraction of cells that stably silence the floral repressor flowering locus C (FLC) increasing with the cold exposure duration. However, during cold exposure itself it is unknown whether vernalizing cold is registered at FLC in individual cells in an all-or-nothing (digital) manner or is continuously varying (analog). Using mathematical modeling, we found that analog registration of cold temperature is problematic due to impaired analog-to-digital conversion into stable memory. This disadvantage is particularly acute when responding to short cold periods, but is absent when cold temperatures are registered digitally at FLC. We tested this prediction experimentally, exposing plants to short periods of cold interrupted with even shorter warm breaks. For FLC expression, we found that the system responds similarly to both interrupted and uninterrupted cold, arguing for a digital mechanism integrating long-term temperature exposure.


Measuring mental health in amyotrophic lateral sclerosis (ALS): a comparison of the SF-36 Mental Health Index with the Psychological General Well-Being Index.
The purpose of this study was to compare the performance of the five-item mental health dimension of SF-36 (the Mental Health Index, MHI-5) with that of the 22-item Psychological General Well-Being Index (PGWB) in patients presenting with amyotrophic lateral sclerosis/motor neuron disease, using tests of reliability and validity. A questionnaire-based survey of patients diagnosed with ALS across 15 European countries. Patients presenting at neurological clinics for treatment of their ALS were asked to join the survey. 1048 patients with ALS have been recruited, of whom 861 (82.2%) have returned baseline questionnaires. There was evidence supporting the internal consistency of both instruments, and for their construct validity in distinguishing between groups, in terms of gender and age. The scores on the two instruments were highly correlated (Spearman rank correlation 0.85). Both the MHI-5 and the PGWB showed high levels of construct validity and internal reliability in this patient group. The MHI-5 has comparable psychometric performance to the PGWB, and can be used to measure and compare mental health in defined populations.


Impact of hepatic rearterialization on reperfusion injury and outcome after mouse liver transplantation.
Nonarterialized mouse liver transplantation is a well-established model for immunologic studies on rejection and tolerance mechanisms. However, the importance of graft arterialization has-in contrast to rat liver transplantation-not been thoroughly examined in the mouse model. The aim of the current study was to investigate the impact of arterial reconstruction on long-term graft survival, histologic alterations, ischemic liver damage, and early immunologic activation pathways. All recipients of arterialized (n=6) and nonarterialized (n=8) syngeneic liver grafts survived indefinitely. There were no differences in their histologic architecture, including no evidence of bile duct proliferation, periductal fibrosis, or alterations in serum transaminases, in long-term survivors from either group. Twenty-four hours after syngeneic liver transplantation, aspartate aminotransferase and alanine aminotransferase levels were increased to an equivalent extent in both groups, in agreement with early reperfusion injury and solitary traumatic injuries as assessed histologically (n=3 per group). Visualized by immunohistochemistry, intercellular adhesion molecule-1 expression was increased on sinusoidal and hepatic vein endothelium at both 1 and 100 days after transplantation, in both arterialized and nonarterialized grafts. Messenger RNA for interleukin-1, interferon-gamma, and tumor necrosis factor-alpha were measured by real-time polymerase chain reaction 24 hr after transplantation. No significant changes in the expression of cytokine mRNA levels were observed. Arterialization of mouse liver grafts does not appear to have a major impact on survival rate or the degree of immunologic activation. Therefore, the value of arterial reconstruction in mouse liver transplantation for experimental investigations is negligible.


The microbiota-gut-brain axis as a key regulator of neural function and the stress response: Implications for human and animal health.
The brain-gut-microbiota axis comprises an extensive communication network between the brain, the gut, and the microbiota residing there. Development of a diverse gut microbiota is vital for multiple features of behavior and physiology, as well as many fundamental aspects of brain structure and function. Appropriate early-life assembly of the gut microbiota is also believed to play a role in subsequent emotional and cognitive development. If the composition, diversity, or assembly of the gut microbiota is impaired, this impairment can have a negative impact on host health and lead to disorders such as obesity, diabetes, inflammatory diseases, and even potentially neuropsychiatric illnesses, including anxiety and depression. Therefore, much research effort in recent years has focused on understanding the potential of targeting the intestinal microbiota to prevent and treat such disorders. This review aims to explore the influence of the gut microbiota on host neural function and behavior, particularly those of relevance to stress-related disorders. The involvement of microbiota in diverse neural functions such as myelination, microglia function, neuronal morphology, and blood-brain barrier integrity across the life span, from early life to adolescence to old age, will also be discussed. Nurturing an optimal gut microbiome may also prove beneficial in animal science as a means to manage stressful situations and to increase productivity of farm animals. The implications of these observations are manifold, and researchers are hopeful that this promising body of preclinical work can be successfully translated to the clinic and beyond.


Isoquercitrin attenuates the osteoclast-mediated bone loss in rheumatoid arthritis via the Nrf2/ROS/NF-κB pathway.
An excess of osteoclastogenesis significantly contributes to the development of rheumatoid arthritis (RA). Activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) ligand (RANKL)-induced reactive oxygen species (ROS)-to-NF-κB signaling cascade are important mechanisms regulating osteoclastogenesis; however, whether Nrf2 is involved in RANKL-induced NF-κB activation is controversial. Isoquercitrin, a natural flavonoid compound, has been shown to have Nrf2-dependent antioxidant effects inprevious studies. We sought to verify whether isoquercitrin could modulate RANKL-induced NF-κB activation by activating Nrf2, thereby affecting osteoclastogenesis. Tartrate-resistant acid phosphatase staining, F-actin ring staining and resorption pit assay suggested that isoquercitrin significantly inhibited osteoclastogenesis and osteolytic function. Mitosox staining showed that RANKL-induced ROS generation was significantly inhibited by isoquercitrin from day 3 of the osteoclast differentiation cycle. Quantitative real-time PCR, Western blot, and immunofluorescence indicated that isoquercitrin activated the Nrf2 signaling pathway and inhibited NF-κB expression. And when we used the Nrf2-specific inhibitor ML385, the inhibition of NF-κB by isoquercitrin disappeared. Moreover, we found that Nrf2 is not uninvolved in RANKL-induced NF-κB activation and may be related to the timing of ROS regulation. When we limited isoquercitrin administration to 2 days, Nrf2 remained activated and the inhibition of NF-κB disappeared. In vivo experiments suggested that isoquercitrin attenuated RA modeling-induced bone loss. Overall, isoquercitrin-activated Nrf2 blocked the RANKL-induced ROS-to-NF-κB signaling cascade response, thereby inhibiting osteoclastogenesis and bone loss. These findings provide new ideas for the treatment of RA.


Human immunodeficiency viruses: neutralization and receptors.
The envelope glycoproteins of HIV, gp120 and gp41, contain epitopes recognized by neutralizing antibodies. Studies of human sera from infected individuals indicate that group-specific neutralization antigens common to most isolates of HIV-1 exist, and that some HIV-2 antisera cross-neutralize HIV-1. Neutralization epitopes for HIV-1 have been identified and mapped, including a group-specific antigen on gp41, and a type-specific antigen on gp120. Neutralization "escape" mutants have been selected in vitro with a neutralizing mab to the type-specific antigenic loop. The CD4 antigen binds HIV-1 gp120 with high affinity and acts as the receptor on human and simian T-lymphocytes and monocytes for all strains of HIV-1, HIV-2, and SIV tested. Following binding to the CD4 receptor, HIV becomes internalized by a pH-independent process. The principle binding domain for gp120 is located in the N-terminal V domain of CD4. Anti-idiotypic sera to CD4 mabs recognizing the same site weakly neutralize HIVs of many strains, and soluble, recombinant forms of CD4 strongly neutralize HIV. Neither anti-CD4 mabs nor sCD4 inhibit the low level of plating of HIV observed on tumour cells in culture of glial (brain) and muscle origin, indicating that CD4 is not essential for infection of these cell types.


The contribution of genomics in the medicine of tomorrow, clinical applications and issues.
Fifteen years after the completion of first human genome sequencing, the technique is almost a commodity but there is still little evidence of its usefulness as a diagnostic, prognostic or therapeutic tool. In France, the France genomics plan 2025 was launched in 2015 with the goal of integrating genomic tests into clinical practice and developing a National genomics network including industrial partnerships. Reflection on scientific applications and operational or societal issues is needed to make recommendations to help better associate Genomics and the medicine of tomorrow. In the perspective of personalized Evidence-based Medicine, studies with an appropriate methodological level to improve the definition of evidence should be promoted. The many operational challenges require the implementation of organisations and means to streamline the process of results reporting, and regulatory adaptations concerning the status of professions involved, the management of data generated, and the consent of patients. In parallel, genetic training for healthcare professionals and raising awareness on genetic tests for the public should be considered. The ethical stake should also be taken into account, especially on the participation of the patient in decisions concerning them and integrating the notion of uncertainty into the information given. The sociological effects on the experience and expectations of patients and the general population towards genomic medicine should also be evaluated to improve information, prevention and support for people. Finally, medico-economic studies must be conducted to inform policy-makers on the cost-effectiveness of complete genome sequencing for population health.


