Smokeless tobacco policy in Bangladesh: A stakeholder study of compatibility with the World Health Organization's Framework Convention on Tobacco Control.
Smokeless tobacco (ST) is the predominant form of tobacco used in Bangladesh and is associated with adverse health outcomes. Bangladesh ratified the World Health Organization's Framework Convention on Tobacco Control (FCTC) in 2004. There are concerns that FCTC legislation and implementation of ST control policy is insufficient in Bangladesh. The aim of this study was to investigate the achievements and challenges of ST policy in Bangladesh and its alignment with the FCTC. We conducted semi-structured key informant interviews with 20 stakeholders from government and non-government offices and international funding agencies, including tobacco control advocates, policy makers and non-governmental organisation workers. We used NVivo software to create key themes and the framework method for thematic analysis. Our findings revealed a lack of national policy in terms of disclosure of harmful contents, illicit trade and standardised packaging of ST. Legislation remains ineffective in relation to graphical health warnings and tax measures. Challenges to ST control identified included inadequate law enforcement; paucity of research, surveillance, and evidence generation; and supply chain control. We identified lack of congruence of ST policies with FCTC due to slow progress in implementation of FCTC measures, lack of a country-specific policy and industry interference. To comply with FCTC, participants recommended strong leadership and political commitment, co-ordination between public and private sectors and proper use of tobacco control resources. Bangladesh has adopted several important FCTC measures, but further strengthening of ST policy is needed to enable full implementation of FCTC.


Hepatitis A outbreak predominantly affecting men who have sex with men in Northern Ireland, October 2008 to July 2009.
We describe an outbreak of hepatitis A which evolved in Northern Ireland between October 2008 and July 2009, against a background of large concurrent hepatitis A outbreaks in various parts of Europe. Thirty-eight cases were defined as outbreak cases using a stratified case definition; 36 were males with a median age of 29 years and of the 28 males whose sexual orientation was known, 26 were men who have sex with men(MSM). Detailed descriptive epidemiology data collected through standardised questionnaires, together with sequencing of a 289 bp fragment of the VP1/2PA region of the virus, significantly aided the understanding of the spread of the outbreak when non-MSM cases occurred. The sequence of the outbreak strain, genotype IA, was indistinguishable from that involved in a large outbreak in the Czech Republic. Although seeded in a generally susceptible Northern Ireland population, the outbreak remained mostly contained in MSM, showing this sub-population to be the most vulnerable despite ongoing hepatitis A vaccination programmes in genito-urinary medicine clinics.


Defining Features of the Upper Extremity in Holt-Oram Syndrome.
To investigate the distinguishing morphological characteristics of children with radial longitudinal deficiency (RLD) in Holt-Oram syndrome (HOS). One hundred fourteen involved extremities in 62 patients with a diagnosis of HOS were identified at 3 institutions. Medical records and radiographs were evaluated. Radial longitudinal deficiency and thumb hypoplasia were classified according to the modified Bayne and Klug classification and Blauth classifications, respectively, when possible. Other unusual or distinguishing characteristics were catalogued. There was bilateral involvement in 84% of patients. The forearm was involved in 81% of the extremities and a shortened distal radius (Bayne and Klug type I RLD) was the most commonly identified forearm anomaly (40%). Radioulnar synostosis was present in 15% of the extremities, all in the proximal forearms with reduced radial heads. Thumb aplasia (Blauth type V hypoplastic thumb) was the most common type of classifiable thumb abnormality and occurred in 35% of involved thumbs. Twenty-seven percent of abnormal thumbs affected were not classifiable according to the Blauth classification, and 19% of involved thumbs (hypoplastic or absent) had first-web syndactyly. The upper extremity in HOS differs from the typical presentation of RLD. The forearm is more often involved and may demonstrate radioulnar synostosis. The thumb is frequently unclassifiable by the Blauth classification and has first-web syndactyly. The presence of radioulnar synostosis and syndactyly of the radial 2 digits in RLD should prompt the hand surgeon to obtain a cardiac evaluation and consider genetic testing for HOS. Diagnostic III.


Adult stem cells: a clinical update.
There has been unprecedented interest in stem cell research mainly because of their true potential and hope that they offer to the patients as a cell therapy with the prospect to treat hitherto incurable diseases. Despite the worldwide interest and efforts that have been put in this research, major fundamental issues are still unresolved. Adult stem cells such as hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) are already under clinical applications and there are several examples of plasticity and self-renewal where adult stem cells or their precursor cells can be re-programmed by extra cellular cues or internal cues to alter their character in a way that could have important application for cell therapy and regenerative medicine. From a clinical perspective, no other area of stem cell biology has been applied as successfully as has transplantation of bone marrow stem cells and cord blood stem cells for the treatment of hematological diseases. In the last few years, research in stem cell biology has expanded staggeringly, engendering new perspectives concerning the identity, origin, and full therapeutic potential of tissue-specific stem cells. This review will focus on the use of adult stem cells, its biology in the context of cell plasticity and their therapeutic potential for repair of different tissues and organs.


Student Hotspotting: Teaching the Interprofessional Care of Complex Patients.
Individuals with complex health and social needs drive much of the total cost of care. Addressing these individuals' needs and decreasing costs requires interprofessional teams, called "hotspotters," who engage with communities with high utilization. Training health professions students to succeed in the hotspotting approach may benefit trainees, academic health centers (AHCs), and communities. The Camden Coalition of Healthcare Providers and the Association of American Medical Colleges launched the Interprofessional Student Hotspotting Learning Collaborative in 2014. The goal was to train health professions students working in interprofessional teams at U.S. AHCs to meet the needs of complex patients, providing home visits and intensive case management for up to five patients over six months. The authors report themes from 20 reflections from the five-student Virginia Commonwealth University (VCU) team. Across 10 sites, 57 students participated during June-December 2014. The review of the VCU experience demonstrated that the hotspotting program was successful in teaching students how social determinants affect health and the benefits of interprofessional teamwork for addressing the unmet health and social needs of complex patients. Key elements that students identified for improvement were more program structure; protected time for program activities; and formalized processes for recruiting, retaining, and transitioning patients. Future iterations of the program should strengthen the curriculum on caring for complex patients, provide protected time or academic credit, and formally integrate teams with primary care. A larger study evaluating the program's impact on patients, health systems, and communities should be undertaken.


Multi-Behavioral Endpoint Testing of an 87-Chemical Compound Library in Freshwater Planarians.
There is an increased recognition in the field of toxicology of the value of medium-to-high-throughput screening methods using in vitro and alternative animal models. We have previously introduced the asexual freshwater planarian Dugesia japonica as a new alternative animal model and proposed that it is particularly well-suited for the study of developmental neurotoxicology. In this article, we discuss how we have expanded and automated our screening methodology to allow for fast screening of multiple behavioral endpoints, developmental toxicity, and mortality. Using an 87-compound library provided by the National Toxicology Program, consisting of known and suspected neurotoxicants, including drugs, flame retardants, industrial chemicals, polycyclic aromatic hydrocarbons (PAHs), pesticides, and presumptive negative controls, we further evaluate the benefits and limitations of the system for medium-throughput screening, focusing on the technical aspects of the system. We show that, in the context of this library, planarians are the most sensitive to pesticides with 16/16 compounds causing toxicity and the least sensitive to PAHs, with only 5/17 causing toxicity. Furthermore, while none of the presumptive negative controls were bioactive in adult planarians, 2/5, acetaminophen and acetylsalicylic acid, were bioactive in regenerating worms. Notably, these compounds were previously reported as developmentally toxic in mammalian studies. Through parallel screening of adults and developing animals, planarians are thus a useful model to detect such developmental-specific effects, which was observed for 13 chemicals in this library. We use the data and experience gained from this screen to propose guidelines for best practices when using planarians for toxicology screens.