Structure and expression of the fliA operon of Salmonella typhimurium.
The fliA gene encodes the flagellum-specific sigma factor sigma28 In Salmonella typhimurium. The transcription in vivo and in vitro of this gene was analysed and it was found that there are two promoters for the expression of this gene. One is a class 2 promoter which is recognized by sigma70-RNA polymerase in the presence of the FlhD and FlhC activator proteins. The other is a class 3 promoter which is recognized by sigma28-RNA polymerase. Therefore, the fliA operon is under dual positive control from FlhD/FlhC and from FliA itself. The nucleotide sequence downstream of the fliA gene was determined. The sequence contains two ORFs following the fliA gene. On the basis of their sequence homology, it is concluded that these two correspond to the fliZ and fliY genes of Escherichia coil. Northern blot analysis revealed that the fliZ gene is transcribed from the fliA promoters, whereas the fliY gene is transcribed from both the fliA promoters and its own FlhD/FlhC-independent promoter. A fliZ-disruption mutant was constructed by inserting a kanamycin-resistance gene cassette into the fliZ gene on the chromosome. The mutant showed poor motility, and introduction of a fliZ+ plasmid into this mutant restored the wildtype level of motility. These results suggest that the fliZ gene may be required for expression of maximal motility.


The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans.
Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115; (3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in humans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis.


Aedes Mosquito Salivary Components and Their Effect on the Immune Response to Arboviruses.
Vector-borne diseases are responsible for over a billion infections each year and nearly one million deaths. Mosquito-borne dengue virus, West Nile, Japanese encephalitis, Zika, Chikungunya, and Rift Valley Fever viruses constitute major public health problems in regions with high densities of arthropod vectors. During the initial step of the transmission cycle, vector, host, and virus converge at the bite site, where local immune cells interact with the vector's saliva. Hematophagous mosquito saliva is a mixture of bioactive components known to modulate vertebrate hemostasis, immunity, and inflammation during the insect's feeding process. The capacity of mosquito saliva to modulate the host immune response has been well-studied over the last few decades and has led to the consensus that the presence of saliva is linked to the enhancement of virus transmission, host susceptibility, disease progression, viremia levels, and mortality. We review some of the major aspects of the interactions between mosquito saliva and the host immune response that may be useful for future studies on the control of arboviruses.


Methodologies and study designs relevant to medical education research.
Research is an important part of educational scholarship. Knowledge of research methodologies is essential for both conducting research as well as determining the soundness of the findings from published studies. Our goals for this paper therefore are to inform medical education researchers of the range and key components of educational research designs. We will discuss both qualitative and quantitative approaches to educational research. Qualitative methods will be presented according to traditions that have a distinguished history in particular disciplines. Quantitative methods will be presented according to an evidence-based hierarchy akin to that of evidence-based medicine with the stronger designs (systematic reviews and well conducted educational randomized controlled trials) at the top, and weaker designs (descriptive studies without comparison groups, or single case studies) at the bottom. It should be appreciated, however, that the research question determines the study design. Therefore, the onus is on the researcher to choose a design that is appropriate to answering the question. We conclude with an overview of how educational researchers should describe the study design and methods in order to provide transparency and clarity.


Ring synthetic chromosome V SCRaMbLE.
Structural variations (SVs) exert important functional impacts on biological phenotypic diversity. Here we show a ring synthetic yeast chromosome V (ring_synV) can be used to continuously generate complex genomic variations and improve the production of prodeoxyviolacein (PDV) by applying Synthetic Chromosome Recombination and Modification by LoxP-mediated Evolution (SCRaMbLE) in haploid yeast cells. The SCRaMbLE of ring_synV generates aneuploid yeast strains with increased PDV productivity, and we identify aneuploid chromosome I, III, VI, XII, XIII, and ring_synV. The neochromosome of SCRaMbLEd ring_synV generated more unbalanced forms of variations, including duplication, insertions, and balanced forms of translocations and inversions than its linear form. Furthermore, of the 29 novel SVs detected, 11 prompted the PDV biosynthesis; and the deletion of uncharacterized gene YER182W is related to the improvement of the PDV. Overall, the SCRaMbLEing ring_synV embraces the evolution of the genome by modifying the chromosome number, structure, and organization, identifying targets for phenotypic comprehension.


The Cutaneous Wound Innate Immunological Microenvironment.
The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.


Posttraumatic Growth Inventory: Factor Structure in the Context of DSM-IV Traumatic Events.
Studies examining the dimensionality of the Posttraumatic Growth Inventory (PTGI) have yielded varying results. To date, no study has investigated the measure's factor structure in the context of DSM-defined traumatic events. The present study examined the structure in an undergraduate student sample (N = 379) reporting DSM-IV Criterion-A potentially traumatic events. Confirmatory factor analysis (CFA) did not support the original five-factor structure. Follow-up exploratory factor analysis and CFA on random halves of the sample showed poor model fit for 1-, 3-, and 7-factor models. Results suggest that the PTGI factor structure is unclear amongst individuals with DSM-IV traumatic events, and continued use of the total score is most appropriate. Future directions including the utility of the PTGI factors are discussed.


Cost of refractory epilepsy in adults in the USA.
A cost of illness of refractory epilepsy was developed based on estimates supplied by an expert panel of physicians and a review of the current literature. The basic elements of model can be divided into two main components: direct and indirect costs. Direct costs include the medical resource utilization patterns associated with epilepsy care while the indirect costs represent lost productivity associated with the disease. The results of the analysis indicate that an estimated 24,578 incident cases of epilepsy incur a total of $318,582,669; while our prevalence estimates indicate that 335,167 individuals incur a total of $3,905,183,463, in a given year. Direct medical costs account for one-third of the total costs while indirect costs constitute the remaining two-thirds.


Wood Smoke Particle Sequesters Cell Iron to Impact a Biological Effect.
The biological effect of an inorganic particle (i.e., silica) can be associated with a disruption in cell iron homeostasis. Organic compounds included in particles originating from combustion processes can also complex sources of host cell iron to disrupt metal homeostasis. We tested the postulate that (1) wood smoke particle (WSP) sequesters host cell iron resulting in a disruption of metal homeostasis, (2) this loss of essential metal results in both an oxidative stress and biological effect in respiratory epithelial cells, and (3) humic-like substances (HULIS), a component of WSP, have a capacity to appropriate cell iron and initiate a biological effect. BEAS-2B cells exposed to WSP resulted in diminished concentrations of mitochondrial (57)Fe, whereas preincubation with ferric ammonium citrate (FAC) prevented significant mitochondrial iron loss after such exposure. Cellular oxidant generation was increased after WSP exposure, but this signal was diminished by coincubation with FAC. Similarly, exposure of BEAS-2B cells to 100 μg/mL WSP activated mitogen-activated protein (MAP) kinases, elevated NF-E2-related factor 2/antioxidant responsive element (Nrf2 ARE) expression, and provoked interleukin (IL)-6 and IL-8 release, but all these changes were diminished by coincubation with FAC. The biological response to WSP was reproduced by exposure to 100 μg/mL humic acid, a polyphenol comparable to HULIS included in the WSP that complexes iron. We conclude that (1) the biological response following exposure to WSP is associated with sequestration of cell iron by the particle, (2) increasing available iron in the cell diminished the biological effects after particle exposure, and (3) HULIS included in WSP can sequester the metal initiating the cell response.


Comparison of Cd(II), Cu(II), and Pb(II) biouptake by green algae in the presence of humic acid.
The present study examines the role of humic acid, as a representative of dissolved organic matter, in Cd(II), Cu(II), and Pb(II) speciation and biouptake by green microalgae. Cellular and intracellular metal fractions were compared in the presence of citric and humic acids. The results demonstrated that Cd and Cu uptake in the presence of 10 mg L(-1) humic acid was consistent with that predicted from measured free metal concentrations, while Pb biouptake was higher. By comparing Cd, Cu, and Pb cellular concentrations in the absence and presence of humic acid, it was found that the influence of the increased negative algal surface charge, resulting from humic acid adsorption, on cellular metal was negligible. Moreover, the experimental results for all three metals were in good agreement with the ternary complex hypothesis. Given that metal has much higher affinity with algal sites than humic acid adsorbed to algae, the contribution of the ternary complex to metal bioavailability was negligible in the case of Cd (II) and Cu (II). In contrast, the ternary complex contributed to over 90% of total cellular metal for Pb(II), due to the comparable affinity of Pb to algal sites in comparison with humic acid adsorbed to algae. Therefore, the extension of the biotic ligand model by including the formation of the ternary complex between the metal, humic acid, and algal surface would help to avoid underestimation of Pb biouptake in the presence of humic substances by green algae Chlorella kesslerii.


Implementation, quality control and selected pregnancy outcomes of the Murmansk County Birth Registry in Russia.
To describe the essential features of the newly established Murmansk County Birth Registry (MCBR); make some preliminary comparisons of selected variables related to pregnancy and delivery in northern counties of the Nordic countries and in cities and towns of Murmansk County [Murmanskaja Oblast (MO)] and explore some research possibilities. A registry-based cohort study. The MCBR was established in 2005 and registration began on 1 January 2006. A registry form draws upon both hospital files and information from the mother. There are 54 major fields consisting primarily of tick-off boxes and International Classification of Diseases (ICD-10) codes. A quality control exercise was conducted in both 2006 and 2007. During 2006, 8,468 births were registered in the MO (coverage = 98.9%). The proportion of errors was below 1% in both years. Limiting the descriptive statistics to 2006, compared to counties of the Nordic counties in the Barents Region, the delivering women in the MO were younger and had fewer and lighter (mean of 200 g) babies. The gestational age was somewhat shorter in the MO than in the Nordic counties and fewer babies had a birthweight above 4,500 g. The perinatal mortality corresponding to a gestational age (GA) of either 22 or 28 completed weeks was higher (p < 0.02) in the MO than the Nordic counties in this study. In the MO, the birth rate does not balance the reported increase in death rate. Our study concludes that a medical birth registry of satisfactory quality has been established for the world's largest arctic population.


Urinary concentrating defect in mice lacking Epac1 or Epac2.
cAMP is a universal second messenger regulating a plethora of processes in the kidney. Two downstream effectors of cAMP are PKA and exchange protein directly activated by cAMP (Epac), which, unlike PKA, is often linked to elevation of [Ca2+]i. While both Epac isoforms (Epac1 and Epac2) are expressed along the nephron, their relevance in the kidney remains obscure. We combined ratiometric calcium imaging with quantitative immunoblotting, immunofluorescent confocal microscopy, and balance studies in mice lacking Epac1 or Epac2 to determine the role of Epac in renal water-solute handling. Epac1-/- and Epac2-/- mice developed polyuria despite elevated arginine vasopressin levels. We did not detect major deficiencies in arginine vasopressin [Ca2+]i signaling in split-opened collecting ducts or decreases in aquaporin water channel type 2 levels. Instead, sodium-hydrogen exchanger type 3 levels in the proximal tubule were dramatically reduced in Epac1-/- and Epac2-/- mice. Water deprivation revealed persisting polyuria, impaired urinary concentration ability, and augmented urinary excretion of Na+ and urea in both mutant mice. In summary, we report a nonredundant contribution of Epac isoforms to renal function. Deletion of Epac1 and Epac2 decreases sodium-hydrogen exchanger type 3 expression in the proximal tubule, leading to polyuria and osmotic diuresis.-Cherezova, A., Tomilin, V., Buncha, V., Zaika, O., Ortiz, P. A., Mei, F., Cheng, X., Mamenko, M., Pochynyuk, O. Urinary concentrating defect in mice lacking Epac1 or Epac2.


Guidelines on treatment of perinatal depression with antidepressants: An international review.
Several countries have developed Clinical Practice Guidelines regarding treatment of perinatal depressive symptoms and perinatal use of antidepressant. We aimed to compare guidelines to guide clinicians in best clinical practice. An extensive search in guideline databases, MEDLINE and PsycINFO was performed. When no guidelines were (publicly) available online, we contacted psychiatric-, obstetric-, perinatal- and mood disorder societies of all first world countries and the five largest second world countries. Only Clinical Practice Guidelines adhering to quality criteria of the Appraisal of Guidelines for Research and Evaluation instrument and including a systematic review of evidence were included. Data extraction focussed on recommendations regarding continuation or withdrawal of antidepressants and preferred treatment in newly depressed patients. Our initial search resulted in 1094 articles. After first screening, 40 full-text articles were screened. Of these, 24 were excluded for not being an official Clinical Practice Guidelines. In total, 16 Clinical Practice Guidelines were included originating from 12 countries. Eight guidelines were perinatal specific and eight were general guidelines. During pregnancy, four guidelines advise to continue antidepressants, while there is a lack of evidence supporting this recommendation. Five guidelines do not specifically advise or discourage continuation. For new episodes, guidelines agree on psychotherapy (especially cognitive behavioural therapy) as initial treatment for mild to moderate depression and antidepressants for severe depression, with a preference for sertraline. Paroxetine is not preferred treatment for new episodes but switching antidepressants for ongoing treatment is discouraged (three guidelines). If mothers use antidepressants, observation of the neonate is generally recommended and breastfeeding encouraged.


Multinational, pilot audit of a Velcro adjustable compression wrap system for venous and lymphatic conditions.
The aim of this small pilot audit was to record the performance of an adjustable Velcro compression wrap, ReadyWrap, and the experiences of patients and health-care professionals using the system as a self-care option for the management of venous and lymphatic leg conditions in both the treatment and maintenance phases. This audit was held within a 4-week review period. Participants included venous leg ulcer (VLU) patients with and without oedema, and patients with lymphoedema. Where open wounds were present they were managed with debridement, skin care and dressings according to clinical need. Lymphoedema patients received manual lymphatic drainage and skin care regimens as per standard practice. The Velcro system evaluated formed part of a treatment pathway with compression bandages and/or compression hosiery as clinically indicated. Patients, carers and health-care professionals applied the garments following assessment and training. Objective data recorded included change in circumferential measurements and improvement in wound status. Observation of health-care professionals, patients and carers with regard to the comfort and ease of application/removal of the device were recorded. There were 17 patients included in the audit. Within the 4-week period a reduction in limb circumference was recorded in all cases. Improvements in open wounds were recorded in most cases. Following the 4-week audit period 94% of the application of the device was performed by either the patient (59%) or the carer (35%) thereby reducing the health-care professional contact that was required for application. Early results in this small audit demonstrate that this adjustable Velcro compression wrap may provide a simple, clinically effective and patient-acceptable solution for self-care with compression. Use of this type of device could have the potential to reduce overall health-care burden by reducing necessary skilled treatment visits and/or cost while still achieving good clinical outcomes. Further studies are required to confirm this pilot study and provide additional data.


Encounter with mesoscale eddies enhances survival to settlement in larval coral reef fishes.
Oceanographic features, such as eddies and fronts, enhance and concentrate productivity, generating high-quality patches that dispersive marine larvae may encounter in the plankton. Although broad-scale movement of larvae associated with these features can be captured in biophysical models, direct evidence of processes influencing survival within them, and subsequent effects on population replenishment, are unknown. We sequentially sampled cohorts of coral reef fishes in the plankton and nearshore juvenile habitats in the Straits of Florida and used otolith microstructure analysis to compare growth and size-at-age of larvae collected inside and outside of mesoscale eddies to those that survived to settlement. Larval habitat altered patterns of growth and selective mortality: Thalassoma bifasciatum and Cryptotomus roseus that encountered eddies in the plankton grew faster than larvae outside of eddies and likely experienced higher survival to settlement. During warm periods, T. bifasciatum residing outside of eddies in the oligotrophic Florida Current experienced high mortality and only the slowest growers survived early larval life. Such slow growth is advantageous in nutrient poor habitats when warm temperatures increase metabolic demands but is insufficient for survival beyond the larval stage because only fast-growing larvae successfully settled to reefs. Because larvae arriving to the Straits of Florida from distant sources must spend long periods of time outside of eddies, our results indicate that they have a survival disadvantage. High productivity features such as eddies not only enhance the survival of pelagic larvae, but also potentially increase the contribution of locally spawned larvae to reef populations.


Investigation and management of an outbreak of Salmonella Typhimurium DT8 associated with duck eggs, Ireland 2009 to 2011.
Salmonella Typhimurium DT8 was a very rare cause of human illness in Ireland between 2000 and 2008, with only four human isolates from three patients being identified. Over a 19-month period between August 2009 and February 2011, 34 confirmed cases and one probable case of Salmonella Typhimurium DT8 were detected, all of which had an MLVA pattern 2-10-NA-12-212 or a closely related pattern. The epidemiological investigations strongly supported a linkbetween illness and exposure to duck eggs. Moreover, S. Typhimurium with an MLVA pattern indistinguishable (or closely related) to the isolates from human cases, was identified in 22 commercial and backyard duck flocks, twelve of which were linked with known human cases. A range of control measures were taken at farm level, and advice was provided to consumers on the hygienic handling and cooking of duck eggs. Although no definitive link was established with a concurrent duck egg-related outbreak of S. Typhimurium DT8 in the United Kingdom, it seems likely that the two events were related. It may be appropriate for other countries with a tradition of consuming duck eggs to consider the need for measures to reduce the risk of similar outbreaks.


Animal performance and economic comparison of novel and toxic endophyte tall fescues to cool-season annuals.
Increased costs of annual establishment of small grain pasture associated with fuel, machinery, and labor are eroding the profitability of stocker cattle enterprises. Interest has therefore increased in development of cool-season perennial grasses that are persistent and high quality. This study occurred on 24 ha (divided into thirty 0.81-ha paddocks) located at the University of Arkansas Division of Agriculture Livestock and Forestry Branch Station, near Batesville. Two tall fescue (Festuca arundinacea Schreb.) cultivars infected with novel endophytes (NE), Jesup infected with AR542 endophyte (Jesup AR542), and HiMag infected with Number 11 endophyte (HM11) were established in September 2002. Jesup AR542 and HM11 were compared with endemic endophyte Kentucky 31 (KY-31) tall fescue; wheat (Triticum aestivum L.) and cereal rye (WR, Secale cereale L.) planted in September 2003, 2004, and 2005; and annual ryegrass [RG, Lolium perenne L. ssp. multiflorum (Lam.) Husnot] planted in September 2004 and 2005. Each year, 3 steers (3.7 steers/ha) were placed on each pasture for fall and winter grazing, and 5 steers (6.2 steers/ha) were placed on each pasture for spring grazing. Animal performance is presented by year in the presence of a year x treatment interaction (P < 0.01). Body weight gain per hectare of steers grazing NE tall fescue was greater (P < 0.01) than those of KY-31 and WR during 2003 to 2004, whereas in 2004 to 2005, BW gain per hectare of steers grazing NE and RG did not differ (P < or = 0.29) and was greater (P < 0.01) than that of WR, which was greater (P < 0.01) than that of KY-31. During 2005 to 2006, BW gain per hectare was greater (P < 0.01) for steers grazing RG than those of NE and WR, which did not differ (P > or = 0.14). Body weight gain per hectare was least (P < 0.01) for steers grazing KY-31. Average net return of NE tall fescue was greater (P < 0.01) than KY-31, but profitability of NE did not consistently differ from cool-season annuals. Across the 3-yr study, NE tall fescue produced net returns per hectare of $219; this level of profitability would require 4 yr for a new planting of NE tall fescue to break even. Novel endophyte tall fescues offer potential benefits related to decreased risk of stand establishment of annual forage crops, longer growing season, and acceptable animal performance.