Host relatedness influences the composition of aphid microbiomes.
Animals are host to a community of microbes, collectively referred to as their microbiome, that can play a key role in their hosts' biology. The bacterial endosymbionts of insects have a particularly strong influence on their hosts, but despite their importance we still know little about the factors that influence the composition of insect microbial communities. Here, we ask: what is the relative importance of host relatedness and host ecology in structuring symbiont communities of diverse aphid species? We used next-generation sequencing to compare the microbiomes of 46 aphid species with known host plant affiliations. We find that relatedness between aphid species is the key factor explaining the microbiome composition, with more closely related aphid species housing more similar bacterial communities. Endosymbionts dominate the microbial communities, and we find a novel bacterium in the genus Sphingopyxis that is associated with numerous aphid species feeding exclusively on trees. The influence of ecology was less pronounced than that of host relatedness. Our results suggest that co-adaptation between insect species and their facultative symbionts is a more important determinant of symbiont species presence in aphids than shared ecology of hosts.


Strain differences in delay discounting using inbred rats.
A heightened aversion to delayed rewards is associated with substance abuse and numerous other neuropsychiatric disorders. Many of these disorders are heritable, raising the possibility that delay aversion may also have a significant genetic or heritable component. To examine this possibility, we compared delay discounting in six inbred strains of rats (Brown Norway, Copenhagen, Lewis, Fischer, Noble and Wistar Furth) using the adjusting amount procedure, which provides a measure of the subjective value of delayed rewards. The subjective value of rewards decreased as the delay to receipt increased for all strains. However, a main effect of strain and a strain x delay interaction indicated that some strains were more sensitive to the imposition of delays than others. Fitting a hyperbolic discount equation showed significant strain differences in sensitivity to delay (k). These data indicate that there are significant strain differences in delay discounting. All strains strongly preferred the 10% sucrose solution (the reinforcer in the delay discounting task) over water and the amount of sucrose consumed was correlated with sensitivity to delay. Locomotor activity was not correlated with delay discounting behavior. Additional research will be required to disentangle genetic influences from maternal effects and to determine how these factors influence the underlying association between heightened delay discounting and neuropsychiatric disorders.


The impact of adult neurogenesis on olfactory bulb circuits and computations.
Modern neuroscience has demonstrated how the adult brain has the ability to profoundly remodel its neurons in response to changes in external stimuli or internal states. However, adult brain plasticity, although possible throughout life, remains restricted mostly to subcellular levels rather than affecting the entire cell. New neurons are continuously generated in only a few areas of the adult brain-the olfactory bulb and the dentate gyrus-where they integrate into already functioning circuitry. In these regions, adult neurogenesis adds another dimension of plasticity that either complements or is redundant to the classical molecular and cellular mechanisms of plasticity. This review extracts clues regarding the contribution of adult-born neurons to the different circuits of the olfactory bulb and specifically how new neurons participate in existing computations and enable new computational functions.


Comparison of population genetic structures of the plant Silene stellata and its obligate pollinating seed predator moth Hadena ectypa.
Population genetic structures and patterns of gene flow of interacting species provide important insights into the spatial scale of their interactions and the potential for local co-adaptation. We analysed the genetic structures of the plant Silene stellata and the nocturnal moth Hadena ectypa. Hadena ectypa acts as one of the important pollinators of S. stellata as well as being an obligate seed parasite on the plant. Although H. ectypa provides a substantial pollination service to S. stellata, this system is largely considered parasitic due to the severe seed predation by the Hadena larvae. Previous research on this system has found variable interaction outcomes across space, indicating the potential for a geographical selection mosaic. Using 11 microsatellite markers for S. stellata and nine markers for H. ectypa, we analysed the population genetic structure and the patterns and intensity of gene flow within and among three local populations in the Appalachians. We found no spatial genetic structure in the moth populations, while significant differentiation was detected among the local plant populations. Additionally, we observed that gene flow rates among H. ectypa populations were more uniform and that the mean gene flow rate in H. ectypa was twice as large as that in S. stellata. Our results suggest that although the moths move frequently among populations, long-distance pollen carryover only happens occasionally. The difference in gene flow rates between S. stellata and H. ectypa could prevent strict local co-adaptation. Furthermore, higher gene flow rates in H. ectypa could also increase resistance of the local S. stellata populations to the parasitic effect of H. ectypa and therefore help to stabilize the Silene-Hadena interaction dynamics.


Reassessment of the association between Guillain-Barré syndrome and receipt of swine influenza vaccine in 1976-1977: results of a two-state study. Expert Neurology Group.
Although the original Centers for Disease Control study of the relation between A/New Jersey/8/76 (swine flu) vaccine and Guillain-Barré syndrome (polyradiculoneuritis) demonstrated a statistical association and suggested a causal relation between the two events, controversy has persisted. To reassess this association, the authors obtained medical records of all previously reported adult patients with Guillain-Barré syndrome in Michigan and Minnesota from October 1, 1976 through January 31, 1977. To identify previously unreported hospitalized cases with onset of symptoms during this period, the authors surveyed medical care facilities. A group of expert neurologists formulated diagnostic criteria for Guillain-Barré syndrome and then reviewed the clinical records in a blinded fashion. Of the 98 adult patients from the original Centers for Disease Control study eligible for consideration, three were found to have been misclassified by date of onset and were excluded. Of the remaining 95, the 28 (29%) who did not meet the diagnostic criteria were equally distributed between the vaccinated group (18 of 60, 30%) and the unvaccinated group (10 of 35, 29%). In addition to the 67 remaining cases who met the diagnostic criteria, six previously unreported cases (three of whom had been vaccinated) were found and included in this analysis. The relative risk of developing Guillain-Barré syndrome in the vaccinated population of these two states during the 6 weeks following vaccination was 7.10, comparable to the relative risk of 7.60 found in the original study. These findings suggest that there was an increased risk of developing Guillain-Barré syndrome during the 6 weeks following vaccination in adults. The excess cases of Guillain-Barré syndrome during the first 6 weeks attributed to the vaccine was 8.6 per million vaccinees in Michigan and 9.7 per million vaccinees in Minnesota. No increase in relative risk for Guillain-Barré syndrome was noted beyond 6 weeks after vaccination.


Relationship between hemoglobin levels and quality of life during radiation therapy plus concomitant or sequential chemotherapy in patients with cancer and anemia treated with epoetin alfa.
This study in patients with cancer and anemia, who were receiving chemoradiation and were treated with epoetin alfa, examined the relationship between hemoglobin level and quality of life (QOL), change in hemoglobin and change in QOL, and incremental (1 g/dL) increase in hemoglobin and related incremental improvement in QOL. Data from a multicenter, open-label, prospective study of once-weekly epoetin alfa therapy in anemic cancer patients receiving chemoradiation were used to retrospectively evaluate the relationship between hemoglobin changes and QOL changes via correlation and longitudinal analyses. A sample selection correction method was used to ensure unbiased results. QOL (energy, activity, overall QOL) was measured using the Linear Analog Scale Assessment. An incremental analysis determined the greatest incremental increase in QOL associated with a 1 g/dL increase in hemoglobin level. Of the 777 patients enrolled, 464 met chemotherapy and radiotherapy eligibility criteria. Of these, 359 (77%) underwent two QOL assessments and were eligible for analysis. A nonlinear and statistically significant positive correlation was found between hemoglobin levels and Linear Analog Scale Assessment QOL scores (r = 0.32 [energy], 0.33 [activity], and 0.29 [overall QOL]; P < .0001). An incremental analysis used regression methods to characterize the changes in hemoglobin levels and QOL scores. Hemoglobin change was found to be a statistically significant determinant of QOL changes (P < .05). The greatest incremental QOL gain associated with a 1-g/dL change in hemoglobin occurred around hemoglobin 12 g/dL (range, 11-13 g/dL). A direct relationship exists between hemoglobin increases and corresponding QOL increases. Maximal incremental gain in QOL occurred when hemoglobin was approximately 12 g/dL (range, 11-13 g/dL).