Male Caregivers: Shifting Roles Among Family Caregivers.
More than 16 million men in the United States are acting in the role of family caregiver. Men are usually viewed as not being caring simply because they provide care differently than women. However, this is not the case. This article explores male caregiving from the perspective of family and professional roles. A review of the literature related to men in the caregiving role was conducted. This review included only men providing care to a family member and was limited to men caring for an adult. The main traits of male caregivers were defined as masculinization of caregiving behaviors, social support needs, and caregiver role strain/emotional aspects of caring. Men in the caregiving role must be supported. Education related to how men provide care is needed. Hands-on education should also be provided to men in the family caregiving role.


hnRNPK Recruits PCGF3/5-PRC1 to the Xist RNA B-Repeat to Establish Polycomb-Mediated Chromosomal Silencing.
The Polycomb-repressive complexes PRC1 and PRC2 play a key role in chromosome silencing induced by the non-coding RNA Xist. Polycomb recruitment is initiated by the PCGF3/5-PRC1 complex, which catalyzes chromosome-wide H2A lysine 119 ubiquitylation, signaling recruitment of other PRC1 complexes, and PRC2. However, the molecular mechanism for PCGF3/5-PRC1 recruitment by Xist RNA is not understood. Here we define the Xist RNA Polycomb Interaction Domain (XR-PID), a 600 nt sequence encompassing the Xist B-repeat element. Deletion of XR-PID abolishes Xist-dependent Polycomb recruitment, in turn abrogating Xist-mediated gene silencing and reversing Xist-induced chromatin inaccessibility. We identify the RNA-binding protein hnRNPK as the principal XR-PID binding factor required to recruit PCGF3/5-PRC1. Accordingly, synthetically tethering hnRNPK to Xist RNA lacking XR-PID is sufficient for Xist-dependent Polycomb recruitment. Our findings define a key pathway for Polycomb recruitment by Xist RNA, providing important insights into mechanisms of chromatin modification by non-coding RNA.


Associations of Distance to Trauma Care, Community Income, and Neighborhood Median Age With Rates of Injury Mortality.
Rural, low-income, and historically underrepresented minority communities face substantial barriers to trauma care and experience high injury incidence and mortality rates. Characteristics of injury incident locations may contribute to poor injury outcomes. To examine the association of injury scene characteristics with injury mortality. In this cross-sectional study, data from trauma center and emergency medical services provided by emergency medical services companies and designated trauma centers in the state of Maryland from January 1, 2015, to December 31, 2015, were geocoded by injury incident locations and linked with injury scene characteristics. Participants included adults who experienced traumatic injury in Maryland and were transported to a designated trauma center or died while in emergency medical services care at the incident scene or in transit. The primary exposures of interest were geographic characteristics of injury incident locations, including distance to the nearest trauma center, designation level and ownership status of the nearest trauma center, and land use, as well as community-level characteristics such as median age and per capita income. Odds of death were estimated with multilevel logistic regression, controlling for individual demographic measures and measures of injury and health. Of the 16 082 patients included in this study, 8716 (52.4%) were white, and 5838 (36.3%) were African American. Most patients were male (10 582; 65.8%) and younger than 65 years (12 383; 77.0%). Odds of death increased by 8.0% for every 5-mile increase in distance to the nearest trauma center (OR, 1.08; 95% CI, 1.01-1.15; P = .03). Compared with privately owned level 1 or 2 centers, odds of death increased by 49.9% when the nearest trauma center was level 3 (OR, 1.50; 95% CI, 1.06-2.11; P = .02), and by 80.7% when the nearest trauma center was publicly owned (OR, 1.81; 95% CI, 1.39-2.34; P < .001). At the zip code tabulation area level, odds of death increased by 16.0% for every 5-year increase in median age (OR, 1.16; 95% CI, 1.03-1.30; P = .02), and decreased by 26.6% when the per capita income was greater than $25 000 (OR, 0.73; 95% CI, 0.54-0.99; P = .05). Injury scene characteristics are associated with injury mortality. Odds of death are highest for patients injured in communities with higher median age or lower per capita income and at locations farthest from level 1 or 2 trauma centers.


BF2-Functionalized Benzothiazole Amyloid Markers: Effect of Donor Substituents on One- and Two-Photon Properties.
Investigation of amyloids with the aid of fluorescence microscopy provides crucial insights into the development of numerous diseases associated with the formation of aggregates. Here, we present a series of BF2-functionalized benzothiazoles with electron-donating methoxy group(s), which are tested as amyloid fluorescent markers. We evaluate how the position of donor functional group(s) influences optical properties (fluorescence lifetime (τ) and fluorescence quantum yield (FQY)) in a solution and upon binding to amyloids. We elucidate the importance of surrounding environmental factors (hydrogen-bonding network, polarity, and viscosity) on the observed changes in FQY and evaluate how the localization of a donor influences radiative and nonradiative decay pathways. We conclude that a donor attached to the benzothiazole ring contributes to the increment of radiative decay pathways upon binding to amyloids (kr), while the donor attached to the flexible part of a molecule (with rotational freedom) contributes to a decrease in nonradiative decay pathways (knr). We find that the donor-acceptor-donor architecture allows us to obtain 58 times higher FQY of the dye upon binding to bovine insulin amyloids. Finally, we measure two-photon absorption (2PA) cross sections (σ2) of the dyes and their change upon binding by the two-photon excited fluorescence (2PEF) technique. Measurements reveal that dyes that exhibit the increase/decrease of σ2 values when transferred from highly polar solvents to CHCl3 present a similar behavior upon amyloid binding. Our 2PA experimental values are supported by quantum mechanics/molecular mechanics (QM/MM) simulations. Despite this trend, the values of σ2 are not the same, which points out the importance of two-photon absorption measurements of amyloid-dye complexes in order to understand the performance of 2P probes upon binding.


DNA probe-based classification of Simulium damnosum s. l.-borne and human-derived filarial parasites in the onchocerciasis control program area.
The development of polymerase chain reaction-based methods using strain- and species-specific DNA probes for Onchocerca volvulus has permitted classification of individual parasites from every stage of the parasite's life cycle. This technology has been applied on a large scale basis by Onchocerciasis Control Program (OCP) in West Africa. The primary objective of the OCP in using the DNA probes was to obtain accurate estimates of the annual transmission potential of the blinding strain of O. volvulus. The DNA probe classification of larvae collected throughout the OCP area demonstrated that larvae of less pathogenic strains of O. volvulus and other filarial parasites carried by Simulium damnosum s.l. have resulted in a significant overestimation of the annual transmission potential for blinding onchocerciasis. This effect is particularly pronounced along the southern border of the OCP, where the blinding and less pathogenic strains of O. volvulus coexist, and in the north of the control area, where animal parasites, particularly O. ochengi, may even predominate. A second objective of the OCP in applying the DNA probe technology was to determine the distribution of blinding and less pathogenic O. volvulus in infected individuals along the southern border of the control area. Results obtained from these studies have generally confirmed the distribution pattern established by previous epidemiologic studies. In addition, DNA probe classifications have demonstrated that in areas where the blinding and less pathogenic strains of O. volvulus coexist, a single individual may simultaneously be infected with both strains of the parasite.


Allelic associations and homozygosity at loci from HLA-B to D6S299 in genetic haemochromatosis.
Haemochromatosis (GH) is an autosomal recessive disorder in which increased iron absorption causes iron overload. The gene (HFE) is closely linked to HLA-A on chromosome 6 (6p21.3) but has not yet been identified. We have examined eight polymorphic loci, HLA-B (most centromeric), I82, D6S265, HLA-A, D6S128, HLA-F, D6S105, and D6S299 (most telomeric) in 37 unrelated patients and 60 control subjects. There are also significant positive associations between GH and alleles at all loci except D6S299. Analysis of 48 GH chromosomes in which haplotypes could be established showed that the most common haplotype was I82-2:D6S265-1:HLA-A3:D6S128-2:HLA-F1:D6S105-8. This was present in 28 of 48 chromosomes. In 14 the haplotype included HLA-B7 but only in seven did this extend beyond the telomere to D6S299-2 (the most common allele on GH chromosomes at this locus). In 36 out of 48 chromosomes the two locus haplotype, F1:D6S105-8 was present. Since haemochromatosis appears to originate from a founder mutation we have examined linkage disequilibrium between these various loci and GH using calculations of pexcess. The maximum value (0.72, 95% CI 0.55-0.85) is given by D6S105-8 but is not significantly different from values for HLA-A3 and HLA-F1 (0.50, 95% CI 0.34-0.61 and 0.49, 0.25-0.66 respectively). However, both HLA-A and D6S105 give a value for pexcess which is significantly higher than that for the most centromeric marker, HLA-B (0.17, 95% CI 0.02-0.30). We have counted the number of patients who are homozygous for the common allele at each locus. At D6S105, 22 patients are homozygous for allele 8, with 18 homozygous for HLA-F1 and 10 homozygous for A3. The pattern of cumulative homozygosity suggests a gene location closer to D6S105 than HLA-A. We have also analysed our data for divergence from the apparent founder haplotype (A3:F1:105-8) and have calculated the theoretical frequencies of crossovers between loci. These data suggest a location telomeric to D6S105. A more precise localisation of the gene may be possible with the identification of new markers around D6S105.


The US Air Force suicide prevention program: implications for public health policy.
We evaluated the effectiveness of the US Air Force Suicide Prevention Program (AFSPP) in reducing suicide, and we measured the extent to which air force installations implemented the program. We determined the AFSPP's impact on suicide rates in the air force by applying an intervention regression model to data from 1981 through 2008, providing 16 years of data before the program's 1997 launch and 11 years of data after launch. Also, we measured implementation of program components at 2 points in time: during a 2004 increase in suicide rates, and 2 years afterward. Suicide rates in the air force were significantly lower after the AFSPP was launched than before, except during 2004. We also determined that the program was being implemented less rigorously in 2004. The AFSPP effectively prevented suicides in the US Air Force. The long-term effectiveness of this program depends upon extensive implementation and effective monitoring of implementation. Suicides can be reduced through a multilayered, overlapping approach that encompasses key prevention domains and tracks implementation of program activities.


Environmental coupling of selection and heritability limits evolution.
There has recently been great interest in applying theoretical quantitative genetic models to empirical studies of evolution in wild populations. However, while classical models assume environmental constancy, most natural populations exist in variable environments. Here, we applied a novel analytical technique to a long-term study of birthweight in wild sheep and examined, for the first time, how variation in environmental quality simultaneously influences the strength of natural selection and the genetic basis of trait variability. In addition to demonstrating that selection and genetic variance vary dramatically across environments, our results show that environmental heterogeneity induces a negative correlation between these two parameters. Harsh environmental conditions were associated with strong selection for increased birthweight but low genetic variance, and vice versa. Consequently, the potential for microevolution in this population is constrained by either a lack of heritable variation (in poor environments) or by a reduced strength of selection (in good environments). More generally, environmental dependence of this nature may act to limit rates of evolution, maintain genetic variance, and favour phenotypic stasis in many natural systems. Assumptions of environmental constancy are likely to be violated in natural systems, and failure to acknowledge this may generate highly misleading expectations for phenotypic microevolution.


Effectiveness of back school versus McKenzie exercises in patients with chronic nonspecific low back pain: a randomized controlled trial.
Back School and McKenzie methods are popular active treatment approaches that include both exercises and information for patients with chronic nonspecific low back pain. The purpose of this study was to compare the effectiveness of Back School and McKenzie methods in patients with chronic nonspecific low back pain. The study was a prospectively registered, 2-arm randomized controlled trial with a blinded assessor. The study was conducted in the outpatient physical therapy clinic in São Paulo, Brazil. The study participants were 148 patients with chronic nonspecific low back pain. The 4-week treatment program (one session/week) was based on the Back School (delivered to the group) or McKenzie (delivered individually) principles. The participants also were instructed to perform a daily set of home exercises. Clinical outcomes were assessed at follow-up appointments at 1, 3, and 6 months after randomization. Primary outcome measures were pain intensity (measured by the 0-10 pain numerical rating scale) and disability (measured by the 24-item Roland-Morris Disability Questionnaire) 1 month after randomization. Secondary outcome measures were pain intensity and disability at 3 and 6 months after randomization, quality of life (measured by the World Health Organization Quality of Life-BREF instrument) at 1, 3, and 6 months after randomization, and trunk flexion range of motion measured by an inclinometer at 1 month after randomization. The data were collected by a blinded assessor. Participants allocated to the McKenzie group had greater improvements in disability at 1 month (mean effect=2.37 points, 95% confidence interval=0.76 to 3.99) but not for pain (mean effect=0.66 points, 95% confidence interval=-0.29 to 1.62). No between-group differences were observed for all secondary outcome measures. It was not possible to monitor the home exercise program. Therapists and participants were not blinded. The McKenzie method (a more resource-intensive intervention) was slightly more effective than the Back School method for disability, but not for pain intensity immediately after treatment in participants with chronic low back pain.


Effect of propafenone on Kv1.4 inactivation.
Interactions between antiarrhythmic drugs and ion channels are important subjects in the field of cardiovascular electro-pharmacology. This study explores the relationship between propafenone and C-type inactivation of Kv1.4 channel. fKvl.4deltaN, a ferret Kv1.4 N-terminal deleted mutant, was employed in this study. fKvl.4deltaN cRNA was injected into Xenopus oocytes to express fKvl.4deltaN channel and two electrode voltage clamp technique was used to record the current. We found that fKvl.4deltaN channel current was rapidly depressed in a frequency-dependent manner and meanwhile, C-type inactivation in this channel was increased more than 7 folds in the presence of 100 microM propafenone. While propafenone has no effect on Kv1.4deltaN recovery. All the results indicate that propafenone blocks Kvl.4deltaN channel through intracellular bindings and that binding of propafenone with Kvl.4deltaN channel leads to a conformational change on the extracellular site which accelerates C-type inactivation, suggesting that propafenone, as an open channel blocker, may affect the mechanism of C-type inactivation.


A transverse isotropic viscoelastic constitutive model for aortic valve tissue.
A new anisotropic viscoelastic model is developed for application to the aortic valve (AV). The directional dependency in the mechanical properties of the valve, arising from the predominantly circumferential alignment of collagen fibres, is accounted for in the form of transverse isotropy. The rate dependency of the valve's mechanical behaviour is considered to stem from the viscous (η) dissipative effects of the AV matrix, and is incorporated as an explicit function of the deformation rate ([Formula: see text]). Model (material) parameters were determined from uniaxial tensile deformation tests of porcine AV specimens at various deformation rates, by fitting the model to each experimental dataset. It is shown that the model provides an excellent fit to the experimental data across all different rates and satisfies the condition of strict local convexity. Based on the fitting results, a nonlinear relationship between η and [Formula: see text] is established, highlighting a 'shear-thinning' behaviour for the AV with increase in the deformation rate. Using the model and these outcomes, the stress-deformation curves of the AV tissue under physiological deformation rates in both the circumferential and radial directions are predicted and presented. To verify the predictive capabilities of the model, the stress-deformation curves of AV specimens at an intermediate deformation rate were estimated and validated against the experimental data at that rate, showing an excellent agreement. While the model is primarily developed for application to the AV, it may be applied without the loss of generality to other collagenous soft tissues possessing a similar structure, with a single preferred direction of embedded collagen fibres.


New method of Scoliosis Deformity Assessment: ISIS2 System.
Scoliosis deformity has been assessed using radiographic angle measurements. Surface topography systems are an alternative and complementary methodology. Working systems include the original ISIS1 system, Quantec and COMOT techniques. Over the last five years the new ISIS2 (Integrated Shape Imaging System) has been developed from basic principles to improve the speed, accuracy, reliability and ease of use of ISIS1. The aim of this study was to confirm that ISIS2 3D back shape measurements are valid for assessment and follow up of patients with scoliosis. Three-dimensional back measurements were performed in Oxford. ISIS2 includes a camera/projector stand, patient stand with a reference plane, and Mac computer. Pixel size is approximately 0.5 mm with fringe frequency of approximately 0.16 fringes/mm ( approximately 6.5 mm/fringe). Clinical reports in pdf format are of coloured images with numerical values. Reports include a height map, contour plot, transverse section plots, coronal plot, sagittal sections and bilateral asymmetry maps. A total of 520 ISIS2 scans on 242 patients were performed from February 2006 to December 2007. There were 58 male patients (median age 16 years, SD 3.71, min 7, max 25) and 184 female patients (median age 14.5 years, SD 3.23, min 5, max 45). Average number of scans per patient was 2.01 with the range of 1-10 scans. Right sided thoracic curves were the most frequent pattern. The median values and 95% CI are reported of back length; pelvic rotation; flexion/extension; imbalance; lateral asymmetry; skin angle; kyphosis angle; lordosis angle; volumetric asymmetry. ISIS2 scoliosis measurements are non-invasive, low-cost, three-dimensional topographic back measurements which can be confidently used in scoliosis assessment and monitoring of curve progression.


Sulfated Polysaccharides in the Freshwater Green Macroalga Cladophora surera Not Linked to Salinity Adaptation.
The presence of sulfated polysaccharides in cell walls of seaweeds is considered to be a consequence of the physiological adaptation to the high salinity of the marine environment. Recently, it was found that sulfated polysaccharides were present in certain freshwater Cladophora species and some vascular plants. Cladophora (Ulvophyceae, Chlorophyta) is one of the largest genera of green algae that are able to grow in both, seas and freshwater courses. Previous studies carried out on the water-soluble polysaccharides of the marine species C. falklandica established the presence of sulfated xylogalactoarabinans constituted by a backbone of 4-linked β-L-arabinopyranose units partially sulfated mainly on C3 and also on C2 with partial glycosylation, mostly on C2, with terminal β-D-xylopyranose or β-D-galactofuranose units. Besides, minor amounts of 3-, 6- and/or 3,6-linked β-D-galactan structures, with galactose in the pyranosic form were detected. In this work, the main water soluble cell wall polysaccharides from the freshwater alga Cladophora surera were characterized. It was found that this green alga biosynthesizes sulfated polysaccharides, with a structure similar to those found in marine species of this genus. Calibration of molecular clock with fossil data suggests that colonization of freshwater environments occurred during the Miocene by its ancestor. Therefore, the presence of sulfated polysaccharides in the freshwater green macroalga C. surera could be, in this case, an adaptation to transient desiccation and changes in ionic strength. Retention of sulfated polysaccharides at the cell walls may represent a snapshot of an evolutionary event, and, thus constitutes an excellent model for further studies on the mechanisms of sulfation on cell wall polysaccharides and environmental stress co-evolution.