Clinical evaluation of human placental extract (placentrex) in radiation-induced oral mucositis.
To evaluate human placental extract in the treatment of radiation mucositis involving the oral/oropharyngeal region, a prospective randomized study was carried out in 120 patients with squamous cell carcinoma of the head and neck from August 1997 to March 1999. The study was conducted in patients receiving radical external radiation therapy, planned for = > 60 Gy/30 F/6 weeks, who developed grade 2 radiation mucositis (patchy mucositis) during radiation treatment. The patients were randomized in two groups of 60 patients each to receive either placentrex treatment (placentrex group) or conventional treatment (control group). Placentrex treatment was given as Inj Placentrex 2 ml by deep intramuscular injection 5 days a week for 15 injections. Conventional treatment given in the control group was disprin gargles and betamethasone oral drops. A subjective decrease in pain was observed in 48/60 (80%) of patients in the placentrex group compared with 22/60 (36.7%) in the control group. The progression to grade 3 radiation mucositis was 24/60 (40%) in the placentrex group compared with 52/60 (86.7%) in the control group. The subjective improvement in difficulty in swallowing was seen in 56/60 (93%) of patients in the placentrex group compared with 9/60 (15%) of patients in the control group. Only one patient in the placentrex group compared with three in the control group required interruption of radiation therapy because of severe radiation reactions. Human placental extract appears to be effective in the management of radiation-induced oral/oropharyngeal mucositis and especially in controlling subjective symptoms.


PASSCLAIM--gut health and immunity.
The gut and immune system form a complex integrated structure that has evolved to provide effective digestion and defence against ingested toxins and pathogenic bacteria. However, great variation exists in what is considered normal healthy gut and immune function. Thus, whilst it is possible to measure many aspects of digestion and immunity, it is more difficult to interpret the benefits to individuals of variation within what is considered to be a normal range. Nevertheless, it is important to set standards for optimal function for use both by the consumer, industry and those concerned with the public health. The digestive tract is most frequently the object of functional and health claims and a large market already exists for gut-functional foods worldwide. To define normal function of the gut and immune system and describe available methods of measuring it. We have defined normal bowel habit and transit time, identified their role as risk factors for disease and how they may be measured. Similarly, we have tried to define what is a healthy gut flora in terms of the dominant genera and their metabolism and listed the many, varied and novel methods for determining these parameters. It has proved less easy to provide boundaries for what constitutes optimal or improved gastric emptying, gut motility, nutrient and water absorption and the function of organs such as the liver, gallbladder and pancreas. The many tests of these functions are described. We have discussed gastrointestinal well being. Sensations arising from the gut can be both pleasant and unpleasant. However, the characteristics of well being are ill defined and merge imperceptibly from acceptable to unacceptable, a state that is subjective. Nevertheless, we feel this is an important area for future work and method development. The immune system is even more difficult to make quantitative judgements about. When it is defective, then clinical problems ensure, but this is an uncommon state. The innate and adaptive immune systems work synergistically together and comprise many cellular and humoral factors. The adaptive system is extremely sophisticated and between the two arms of immunity there is great redundancy, which provides robust defences. New aspects of immune function are discovered regularly. It is not clear whether immune function can be "improved". Measuring aspects of immune function is possible but there is no one test that will define either the status or functional capacity of the immune system. Human studies are often limited by the ability to sample only blood or secretions such as saliva but it should be remembered that only 2% of lymphocytes circulate at any given time, which limits interpretation of data. We recommend assessing the functional capacity of the immune system by: measuring specific cell functions ex vivo. measuring in vivo responses to challenge, e. g. change in antibody in blood or response to antigens. determining the incidence and severity of infection in target populations during naturally occurring episodes or in response to attenuated pathogens.


The impact of residual infections on Anopheles-transmitted Wuchereria bancrofti after multiple rounds of mass drug administration.
Many countries have made significant progress in the implementation of World Health Organization recommended preventive chemotherapy strategy, to eliminate lymphatic filariasis (LF). However, pertinent challenges such as the existence of areas of residual infections in disease endemic districts pose potential threats to the achievements made. Thus, this study was undertaken to assess the importance of these areas in implementation units (districts) where microfilaria (MF) positive individuals could not be found during the mid-term assessment after three rounds of mass drug administration. This study was undertaken in Bo and Pujehun, two LF endemic districts of Sierra Leone, with baseline MF prevalence of 2 % and 0 % respectively in sentinel sites for monitoring impact of the national programme. Study communities in the districts were purposefully selected and an assessment of LF infection prevalence was conducted together with entomological investigations undertaken to determine the existence of areas with residual MF that could enable transmission by local vectors. The transmission Assessment Survey (TAS) protocol described by WHO was applied in the two districts to determine infection of LF in 6-7 year old children who were born before MDA against LF started. The results indicated the presence of MF infected children in Pujehun district. An. gambiae collected in the district were also positive for W. bancrofti, even though the prevalence of infection was below the threshold associated with active transmission. Residual infection was detected after three rounds of MDA in Pujehun--a district of 0 % Mf prevalence at the sentinel site. Nevertheless, our results showed that the transmission was contained in a small area. With the scale up of vector control in Anopheles transmission zones, some areas of residual infection may not pose a serious threat for the resurgence of LF if the prevalence of infections observed during TAS are below the threshold required for active transmission of the parasite. However, robust surveillance strategies capable of detecting residual infections must be implemented, together with entomological assessments to determine if ongoing vector control activities, biting rates and infection rates of the vectors can support the transmission of the disease. Furthermore, in areas where mid-term assessments reveal MF prevalence below 1 % or 2 % antigen level, in Anopheles transmission areas with active and effective malaria vector control efforts, the minimum 5 rounds of MDA may not be required before implementing TAS. Thus, we propose a modification of the WHO recommendation for the timing of sentinel and spot-check site assessments in national programs.