Outbreak of Shiga toxin-producing Escherichia coli O104:H4 associated with organic fenugreek sprouts, France, June 2011.
On 22 June 2011, 8 patients with hemolytic uremic syndrome (HUS) or bloody diarrhea were reported in France. All 8 were attendees of a community center event on 8 June near Bordeaux. Three Escherichia coli cases were confirmed by isolation of Shiga toxin-producing E. coli O104:H4 stx2 aggR producing a cefotaximase (CTX-M) β-lactamase (STEC O104:H4); the same rare serotype caused the outbreak in Germany in May-July 2011. An investigation was initiated to describe the outbreak, identify the vehicle for infection, and guide control measures. We conducted a retrospective cohort study among all adults attending the event, including food handlers. A standardized questionnaire was administered to participants. A case was an attendee who developed HUS or diarrhea between 8 and 24 June. Cases were confirmed by isolation of STEC O104:H4 or O104 serology. Relative risks (RRs) and 95% confidence intervals (CIs) by exposure were calculated using a Poisson regression model. Twenty-four cases were identified (14% attack rate). Of these, 18 (75%) were women, 22 (92%) were adults, 7 (29%) developed HUS, 5 (21%) developed bloody diarrhea, and 12 (50%) developed diarrhea. Ten (42%) cases were confirmed. Fenugreek was the only sprout type with an independent association to illness (RR, 5.1; 95% CI, 2.3-11.1) in multivariable analysis. This investigation identified a point-source STEC O104:H4 outbreak associated with consumption of fenugreek sprouts. Comparison of results from French and German STEC O104:H4 outbreak investigations enabled identification of a common food vehicle, fenugreek sprouts, and resulted in implementation of Europe-wide control measures in July 2011.


High frequency of HIV mutations associated with HLA-C suggests enhanced HLA-C-restricted CTL selective pressure associated with an AIDS-protective polymorphism.
Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the HLA-C gene that correlates with differential expression of the HLA-C Ag. This polymorphism was recently shown to be a marker for a protective variant in the 3'UTR of HLA-C that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with "high" HLA-C expression show a stronger HLA-C-restricted immune response exerting better viral control than that of their counterparts has not been established. We hypothesized that the magnitude of the HLA-C-restricted immune pressure on HIV would be greater in subjects with highly expressed HLA-C alleles. Using a cohort derived from a unique narrow source epidemic in China, we identified mutations in HIV proviral DNA exclusively associated with HLA-C, which were used as markers for the intensity of the immune pressure exerted on the virus. We found an increased frequency of mutations in individuals with highly expressed HLA-C alleles, which also correlated with IFN-γ production by HLA-C-restricted CD8(+) T cells. These findings show that immune pressure on HIV is stronger in subjects with the protective genotype and highlight the potential role of HLA-C-restricted responses in HIV control. This is, to our knowledge, the first in vivo evidence supporting the protective role of HLA-C-restricted responses in nonwhites during HIV infection.


Association Between Dyslipidemia and Dry Eye Syndrome Among the Korean Middle-Aged Population.
Dry eye syndrome (DES) is a common eye disease caused by tear deficiency or excessive tear evaporation. Because the tear film layers play a major role in the pathogenesis of the evaporative dry eye, some previous articles have suggested the possible mechanism of dyslipidemia and DES. However, the previous results were inconsistent and few studies were conducted to find the independent relationship between dyslipidemia and DES. Therefore, we investigated the association of dyslipidemia with DES in middle-aged Korean adults. This study was conducted on 2272 participants (854 men and 1418 women) enrolled in the Study Group for Environmental Eye Disease (2013-2017) after excluding people who have taken lipid-lowering medication. Participants with total cholesterol ≥240 mg/dL or high-density lipoprotein cholesterol <40 mg/dL or low-density lipoprotein cholesterol ≥160 mg/dL or triglycerides ≥200 mg/dL are defined as having dyslipidemia. Using the ocular surface disease index, we measured the DES severity and defined DES as an ocular surface disease index score ≥13. Men with dyslipidemia had an odds ratio of 1.29 (95% confidence interval, 0.97-1.71) for DES in an unadjusted model compared with those without DES. After adjusting for age, body mass index, hypertension, diabetes, occupations, smoking and drinking status, exercise, contact lens use, computer use, study cohorts, and calendar year of examinations, the adjusted odds ratio for DES was 1.40 (1.03-1.90) in men. However, there was no significant association between dyslipidemia and DES in women, even after stratifying by menopausal status. Our findings suggest that dyslipidemia may be associated with the prevalence of DES in Korean men, but not in women.


In-kind incentives and health worker performance: Experimental evidence from El Salvador.
We experimentally evaluated the effects of in-kind team incentives on health worker performance in El Salvador, with 38 out of 75 community health teams randomly assigned to performance incentives over a 12-month period. All teams received monitoring, performance feedback and recognition for their achievements allowing us to isolate the effect of the incentive. While both treatment and control groups exhibit improvements in performance measures over time, the in-kind incentives generated significant improvements in community outreach, quality of care, timeliness of care, and utilization of maternal and child health services after 12 months. Gains were largest for teams at the bottom and top of the baseline performance distribution. We find no evidence of results being driven by changes in reporting or by shifting away effort from non-contracted outcomes. These results suggest that in-kind team incentives may be a viable alternative to monetary or individual incentives in certain contexts.


Whole-face procedures for recovering facial images from memory.
Research has indicated that traditional methods for accessing facial memories usually yield unidentifiable images. Recent research, however, has made important improvements in this area to the witness interview, method used for constructing the face and recognition of finished composites. Here, we investigated whether three of these improvements would produce even-more recognisable images when used in conjunction with each other. The techniques are holistic in nature: they involve processes which operate on an entire face. Forty participants first inspected an unfamiliar target face. Nominally 24h later, they were interviewed using a standard type of cognitive interview (CI) to recall the appearance of the target, or an enhanced 'holistic' interview where the CI was followed by procedures for focussing on the target's character. Participants then constructed a composite using EvoFIT, a recognition-type system that requires repeatedly selecting items from face arrays, with 'breeding', to 'evolve' a composite. They either saw faces in these arrays with blurred external features, or an enhanced method where these faces were presented with masked external features. Then, further participants attempted to name the composites, first by looking at the face front-on, the normal method, and then for a second time by looking at the face side-on, which research demonstrates facilitates recognition. All techniques improved correct naming on their own, but together promoted highly-recognisable composites with mean naming at 74% correct. The implication is that these techniques, if used together by practitioners, should substantially increase the detection of suspects using this forensic method of person identification.


The role of stress in absenteeism: cortisol responsiveness among patients on long-term sick leave.
This study aimed to (1) See whether increased or decreased variation relate to subjective reports of common somatic and psychological symptoms for a population on long-term sick leave; and (2) See if this pattern in variation is correlated with autonomic activation and psychological appraisal. Our participants (n = 87) were referred to a 3.5-week return-to-work rehabilitation program, and had been on paid sick leave >8 weeks due to musculoskeletal pain, fatigue and/or common mental disorders. An extensive survey was completed, addressing socio-demographics, somatic and psychological complaints. In addition, a physician and a psychologist examined the participants, determining baseline heart rate, medication use and SCID-I diagnoses. During the 3.5-week program, the participants completed the Trier Social Stress Test for Groups. Participants wore heart rate monitors and filled out Visual Analogue Scales during the TSST-G. Our participants presented a low cortisol variation, with mixed model analyses showing a maximal increase in free saliva cortisol of 26% (95% CI, 0.21-0.32). Simultaneously, the increase in heart rate and Visual Analogue Scales was substantial, indicating autonomic and psychological activation consistent with intense stress from the Trier Social Stress Test for Groups. The current findings are the first description of a blunted cortisol response in a heterogeneous group of patients on long-term sick leave. The results suggest lack of cortisol reactivity as a possible biological link involved in the pathway between stress, sustained activation and long-term sick leave.


Aetiopathogenesis of atopic dermatitis.
The aetiopathogenesis of atopic dermatitis (AD) is complex and during recent years much has been learnt regarding the genetic predisposition to the development of this condition and how its interaction with the environment influences clinical manifestations. AD is not a simple condition. An inherited stratum corneum barrier defect, transepidermal water loss, early antigen exposure through the skin and over-hygienic care of the young child seem to be the major drivers in the manifestation of the disease. Many other, more specific, environmental factors may influence the clinical picture in individual patients; some of these have an allergic basis, while others do not. In this article, the terminology used in this issue of CME is explained, the evidence for the different aetiopathological factors is presented and the factors that worsen or improve AD are listed.


Bone protection by estrens occurs through non-tissue-selective activation of the androgen receptor.
The use of estrogens and androgens to prevent bone loss is limited by their unwanted side effects, especially in reproductive organs and breast. Selective estrogen receptor modulators (SERMs) partially avoid such unwanted effects, but their efficacy on bone is only moderate compared with that of estradiol or androgens. Estrens have been suggested to not only prevent bone loss but also exert anabolic effects on bone while avoiding unwanted effects on reproductive organs. In this study, we compared the effects of a SERM (PSK3471) and 2 estrens (estren-alpha and estren-beta) on bone and reproductive organs to determine whether estrens are safe and act via the estrogen receptors and/or the androgen receptor (AR). Estrens and PSK3471 prevented gonadectomy-induced bone loss in male and female mice, but none showed true anabolic effects. Unlike SERMs, the estrens induced reproductive organ hypertrophy in both male and female mice and enhanced MCF-7 cell proliferation in vitro. Estrens directly activated transcription in several cell lines, albeit at much higher concentrations than estradiol or the SERM, and acted for the most part through the AR. We conclude that the estrens act mostly through the AR and, in mice, do not fulfill the preclinical efficacy or safety criteria required for the treatment or prevention of osteoporosis.