Suppression of Common Scab of Potato Caused by Streptomyces turgidiscabies Using Lopsided Oat Green Manure.
Field experiments were conducted to determine the effect of green manure as fallow on common scab of potato caused by Streptomyces turgidiscabies. Significantly fewer diseased tubers were harvested from soil incorporated with lopsided oat or woolly pod vetch compared with those from oat and continuous potato cultivation in a planter experiment. Each field experiment consisted of lopsided oat cultivated during the spring and summer prior to the potato planting. Comparisons were also made with several other treatments, including cultivation of woolly pod vetch, oat, soybean, sugar beet, and potato ('Yukirasya', which is resistant to potato common potato scab) and soil application of Ferosand (Fe, mainly FeSO4, to decrease the soil pH). In field experiments conducted during 1999-2000, treatment with lopsided oat followed by lopsided oat or woolly pod vetch was significantly more effective at suppressing the disease severity than oat and continuous potato cultivation (P < 0.001). An increase in the marketable tuber ratio was also more significant than for oat and continuous potato cultivation (P < 0.001). In field experiments conducted during 2000-01, lopsided oat cultivation alone and with the application of Ferosand (1.8 t/ha) or resistant potato cultivar treatment were significantly more effective at suppressing the disease severity and incidence than sugar beet cultivation (P < 0.001), even under high disease intensity in the field. However, potato yield had a tendency to reduce after lopsided oat treatment with an application of Ferosand (1.8 t/ha) compared with lopsided oat alone or the application of Ferosand at 600 kg/ha, due to low pH conditions. In field experiments conducted during 2001-02, the lowest severity and incidence of common scab of potato were observed in soil treated with lopsided oat than with other treatments (P < 0.05 and P < 0.001, respectively). These findings suggest that lopsided oat used as fallow green manure can reduce the severity of common scab and increase potato yield.


A rare case of a double phytobezoar causing gastric and jejunum obstruction in an adult man: a case report.
Bezoars are an uncommon cause of mechanical intestinal occlusion. There are four different kinds of bezoars: phytobezoars, made of vegetables and fibers; trichobezoars, resulting from the ingestion of hair and frequently an expression of psychiatric disorders; lactobezoars, which are formed of milk curd; and pharmacobezoars, caused by drugs and medications. Symptoms are classically indistinguishable from one another and from more common causes of intestinal occlusion, so it can be difficult to establish a correct diagnosis in order to apply the correct treatment. We present a rare case of two different phytobezoars causing intestinal occlusion (gastric and jejunal). We also describe the correct techniques for making a correct and fast diagnosis of occlusion caused by phytobezoars, and the possible conservative and operative treatments. We present the case of a double phytobezoar that was surgically treated with a double enterotomy. Our patient was a 68-year-old Caucasian man with a medical history of hypertension, a previous open appendectomy, and open repair of a perforated gastric ulcer. He was admitted with a 5-day history of abdominal pain located in his upper quadrants along with vomiting. After a preoperative examination, he was taken to the operating room. He was discharged in a good clinical condition 11 days after surgical intervention. A physical examination at 6 months demonstrated our patient was in good health. Diagnosing bezoars is difficult because of their rarity. However, they must be taken into consideration in a differential diagnosis because their treatment is not always surgical. In fact, it may be conservative in many cases and a correct diagnosis will guide towards the correct therapy.


Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development.
Bone morphogenetic protein (BMP) signaling is thought to perform multiple functions in the regulation of skin appendage morphogenesis and the postnatal growth of hair follicles. However, definitive genetic evidence for these roles has been lacking. Here, we show that Cre-mediated mutation of the gene encoding BMP receptor 1A in the surface epithelium and its derivatives causes arrest of tooth morphogenesis and lack of external hair. The hair shaft and hair follicle inner root sheath (IRS) fail to differentiate, and expression of the known transcriptional regulators of follicular differentiation Msx1, Msx2, Foxn1 and Gata3 is markedly downregulated or absent in mutant follicles. Lef1 expression is maintained, but nuclear beta-catenin is absent from the epithelium of severely affected mutant follicles, indicating that activation of the WNT pathway lies downstream of BMPR1A signaling in postnatal follicles. Mutant hair follicles fail to undergo programmed regression, and instead continue to proliferate, producing follicular cysts and matricomas. These results provide definitive genetic evidence that epithelial Bmpr1a is required for completion of tooth morphogenesis, and regulates terminal differentiation and proliferation in postnatal hair follicles.


Transition of Care from the Emergency Department to the Outpatient Setting: A Mixed-Methods Analysis.
The goal of this study was to characterize current practices in the transition of care between the emergency department and primary care setting, with an emphasis on the use of the electronic medical record (EMR). Using literature review and modified Delphi technique, we created and tested a pilot survey to evaluate for face and content validity. The final survey was then administered face-to-face at eight different clinical sites across the country. A total of 52 emergency physicians (EP) and 49 primary care physicians (PCP) were surveyed and analyzed. We performed quantitative analysis using chi-square test. Two independent coders performed a qualitative analysis, classifying answers by pre-defined themes (inter-rater reliability > 80%). Participants' answers could cross several pre-defined themes within a given question. EPs were more likely to prefer telephone communication compared with PCPs (30/52 [57.7%] vs. 3/49 [6.1%] P < 0.0001), whereas PCPs were more likely to prefer using the EMR for discharge communication compared with EPs (33/49 [67.4%] vs. 13/52 [25%] p < 0.0001). EPs were more likely to report not needing to communicate with a PCP when a patient had a benign condition (23/52 [44.2%] vs. 2/49 [4.1%] p < 0.0001), but were more likely to communicate if the patient required urgent follow-up prior to discharge from the ED (33/52 [63.5%] vs. 20/49 [40.8%] p = 0.029). When discussing barriers to effective communication, 51/98 (52%) stated communication logistics, followed by 49/98 (50%) who reported setting/environmental constraints and 32/98 (32%) who stated EMR access was a significant barrier. Significant differences exist between EPs and PCPs in the transition of care process. EPs preferred telephone contact synchronous to the encounter whereas PCPs preferred using the EMR asynchronous to the encounter. Providers believe EP-to-PCP contact is important for improving patient care, but report varied expectations and multiple barriers to effective communication. This study highlights the need to optimize technology for an effective transition of care from the ED to the outpatient setting.


Structural Insights to the Heterotetrameric Interaction between the Vibrio parahaemolyticus PirAvp and PirBvp Toxins and Activation of the Cry-Like Pore-Forming Domain.
Acute hepatopancreatic necrosis disease (AHPND) is a newly emergent penaeid shrimp disease which can cause 70-100% mortality in Penaeus vannamei and Penaeus monodon, and has resulted in enormous economic losses since its appearance. AHPND is caused by the specific strains of Vibrio parahaemolyticus that harbor the pVA1 plasmid and express PirAvp and PirBvp toxins. These two toxins have been reported to form a binary complex. When both are present, they lead to the death of shrimp epithelial cells in the hepatopancreas and cause the typical histological symptoms of AHPND. However, the binding mode of PirAvp and PirBvp has not yet been determined. Here, we used isothermal titration calorimetry (ITC) to measure the binding affinity of PirAvp and PirBvp. Since the dissociation constant (Kd = 7.33 ± 1.20 μM) was considered too low to form a sufficiently stable complex for X-ray crystallographic analysis, we used alternative methods to investigate PirAvp-PirBvp interaction, first by using gel filtration to evaluate the molecular weight of the PirAvp/PirBvp complex, and then by using cross-linking and hydrogen-deuterium exchange (HDX) mass spectrometry to further understand the interaction interface between PirAvp and PirBvp. Based on these results, we propose a heterotetrameric interaction model of this binary toxin complex. This model provides insight of how conformational changes might activate the PirBvp N-terminal pore-forming domain and should be helpful for devising effective anti-AHPND strategies in the future.