Histamine Iontophoresis as in vivo Model to Study Human Skin Inflammation with Minimal Barrier Impairment: Pilot Study Results of Application of the Model to a Sensitive Skin Panel.
Histamine iontophoresis is known to elicit itch and a wheal-and-flare reaction; however, its impact on the skin barrier and underlying compartments has not been thoroughly evaluated yet. The primary objective of this study was to characterize that using immunohistochemistry, biophysical measurements, and image analysis, and secondly, to explore whether skin reactions to this model differ in sensitive skin (SS). Eighteen healthy subjects, n = 9 with SS and n = 9 with non-sensitive skin (NSS), were included based on a perception-based questionnaire. Histamine iontophoresis was performed on the buttock, and skin reactions were evaluated up to 72 h after stimulation. The wheal-and-flare peaked at 30 min; after 8 h, no clinical signs were visible. No signs of disruption of the stratum corneum, as well as no increase in the number of Ki67-positive cells emerged, whereas fewer tryptase-positive mast cells and increased epidermal thickness were observed at 1 and 72 h, respectively. SS subjects showed higher perception of itch compared to NSS subjects. Histamine iontophoresis is a well-standardized in vivo model to quantitatively study the early stages of cutaneous inflammation with minimal impact on the skin barrier. In line with previous studies, it highlighted increased sensory perceptions in SS.


Molecular model for messenger RNA splicing.
A molecular model is presented for a messenger RNA (mRNA) "splice region." The model requires cation coordination to reduce backbone-backbone electrostatic repulsion and it allows for every base residue on the pre-mRNA to be stacked in A-form helical geometry with a recognition element on the intron or exon (or both) sides of the splice junction. The two nucleotides involved in the initial steps of the cleavage-ligation mechanism must adopt a non-A-form geometry, which ideally positions reactive groups on the pre-mRNA for the necessary catalytic chemistry. The model is also consistent with available biochemical data on splicing reactions.


Attenuation of peripheral salt taste responses and local immune function contralateral to gustatory nerve injury: effects of aldosterone.
Dietary sodium restriction coupled with axotomy of the rat chorda tympani nerve (CTX) results in selectively attenuated taste responses to sodium salts in the contralateral, intact chorda tympani nerve. Converging evidence indicates that sodium deficiency also diminishes the activated macrophage response to injury on both the sectioned and contralateral, intact sides of the tongue. Because a sodium-restricted diet causes a robust increase in circulating aldosterone, we tested the hypothesis that changes in neurophysiological and immune responses contralateral to the CTX could be mimicked by aldosterone administration instead of the low-sodium diet. Taste responses in rats with CTX and supplemental aldosterone for 4-6 days were similar to rats with CTX and dietary sodium restriction. Responses to sodium salts were as much as 50% lower compared with sham-operated and vehicle-supplemented rats. The group-related functional differences were eliminated with lingual application of amiloride, suggesting that a major transduction pathway affected was through epithelial sodium channels. Consistent with the functional results, few macrophages were observed on either side of the tongue in rats with CTX and aldosterone. In contrast, macrophages were elevated on both sides of the tongue in rats with CTX and the vehicle. These results show that sodium deficiency or administration of aldosterone suppresses the immune response to neural injury, resulting in attenuation of peripheral gustatory function. They also show a potential key link among downstream consequences of sodium imbalance, taste function, and immune activity.


High harmonic generation from multiple orbitals in N2.
Molecular electronic states energetically below the highest occupied molecular orbital (HOMO) should contribute to laser-driven high harmonic generation (HHG), but this behavior has not been observed previously. Our measurements of the HHG spectrum of N2 molecules aligned perpendicular to the laser polarization showed a maximum at the rotational half-revival. This feature indicates the influence of electrons occupying the orbital just below the N2 HOMO, referred to as the HOMO-1. Such observations of lower-lying orbitals are essential to understanding subfemtosecond/subangstrom electronic motion in laser-excited molecules.


Molecular epidemiologic analysis of Mycobacterium bovis isolates from Mexico.
To assess phylogenetic relationships among Mycobacterium bovis isolates by use of random amplified polymorphic DNA polymerase chain reaction (RAPD-PCR) fingerprinting and to relate genetic profiles of isolates to epidemiologic characteristics. 400 cattle with tuberculosis. Mycobacterium bovis was isolated from various organs of cattle slaughtered in 6 geographic regions of Mexico. Most cattle were adult Holsteins from large herds that did not participate in a tuberculosis control program. Four random primers and 2 selected primers were used in RAPD-PCR fingerprinting of 88 isolates. Pairwise genetic distance between isolates was obtained and subjected to cluster analysis with bootstrapping to test for levels of support. 98 different fragments were obtained; there was broad genetic diversity among isolates, and each isolate had a unique RAPD-genotype, including those originating from the same herd. Clustering by geographic location, affected organ, or severity of lesion was not detected. Linkage disequilibrium analysis suggested that M. bovis was highly clonal and that mutations develop at a rapid rate among isolates. Use of RAPD-PCR could not differentiate M. bovis isolates by epidemiologic characteristics or identify common sources of infection.


Large-scale patterns of turnover and Basal area change in Andean forests.
General patterns of forest dynamics and productivity in the Andes Mountains are poorly characterized. Here we present the first large-scale study of Andean forest dynamics using a set of 63 permanent forest plots assembled over the past two decades. In the North-Central Andes tree turnover (mortality and recruitment) and tree growth declined with increasing elevation and decreasing temperature. In addition, basal area increased in Lower Montane Moist Forests but did not change in Higher Montane Humid Forests. However, at higher elevations the lack of net basal area change and excess of mortality over recruitment suggests negative environmental impacts. In North-Western Argentina, forest dynamics appear to be influenced by land use history in addition to environmental variation. Taken together, our results indicate that combinations of abiotic and biotic factors that vary across elevation gradients are important determinants of tree turnover and productivity in the Andes. More extensive and longer-term monitoring and analyses of forest dynamics in permanent plots will be necessary to understand how demographic processes and woody biomass are responding to changing environmental conditions along elevation gradients through this century.


Fabrication, characterization, and evaluation of microsponge delivery system for facilitated fungal therapy.
The rationale behind present research vocation was to develop and investigate a novel microsponge based gel as a topical carrier for the prolonged release and cutaneous drug deposition of fluconazole (FLZ); destined for facilitated fungal therapy. Microsponges were prepared using quasi-emulsion solvent diffusion method using Eudragit S-100. In the direction of optimization, the effect of formulation variables (drug-polymer ratio and amount of emulsifier) and diverse factors affecting physical characteristics of microsponge were investigated as well. Fabricated microsponges were characterized by differential scanning calorimetry, Fourier transform-infrared, scanning electron microscopy (SEM), particle size analysis, and also evaluated for drug content, encapsulation efficiency, in vitro drug release and in vitro antifungal activity. Compatibility studies results reflected no sign of any chemical interaction between the drug and polymers used. Whereas, varied drug-polymer ratios and emulsifier concentration indicated significant effect on production yield, drug content, encapsulation efficiency, particle size and drug release. Spherical microsponges with a porous surface and 29.327 ± 0.31 μm mean particle size were evident from SEM micrographs. In vitro release outcomes, from microsponge loaded gels depicted that F1 formulation was more efficient to give extended drug release of 85.38% at the end of 8 h, while conventional formulation by releasing 83.17% of drug got exhausted incredibly earlier at the end of 4 h merely. Moreover, microsponge gels demonstrated substantial spreadability and extrudability along with promising antifungal activity. Fabricated microsponges would be impending pharmaceutical topical carriers of FLZ and a leading alternative to conventional therapy for efficient, safe and facilitated eradication of fungal infections.


Doubling genome size without polyploidization: dynamics of retrotransposition-driven genomic expansions in Oryza australiensis, a wild relative of rice.
Retrotransposons are the main components of eukaryotic genomes, representing up to 80% of some large plant genomes. These mobile elements transpose via a "copy and paste" mechanism, thus increasing their copy number while active. Their accumulation is now accepted as the main factor of genome size increase in higher eukaryotes, besides polyploidy. However, the dynamics of this process are poorly understood. In this study, we show that Oryza australiensis, a wild relative of the Asian cultivated rice O. sativa, has undergone recent bursts of three LTR-retrotransposon families. This genome has accumulated more than 90,000 retrotransposon copies during the last three million years, leading to a rapid twofold increase of its size. In addition, phenetic analyses of these retrotransposons clearly confirm that the genomic bursts occurred posterior to the radiation of the species. This provides direct evidence of retrotransposon-mediated variation of genome size within a plant genus.


Satellite estimates of precipitation-induced dissipation in the atmosphere.
A substantial amount of frictional dissipation in the atmosphere occurs in the microphysical shear zones surrounding falling precipitation. The dissipation rate is computed here from recently available satellite retrieval from the Tropical Rainfall Measurement Missions and is found to average 1.8 watts per square meter between 30°S and 30°N. The geographical distribution of the precipitation-induced dissipation is closely tied to that of precipitation but also reveals a stronger dissipation rate for continental convection than for maritime convection. Because the precipitation-induced dissipation is of the same magnitude as the turbulent dissipation of the kinetic energy in the atmosphere, changes in the hydrological cycle could potentially have a direct impact on the amount of kinetic energy generated and dissipated by the atmospheric circulation.


Directed evolution of bicyclic peptides for therapeutic application.
Many naturally occurring cyclic peptides or derivatives thereof are used as therapeutics such as the human hormones vasopressin and oxytocin or the antibiotics vancomycin and daptomycin. The success of cyclic peptide therapeutics is based on their ability to bind with high affinity, their good target selectivity and their low toxicity. As nature provides cyclic peptides to only a small number of disease targets, strategies have been developed to generate cyclic peptide ligands with tailored specificity de novo. Our laboratory is specialized on the directed evolution of bicyclic peptide ligands by phage display. In this article, we review our recent work to in vitro evolve bicyclic peptide antagonists, the binding and pharmacokinetic properties of bicyclic peptides, as well as efforts to generate bicyclic peptides for therapeutic application.


Predictors of neurologic outcome after surgery for cervical ossification of the posterior longitudinal ligament differ based on myelopathy severity: a multicenter study.
The purpose of this retrospective multicenter study was to compare prognostic factors for neurological recovery in patients undergoing surgery for cervical ossification of the posterior longitudinal ligament (OPLL) based on their presenting mild, moderate, or severe myelopathy. The study included 372 consecutive patients with OPLL who underwent surgery for cervical myelopathy between 2006 and 2016 in East Asian countries with a high OPLL prevalence. Baseline and postoperative clinical outcomes were assessed using the Japanese Orthopaedic Association (JOA) myelopathy score and recovery ratio. Radiographic assessment included occupying ratio, cervical range of motion, and sagittal alignment parameters. Patient myelopathy was classified as mild, moderate, or severe based on the preoperative JOA score. Linear and multivariate regression analyses were performed to identify patient and surgical factors associated with neurological recovery stratified by baseline myelopathy severity. The mean follow-up period was 45.4 months (range 25-140 months). The mean preoperative and postoperative JOA scores and recovery ratios for the total cohort were 11.7 ± 3.0, 14.5 ± 2.7, and 55.2% ± 39.3%, respectively. In patients with mild myelopathy, only age and diabetes correlated with recovery. In patients with moderate to severe myelopathy, older age and preoperative increased signal intensity on T2-weighted imaging were significantly correlated with a lower likelihood of recovery, while female sex and anterior decompression with fusion (ADF) were associated with better recovery. Various patient and surgical factors are correlated with likelihood of neurological recovery after surgical treatment for cervical OPLL, depending on the severity of presenting myelopathy. Older age, male sex, intramedullary high signal intensity, and posterior decompression are associated with less myelopathy improvement in patients with worse baseline function. Therefore, myelopathy-specific preoperative counseling regarding prognosis for postoperative long-term neurological improvement should include consideration of these individual and surgical factors.


A bioarchaeological analysis of oral and physiological health on the south coast of New Guinea.
The south coast of New Guinea has a complex prehistory known for its exchange systems that linked distinct cultural groups living along the coast, inland, and on offshore islands. Here we compare the palaeohealth of two relatively contemporaneous skeletal samples from the south coast of New Guinea (850-200 BP) that were from two ecologically different sites (one inland and one offshore island) and likely represent distinct cultural groups. We aim to elucidate health patterns that may provide information about the specific lifeways and quality of life of each community. Oral conditions (caries, calculus, alveolar lesions, and antemortem tooth loss [AMTL]) were analyzed macroscopically to assess possible intra- and inter-population variation in oral and physiological health. The frequency of linear enamel hypoplasia (LEH) was also used as a nonspecific indicator of stress to assess childhood health at each site. The inhabitants from the small offshore island of Motupore, thought to be associated with Austronesian-speaking Motu tribes, displayed different patterns of oral pathological conditions (more carious lesions on the tooth crown and calculus) and LEH (lower frequencies) compared with inland people residing at the site of Nebira. It is suggested that the causes for the variation in oral and physiological health were likely multifactorial and potentially associated with variables such as the ecological and geographical settings of the sites, cultural differences, infectious disease, differential fertility and, potentially, diet. This research provides previously unknown information about possible culturally-moderated practices that affected health in the past. Am J Phys Anthropol 160:414-426, 2016. © 2016 Wiley Periodicals, Inc.


Long-term anticonvulsant therapy leads to low bone mineral density--evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells.
Anticonvulsant therapy causes changes in calcium and bone metabolism and may lead to decreased bone mass with the risk of osteoporotic fractures. The two widely used antiepileptic drugs phenytoin and carbamazepine are recognized to have direct effects on bone cells. The aim of our study was to measure the influence of long-term treatment with antiepileptic drugs on bone mineral density (BMD) and to look on direct effects of carbamazepine and phenytoin on human osteoblast-like cells. BMD was measured by dual-energy X-ray absorptiometry. Markers of bone formation and bone resorption were determined in serum and urine. Data of 59 patients were compared to 55 age and sex matched controls. Direct effects of phenytoin and carbamazepine on human osteoblast-like cells were investigated in experimental studies. BMD in the lumbar spine region (L2 through L4) was significantly lower in the patient group as compared to controls (p < 0.0004). At femoral sites BMD was lower in patients, but this difference did not reach statistical significance. The decrease in BMD at both sites was dependent on the duration of therapy. Excretion of pyridinoline crosslinks was markedly increased in the patients. 25-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 were significantly decreased in patients. Proliferation rate of human osteoblast-like cells was increased by phenytoin in low doses. Both, phenytoin and carbamazepine inhibited cell growth at concentrations equivalent to therapeutic doses for the treatment of epileptic diseases. Our clinical and experimental data indicate that long-term treatment with anticonvulsant drugs leads to a lower BMD. The experimentally observed decrease in bone cell proliferation might be clinically associated with impaired new bone formation. Beside alterations in calcium and vitamin D homeostasis leading to osteomalazia, direct effects of anticonvulsant drugs on bone cells may contribute to the damaging effects on the skeletal system.


UnPAKing the class differences among p21-activated kinases.
The p21-activated kinases (PAKs) are signal transducers, central to many vital cellular processes, including cell morphology, motility, survival, gene transcription and hormone signalling. The mammalian PAK family contains six serine/threonine kinases divided into two subgroups, group I (PAK 1-3) and group II (PAK4-6), based on their domain architecture and regulation. PAKs functioning as dynamic signalling nodes present themselves as attractive therapeutic targets in tumours, neurological diseases and infection. The recent findings across all PAKs, including newly reported structures, shed light on the cellular functions of PAKs, highlighting molecular mechanisms of activation, catalysis and substrate specificity. We believe that a comprehensive understanding of the entire PAK family is essential for developing strategies towards PAK-targeted therapeutics.


The core apoptotic executioner proteins CED-3 and CED-4 promote initiation of neuronal regeneration in Caenorhabditis elegans.
A critical accomplishment in the rapidly developing field of regenerative medicine will be the ability to foster repair of neurons severed by injury, disease, or microsurgery. In C. elegans, individual visualized axons can be laser-cut in vivo and neuronal responses to damage can be monitored to decipher genetic requirements for regeneration. With an initial interest in how local environments manage cellular debris, we performed femtosecond laser axotomies in genetic backgrounds lacking cell death gene activities. Unexpectedly, we found that the CED-3 caspase, well known as the core apoptotic cell death executioner, acts in early responses to neuronal injury to promote rapid regeneration of dissociated axons. In ced-3 mutants, initial regenerative outgrowth dynamics are impaired and axon repair through reconnection of the two dissociated ends is delayed. The CED-3 activator, CED-4/Apaf-1, similarly promotes regeneration, but the upstream regulators of apoptosis CED-9/Bcl2 and BH3-domain proteins EGL-1 and CED-13 are not essential. Thus, a novel regulatory mechanism must be utilized to activate core apoptotic proteins for neuronal repair. Since calcium plays a conserved modulatory role in regeneration, we hypothesized calcium might play a critical regulatory role in the CED-3/CED-4 repair pathway. We used the calcium reporter cameleon to track in vivo calcium fluxes in the axotomized neuron. We show that when the endoplasmic reticulum calcium-storing chaperone calreticulin, CRT-1, is deleted, both calcium dynamics and initial regenerative outgrowth are impaired. Genetic data suggest that CED-3, CED-4, and CRT-1 act in the same pathway to promote early events in regeneration and that CED-3 might act downstream of CRT-1, but upstream of the conserved DLK-1 kinase implicated in regeneration across species. This study documents reconstructive roles for proteins known to orchestrate apoptotic death and links previously unconnected observations in the vertebrate literature to suggest a similar pathway may be conserved in higher organisms.


Genome diversification within a clonal population of pandemic Vibrio parahaemolyticus seems to depend on the life circumstances of each individual bacteria.
New strains of Vibrio parahaemolyticus that cause diarrhea in humans by seafood ingestion periodically emerge through continuous evolution in the ocean. Influx and expansion in the Southern Chilean ocean of a highly clonal V. parahaemolyticus (serotype O3:K6) population from South East Asia caused one of the largest seafood-related diarrhea outbreaks in the world. Here, genomics analyses of isolates from this rapidly expanding clonal population offered an opportunity to observe the molecular evolutionary changes often obscured in more diverse populations. Whole genome sequence comparison of eight independent isolates of this population from mussels or clinical cases (from different years) was performed. Differences of 1366 to 217,729 bp genome length and 13 to 164 bp single nucleotide variants (SNVs) were found. Most genomic differences corresponded to the presence of regions unique to only one or two isolates, and were probably acquired by horizontal gene transfer (HGT). Some DNA gain was chromosomal but most was in plasmids. One isolate had a large region (8,644 bp) missing, which was probably caused by excision of a prophage. Genome innovation by the presence of unique DNA, attributable to HGT from related bacteria, varied greatly among the isolates, with values of 1,366 (ten times the number of highest number of SNVs) to 217,729 (a thousand times more than the number of highest number of SNVs). The evolutionary forces (SNVs, HGT) acting on each isolate of the same population were found to differ to an extent that probably depended on the ecological scenario and life circumstances of each bacterium.