National Osteoporosis Society vitamin D guideline summary.
The National Osteoporosis Society (NOS) published its document, Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management, in 2013 as a practical clinical guideline on the management of vitamin D deficiency in adult patients with, or at risk of developing, bone disease. There has been no clear consensus in the UK on vitamin D deficiency its assessment and treatment, and clinical practice is inconsistent. This guideline is aimed at clinicians, including doctors, nurses and dieticians. It recommends the measurement of serum 25 (OH) vitamin D (25OHD) to estimate vitamin D status in the following clinical scenarios: bone diseases that may be improved with vitamin D treatment; bone diseases, prior to specific treatment where correcting vitamin D deficiency is appropriate; musculoskeletal symptoms that could be attributed to vitamin D deficiency. The guideline also states that routine vitamin D testing is unnecessary where vitamin D supplementation with an oral antiresorptive treatment is already planned and sets the following serum 25OHD thresholds: <30 nmol/l is deficient; 30-50 nmol/l may be inadequate in some people; >50 nmol/l is sufficient for almost the whole population. For treatment, oral vitamin D3 is recommended with fixed loading doses of oral vitamin D3 followed by regular maintenance therapy when rapid correction of vitamin D deficiency is required, although loading doses are not necessary where correction of deficiency is less urgent or when co-prescribing with an oral antiresorptive agent. For monitoring, serum calcium (adjusted for albumin) should be checked 1 month after completing a loading regimen, or after starting vitamin D supplementation, in case primary hyperparathyroidism has been unmasked. However, routine monitoring of serum 25OHD is generally unnecessary but may be appropriate in patients with symptomatic vitamin D deficiency or malabsorption and where poor compliance with medication is suspected. The guideline focuses on bone health as, although there are numerous putative effects of vitamin D on immunity modulation, cancer prevention and the risks of cardiovascular disease and multiple sclerosis, there remains considerable debate about the evaluation of extraskeletal factors and optimal vitamin D status in these circumstances.


Depot antipsychotics: Where do we stand?
Nonadherence to medication is a major problem for patients with schizophrenia. To counter this problem, pharmaceutical companies began developing depot antipsychotics. Although there are currently 5 first-generation and 6 second-generation depot antipsychotics available worldwide, many physicians are still reluctant to use this category of drug initially. This review provides the latest information about the use of depot antipsychotics in schizophrenia treatment as well as several studies in support of depot antipsychotic use as first-line treatment for patients with schizophrenia. A systematic review of 4 milestone schizophrenia studies was performed to provide an aggregate analysis of the history and use of depot antipsychotics. Results and findings from several clinical trials--the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), European First Episode Schizophrenia Trial (EUFEST), A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS), and Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE)--were summarized to provide more information on the development and evolution of depot antipsychotics, common factors that contribute to nonadherence, and guidelines for each long-acting injectable currently available. The CATIE schizophrenia study revealed a 74% rate of discontinuation of oral antipsychotics within 6 months of use. Similar findings from the EUFEST study indicated that 42% of participants discontinued oral medications after 12 months of use. The ACLAIMS study reported no statistically significant difference in efficacy failure rate between haloperidol decanoate and paliperidone palmitate. The PRIDE study found that first hospitalization or arrest was 43% higher among patients in the oral antipsychotic group vs the depot group during the study. This review provides clinical evidence to support the use of depot formulations as first-line treatment for patients with schizophrenia, which may improve adherence and thereby lower risk of relapse, suicide, rehospitalization, and incarceration.


The effects of acute and chronic cocaine use on the heart.
It is clear that cocaine has cardiotoxic effects. Acute doses of cocaine suppress myocardial contractility, reduce coronary caliber and coronary blood flow, induce electrical abnormalities in the heart, and in conscious preparations increase heart rate and blood pressure. These effects will decrease myocardial oxygen supply and may increase demand (if heart rate and blood pressure rise). Thus, myocardial ischemia and/or infarction may occur, the latter leading to large areas of confluent necrosis. Increased platelet aggregability may contribute to ischemia and/or infarction. Young patients who present with acute myocardial infarction, especially without other risk factors, should be questioned regarding use of cocaine. As recently pointed out by Cregler, cocaine is a new and sometimes unrecognized risk factor for heart disease. Acute depression of LV function by cocaine may lead to the presence of a transient cardiomyopathic presentation. Chronic cocaine use can lead to the above problems as well as to acceleration of atherosclerosis. Direct toxic effects on the myocardium have been suggested, including scattered foci of myocyte necrosis (and in some but not all studies, contraction band necrosis), myocarditis, and foci of myocyte fibrosis. These abnormalities may lead to cases of cardiomyopathy. Left ventricular hypertrophy associated with chronic cocaine recently has been described. Arrhythmias and sudden death may be observed in acute or chronic use of cocaine. Miscellaneous cardiovascular abnormalities include ruptured aorta and endocarditis. Most of the cardiac toxicity with cocaine can be traced to two basic mechanisms: one is its ability to block sodium channels, leading to a local anesthetic or membrane-stabilizing effect; the second is its ability to block reuptake of catecholamines in the presynaptic neurons in the central and peripheral nervous system, resulting in increased sympathetic output and increased catecholamines. Other potential mechanisms of cocaine cardiotoxicity include a possible direct calcium effect leading to contraction of vessels and contraction bands in myocytes, hypersensitivity, and increased platelet aggregation (which may be related to increased catecholamine). The correct therapy for cocaine cardiotoxicity is not known. Calcium blockers, alpha-blockers, nitrates, and thrombolytic therapy show some promise for acute toxicity. Beta-Blockade is controversial and may worsen coronary blood flow. In patients who develop cardiomyopathy, the usual therapy for this entity is appropriate.


Quantifying neuronal network dynamics through coarse-grained event trees.
Animals process information about many stimulus features simultaneously, swiftly (in a few 100 ms), and robustly (even when individual neurons do not themselves respond reliably). When the brain carries, codes, and certainly when it decodes information, it must do so through some coarse-grained projection mechanism. How can a projection retain information about network dynamics that covers multiple features, swiftly and robustly? Here, by a coarse-grained projection to event trees and to the event chains that comprise these trees, we propose a method of characterizing dynamic information of neuronal networks by using a statistical collection of spatial-temporal sequences of relevant physiological observables (such as sequences of spiking multiple neurons). We demonstrate, through idealized point neuron simulations in small networks, that this event tree analysis can reveal, with high reliability, information about multiple stimulus features within short realistic observation times. Then, with a large-scale realistic computational model of V1, we show that coarse-grained event trees contain sufficient information, again over short observation times, for fine discrimination of orientation, with results consistent with recent experimental observation.


Using Medicaid Data to Characterize Persons With Intellectual and Developmental Disabilities in Five U.S. States.
This project sought to identify Medicaid members with intellectual and developmental disabilities (IDD) in five states (Delaware, Iowa, Massachusetts, New York, and South Carolina) to develop a cohort for subsequent analyses of medical conditions and service utilization. We estimated that over 300,000 Medicaid members in these states had IDD. All members with diagnostic codes for IDD were identified and the three most frequent diagnoses were unspecified intellectual disability, autism or pervasive developmental disorder, and cerebral palsy. The percentage of Medicaid members with IDD ranged from 2.3% in New York to 4.2% in South Carolina. Identifying and characterizing people with IDD is a first step that could guide public health promotion efforts for this population.


Polyphenol oxidase activity and antioxidant properties of Yomra apple (Malus communis L.) from Turkey.
In this study, firstly, antioxidant and polyphenol oxidase (PPO) properties of Yomra apple were investigated. Seventeen phenolic constituents were measured by reverse phase-high-performance liquid chromatography (RP-HPLC). Total phenolic compounds (TPCs), ferric reducing antioxidant power (FRAP) and 2, 2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activities were performed to measure antioxidant capacity. Some kinetic parameters (Km, Vmax), and inhibition behaviors against five different substrates were measured in the crude extract. Catechin and chlorogenic acid were found as the major components in the methanolic extract, while ferulic acid, caffeic acid, p-hydroxybenzoic acid, quercetin and p-coumaric acid were small quantities. Km values ranged from 0.70 to 10.10 mM in the substrates, and also 3-(4-hydroxyphenyl) propanoic acid (HPPA) and L-DOPA showed the highest affinity. The inhibition constant of Ki were ranged from 0.05 to 14.90 mM against sodium metabisulphite, ascorbic acid, sodium azide and benzoic acid, while ascorbic acid and sodium metabisulphite were the best inhibitors.


Detection of Escherichia coli O157:H7 with langasite pure shear horizontal surface acoustic wave sensors.
The toxigenic Escherichia coli O157:H7 bacterium has been connected with hemorrhagic colitis and hemolytic uremic syndrome, which may be characterized by diarrhea, kidney failure and death. On average, O157:H7 causes 73,000 illnesses, 2100 hospitalizations and 60 deaths annually in the United States alone. There is the need for sensors capable of rapidly detecting dangerous microbes in food and water supplies to limit the exposure of human and animal populations. Previous work by the authors used shear horizontal surface acoustic wave (SH SAW) devices fabricated on langasite (LGS) Euler angles (0 degrees, 22 degrees, 90 degrees) to successfully detect macromolecular protein assemblies. The devices also demonstrated favorable temperature stability, biocompatibility and low attenuation in liquid environments, suggesting their applicability to bacterial detection. In this paper, a biosensor test setup utilizing a small volume fluid injection system, stable temperature control and high frequency phase measurement was applied to validate LGS SH SAW biosensors for bacterial detection. The LGS SH SAW delay lines were fabricated and derivatized with a rabbit polyclonal IgG antibody, which selectively binds to E. coli O157:H7, in this case a non-toxigenic test strain. To quantify the effect of non-specific binding (negative control), an antibody directed against the trinitrophenyl hapten (TNP) was used as a binding layer. Test E. coli bacteria were cultured, fixed with formaldehyde, stained with cell-permeant nucleic acid stain, suspended in phosphate buffered saline and applied to the antibody-coated sensing surfaces. The biosensor transmission coefficient phase was monitored using a network analyzer. Phase responses of about 14 degrees were measured for the E. coli detection, as compared to 2 degrees due to non-specific anti-TNP binding. A 30:1 preference for E. coli binding to the anti-O157:H7 layer when compared to the anti-TNP layer was observed with fluorescence microscopy, thus confirming the selectivity of the antibody surface to E. coli.


Investigation of the effect of UV irradiation on DNA damage: comparison between skin cancer patients and normal volunteers.
Susceptibility to environmental carcinogenesis is the consequence of a complex interplay between intrinsic hereditary factors and actual exposure to potential carcinogenic agents. Exposure to sunlight is the primary etiological agent for basal cell carcinoma (BCC). The aim of this study was to determine the effects of different ultraviolet (UV) doses on DNA damage in epidermal keratinocytes in vivo and to elucidate if patients with BCC are more susceptible to UV-induced DNA damage in comparison with normal healthy volunteers in response to solar simulator radiation (SSR). Skin biopsies obtained post-UV irradiation from both normal healthy volunteers and BCC patients were analyzed for DNA damage, using immunohistochemical approach with TDM-2 antibody, which binds specifically to cyclobutane pyrimidine dimmers (CPDs). In both normal volunteers and BCC patients, the peak of CPD-positive cells occurred at 4.5 h post-SSR. There was a statistically significant difference in CPD positivity between BCC patients and normal volunteers, at time points (from 4.5 h to 48 h post-SSR). For a given dose of SSR based on each individual minimal erythema dose (MED), a greater number of CPD-positive cells could be shown. This study has shown for the first time and in vivo in human volunteers that BCC patients are more susceptible to UV-induced DNA damage in comparison with normal healthy volunteers.


Post-translational modification of the protein-synthesis initiation factor eIF-4D by spermidine in rat hepatoma cells.
The rates of synthesis and turnover of the rare amino acid hypusine [N6-(4-amino-2-hydroxybutyl)-2,6-diaminohexanoic acid] in protein were studied in relationship to polyamine metabolism and growth rates in rat hepatoma tissue-culture (HTC) cells. Hypusine is selectively formed in the eukaryotic translation initiation factor eIF-4D, by a post-translational mechanism involving spermidine [Cooper, Park, Folk, Safer & Braverman (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 1854-1857]. The half-life of the hypusine-containing protein was longer than 24 h. In cells whose intracellular spermidine pools had been initially depleted, by using DL-alpha-difluoromethylornithine (DFMO), maximum synthesis rates of hypusine in protein were 5-10 times higher, on restoration of endogenous spermidine contents by exogenous addition, than those observed in untreated exponential-phase cultures. In cells pretreated with DFMO, the rate of hypusine synthesis was constant for up to 1 h after the addition of 5 microM-spermidine, whereas endogenous spermidine contents varied from less than 1 to more than 10 nmol/mg of protein. However, the overall amount of hypusine formed, during the first 1 h after the addition of various concentrations of spermidine (0.05-10 microM) to the culture medium, was markedly dependent on the final endogenous spermidine content achieved at the end of the 1 h measurement interval. Early in exponential-phase growth, protein-bound hypusine was synthesized at a rate of 1-2 pmol/h per mg of protein. This rate decreased to less than 0.5 pmol/h per mg of protein when cell growth rates decreased as cultures reached high cell densities. Analysis of the polyamine substrate specificity for hypusine formation showed that N1-acetylspermidine did not compete with spermidine in the reaction, nor did N1-(buta-2,3-dienyl)-N2-methylbutane-1,4-diamine, and irreversible inhibitor of polyamine oxidase, block the reaction. On the basis of comparative radiolabelling experiments, spermine was either a poor substrate, or not a substrate, for hypusine formation. These results confirm that spermidine is the likely precursor of the aminohydroxybutyl moiety of hypusine, and show that overall hypusine formation, but not necessarily the synthesis rate, is dependent on the endogenous spermidine concentration, especially under conditions where spermidine concentrations are initially low, as is the case after DFMO treatment, and then increase.


The Relationship between Intramuscular Adipose Tissue, Functional Mobility, and Strength in Postmenopausal Women with and without Type 2 Diabetes.
Objectives. To determine (1) whether intramuscular adipose tissue (IntraMAT) differs between women with and without type 2 diabetes and (2) the association between IntraMAT and mobility and strength. Methods. 59 women ≥ 65 years with and without type 2 diabetes were included. A 1-Tesla MRI was used to acquire images of the leg. Timed-up-and-go (TUG) and grip strength were measured. Regression was used to determine associations between the following: (1) type 2 diabetes and IntraMAT (covariates: age, ethnicity, BMI, waist : hip ratio, and energy expenditure), (2) IntraMAT and TUG (covariates: diabetes, age, BMI, and energy expenditure), and (3) IntraMAT and grip strength (covariates: diabetes, age, height, and lean mass). Results. Women with diabetes had more IntraMAT. After adjustment, IntraMAT was similar between groups (diabetes mean [SD] = 13.2 [1.4]%, controls 11.8 [1.3]%, P = 0.515). IntraMAT was related to TUG and grip strength, but the relationships became nonsignificant after adjustment for covariates (difference/percent IntraMAT [95% CI]: TUG = 0.041 seconds [-0.079-0.161], P = 0.498, grip strength = -0.144 kg [-0.335-0.066], P = 0.175). Conclusions. IntraMAT alone may not be a clinically important predictor of functional mobility and strength; however, whether losses in functional mobility and strength are promoted by IntraMAT accumulation should be explored.


n-3 Polyunsaturated fatty acids modulate metabolism of insulin-sensitive tissues: implication for the prevention of type 2 diabetes.
Obesity is frequently associated with the development of type 2 diabetes which is firstly characterized by a defect in the response of key metabolic tissues to insulin (insulin resistance). The imbalance in fatty composition of the diet, a low-grade inflammatory state have been described to be involved in the initiation or the amplification of the molecular events involved in this process. The concept of a specific nutritional intervention has emerged as a promising tool against metabolic disorders associated with obesity. In this context, many investigations were conducted to evaluate the potential beneficial impacts of n-3 polyunsaturated fatty acids (n-3 PUFA). The aim of the present review was to summarize the current knowledge about the role of docosahexanoic acid (DHA, 22:6n-3) and eicosapentanoic acid (EPA, 20:5n-3) on key metabolic organs. Only studies aiming to understand the mechanism of actions were selected. The analysis of randomized clinical trial about n-3 PUFA was not considered here. The effects of n-3 PUFA were analyzed in the adipose tissue, the liver, skeletal muscle and the pancreas in the context of obesity and lipid oversupply. Furthermore, in line with recent findings about the role of the modulation of gut microbiota in obesity-related disorders, we summarized the recent findings about the possible link between n-3 PUFA and change in microbiota composition.


Development and evaluation of rapid data-enabled access to routine clinical information to enhance early recruitment to the national clinical platform trial of COVID-19 community treatments.
The COVID-19 pandemic has presented unique challenges for rapidly designing, initiating, and delivering therapeutic clinical trials. PRINCIPLE (Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses) is the UK national platform investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications. Standard methods of patient recruitment were failing to meet the required pace and scale of enrolment. This paper describes the development and appraisal of a near real-time, data-driven, ethical approach for enhancing recruitment in community care by contacting people with a recent COVID-19 positive test result from the central NHS Test and Trace service within approximately 24-48 h of their test result. A multi-disciplinary team was formed to solve the technical, ethical, public perception, logistical and information governance issues required to provide a near-real time (approximately within 24-48 h of receiving a positive test) feed of potential trial participants from test result data to the research team. PRINCIPLE was also given unique access to the Summary Care Record (SCR) to ensure safe prescribing, and to enable the trial team to quickly and safely bring consented patients into the trial. A survey of the public was used to understand public perceptions of the use of test data for this proposed methodology. Prior to establishing the data service, PRINCIPLE registered on average 87 participants per week. This increased by up to 87 additional people registered per week from the test data, contributing to an increase from 1013 recruits to PRINCIPLE at the start of October 2020 to 2802 recruits by 20 December 2020. Whilst procedural caveats were identified by the public consultation, out of 2639 people contacted by PRINCIPLE following a positive test result, no one raised a concern about being approached. This paper describes a novel approach to using near-real time NHS operational data to recruit community-based patients within a few days of presentation with acute illness. This approach increased recruitment and reduced time between positive test and randomisation, allowing more rapid evaluation of treatments and increased safety for participants. End-to-end public and patient involvement in the design of the approach provided evidence to inform information governance decisions. PRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research. EudraCT number: 2020-001209-22 . 26/03/2020 ISRCTN registry: ISRCTN86534580 . 20/03/2020 REC number: 20/SC/058 IRAS number: 281958.


Cerebrovascular disease in dementia: the importance of atrial fibrillation.
The relationship between cardiovascular disease and cerebral infarction was analysed in a prospectively assessed post mortem series of 48 demented patients. Hypertension was rare in this group of patients whose mean age was 82.7 y. Atrial fibrillation was the most important underlying cardiac abnormality. It is suggested that atrial fibrillation is more important than hypertension in the aetiology of cerebral infarction in the very aged and that this may be relevant to the pathogenesis of cerebrovascular dementia.


No wavefront sensor adaptive optics system for compensation of primary aberrations by software analysis of a point source image. 1. Methods.
Adaptive optics (AO) has been recently used for the development of ophthalmic devices. Its main objective has been to obtain high-resolution images for diagnostic purposes or to estimate high-order eye aberrations. The core of every AO system is an optical device that is able to modify the wavefront shape of the light entering the system; if you know the shape of the incoming wavefront, it is possible to correct the aberrations introduced in the optical path from the source to the image. The aim of this paper is to demonstrate the feasibility, although in a simulated system, of estimating and correcting an aberrated wavefront shape by means of an iterative gradient-descent-like software procedure, acting on a point source image, without expensive wavefront sensors or the burdensome computation of the point-spread-function (PSF) of the optical system. In such a way, it is possible to obtain a speed and repeatability advantage over classical stochastic algorithms. A hierarchy in the aberrations is introduced, in order to reduce the dimensionality of the state space to be searched. The proposed algorithm is tested on a simple optical system that has been simulated with ray-tracing software, with randomly generated aberrations, and compared with a recently proposed algorithm for wavefront sensorless adaptive optics.


Closed Financial Loops: When They Happen in Government, They're Called Corruption; in Medicine, They're Just a Footnote.
Many physicians are involved in relationships that create tension between a physician's duty to work in her patients' best interest at all times and her financial arrangement with a third party, most often a pharmaceutical manufacturer, whose primary goal is maximizing sales or profit. Despite the prevalence of this threat, in the United States and globally, the most common reaction to conflicts of interest in medicine is timid acceptance. There are few calls for conflicts of interest to be banned, and, to our knowledge, no one calls for conflicted practitioners to be reprimanded. Contrast our attitudes in medicine with public attitudes toward financial conflicts among government employees. When enforcement of rules against conflict of interest slackens in the public sector, news organizations investigate and publish their criticism. Yet even when doctors are quoted in the media promoting specific drugs, their personal financial ties to the drug maker are rarely mentioned. Policies for governmental employees are strict, condemnation is strong, and criminal statutes exist (allowing for corruption charges). Yet the evidence that conflict is problematic is, if anything, stronger in medicine than in the public sector. Policies against conflicts of interest in medicine should be at least as strong as those already existing in the public sector.


The Rhodobacter sphaeroides flagellar motor is a variable-speed rotor.
The rotation rate of the unidirectional stop/start motor of Rhodobacter sphaeroides was investigated using computerised motion analysis of tethered cells. The R. sphaeroides motor was found to have a variable rotation rate compared to the virtually constant-speed motor of wild-type and CheR mutant (smooth swimming) Escherichia coli. In addition, the dynamics of the R. sphaeroides motor during stopping was analysed with no consistent correlation behaviour. The motor could go from full rotation to stop, or stop to full rotation within one video frame, i.e. 0.02 s, but it could also slow down into a stop or restart slowly, taking up to 0.25 s. The R. sphaeroides motor under chemokinetic stimulation was also analysed and was found to show increased torque generation and reduced variation in rotation rate.


The grab-and-drop protocol: a novel strategy for membrane protein isolation and reconstitution from single cells.
We present a rapid and robust technique for the sampling of membrane-associated proteins from the surface of a single, live cell and their subsequent deposition onto a solid-supported lipid bilayer. As a proof of principle, this method has been used to extract green fluorescent protein (EGFP) labelled K-ras proteins located at the inner leaflet of the plasma membrane of colon carcinoma cells and to transfer them to an S-layer supported lipid bilayer system. The technique is non-destructive, meaning that both the cell and proteins are intact after the sampling operation, offering the potential for repeated measurements of the same cell of interest. This system provides the ideal tool for the investigation of cellular heterogeneity, as well as a platform for the investigation of rare cell types such as circulating tumour cells.


Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma.
Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5β1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5β1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5β1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5β1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5β1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5β1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.


General adaptive-neighborhood technique for improving synthetic aperture radar interferometric coherence estimation.
A new method for filtering the coherence map issued from synthetic aperture radar (SAR) interferometric data is presented. For each pixel of the interferogram, an adaptive neighborhood is determined by a region-growing technique driven by the information provided by the amplitude images. Then pixels in the derived adaptive neighborhood are complex averaged to yield the filtered value of the coherence, after a phase-compensation step is performed. An extension of the algorithm is proposed for polarimetric interferometric SAR images. The proposed method has been applied to both European Remote Sensing (ERS) satellite SAR images and airborne high-resolution polarimetric interferometric SAR images. Both subjective and objective performance analysis, including coherence edge detection, shows that the proposed method provides better results than the standard phase-compensated fixed multilook filter and the Lee adaptive coherence filter.


Insulin-like growth factor 2 receptor is an IFNgamma-inducible microglial protein that facilitates intracellular HIV replication: implications for HIV-induced neurocognitive disorders.
Insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose 6-phosphate (M6P) receptor, is a transmembrane glycoprotein localized in the trans-Golgi region and is involved in targeting both M6P-bearing enzymes and IGF2 to the lysosomal compartment. During development, IGF2R plays a crucial role in removing excess growth factors from both tissue and blood. Due to the perinatal lethality of the global Igf2r knockout, the function of IGF2R in adults, particularly in the CNS, is not known. We made a novel observation that IGF2R is highly expressed in microglial nodules in human brains with HIV encephalitis. In vitro, microglial IGF2R expression was uniquely enhanced by IFNγ among the several cytokines and TLR ligands examined. Furthermore, in several in vitro models of HIV infection, including human and murine microglia, macrophages, and nonmacrophage cells, IGF2R is repeatedly shown to be a positive regulator of HIV infection. IGF2R RNAi also down-regulated the production of the IP-10 chemokine in HIV-infected human microglia. Injection of VSVg env HIV into mouse brain induced HIV p24 expression in neurons, the only cell type normally expressing IGF2R in the adult brain. Our results demonstrate a novel role for IGF2R as an inducible microglial protein involved in regulation of HIV and chemokine expression. Mice with the Csf1r- driven Igf2r knockout should be useful for the investigation of macrophage-specific IGF2R function.


Simultaneous discrimination between 15 fish pathogens by using 16S ribosomal DNA PCR and DNA microarrays.
We developed a DNA microarray suitable for simultaneous detection and discrimination between multiple bacterial species based on 16S ribosomal DNA (rDNA) polymorphisms using glass slides. Microarray probes (22- to 31-mer oligonucleotides) were spotted onto Teflon-masked, epoxy-silane-derivatized glass slides using a robotic arrayer. PCR products (ca. 199 bp) were generated using biotinylated, universal primer sequences, and these products were hybridized overnight (55 degrees C) to the microarray. Targets that annealed to microarray probes were detected using a combination of Tyramide Signal Amplification and Alexa Fluor 546. This methodology permitted 100% specificity for detection of 18 microbes, 15 of which were fish pathogens. With universal 16S rDNA PCR (limited to 28 cycles), detection sensitivity for purified control DNA was equivalent to <150 genomes (675 fg), and this sensitivity was not adversely impacted either by the presence of competing bacterial DNA (1.1 x 10(6) genomes; 5 ng) or by the addition of up to 500 ng of fish DNA. Consequently, coupling 16S rDNA PCR with a microarray detector appears suitable for diagnostic detection and surveillance for commercially important fish pathogens.


Uncertainty in measurements of the photorespiratory CO2 compensation point and its impact on models of leaf photosynthesis.
Rates of carbon dioxide assimilation through photosynthesis are readily modeled using the Farquhar, von Caemmerer, and Berry (FvCB) model based on the biochemistry of the initial Rubisco-catalyzed reaction of net C3 photosynthesis. As models of CO2 assimilation rate are used more broadly for simulating photosynthesis among species and across scales, it is increasingly important that their temperature dependencies are accurately parameterized. A vital component of the FvCB model, the photorespiratory CO2 compensation point (Γ *), combines the biochemistry of Rubisco with the stoichiometry of photorespiratory release of CO2. This report details a comparison of the temperature response of Γ * measured using different techniques in three important model and crop species (Nicotiana tabacum, Triticum aestivum, and Glycine max). We determined that the different Γ * determination methods produce different temperature responses in the same species that are large enough to impact higher-scale leaf models of CO2 assimilation rate. These differences are largest in N. tabacum and could be the result of temperature-dependent increases in the amount of CO2 lost from photorespiration per Rubisco oxygenation reaction.


The potential of immunomodulatory drugs in the treatment of solid tumors.
Lenalidomide (REVLIMID®) CC-5013 (Celgene, NJ, USA) is approved, in both the USA and Europe, in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy, and is rapidly being accepted worldwide for this condition. Lenalidomide is also approved in the USA and Canada for use in transfusion-dependent anemia in patients with low- and intermediate-1-risk myelodysplastic syndromes associated with del (5q) abnormality with or without additional abnormalities. Lenalidomide is an IMiD® immunomodulatory compound, incorporating structural modification of the drug thalidomide, which is active against a wide variety of autoimmune Th-2-dependent disorders, including erythema nodosum of leprosy, leishmaniasis, as well as severe ulcerative disorders such as Behcet's syndrome. Unfortunately, long-term use of thalidomide is limited, particularly by neurotoxicity. To date, results suggest that lenalidomide is more active than thalidomide and does not cause the neurotoxicity seen with thalidomide. Lenalidomide has multiple properties, including anti-inflammatory, antiangiogenic and costimulatory effects, as well as being able to inhibit T-regulatory cells, all of which are properties deemed desirable for anticancer activity. This article covers the evidence that lenalidomide may have a major role in the treatment and control of many cancer types other than del (5q) myelodysplastic syndrome and multiple myeloma.


Experiences of living with increased risk of developing colorectal and gynaecological cancer in individuals with no identified gene mutation.
In most families with familial cancers, mutations have not been demonstrated; thus, healthy individuals cannot be tested for mutation status. As a consequence, many persons at risk of familial cancer live with an unknown, but presumably high, risk of developing cancer. The aim of this study was to describe individuals' perceptions of living with an increased risk of colorectal and gynaecologic cancer where the gene mutation is unknown. Interviews were conducted with 30 individuals with familial colorectal cancer. These persons have no known mutation and therefore should be considered presumptive carriers. In connection with the interviews, all participants were offered to take part in a surveillance programme consisting of a colonoscopy and gynaecological examinations. The interview transcriptions were analysed by the use of qualitative content analysis. Two themes emerged from the analyses: first, living under a threat with two subthemes, threat awareness and distancing oneself from the threat. The second theme, living with uncertainty, was divided into four subthemes: influencing one's family, being on the safe side, facing emotions evoked by examinations and trust and disappointment to the medical services. These persons live with a lifelong uncertainty with a varying intensity depending on what happens throughout the life trajectory. They have no diagnosis or patient group to relate to; therefore, the entire situation is often perceived as abstract. Thus, providing information and counselling needs to be more deeply elucidated, and we need to address both situational and existential ways of uncertainty. This will, however, require professionals of all disciplines to understand the meaning of uncertainty and help ensure that its adverse effects are decreased with adequate nursing interventions.


A DPP-mediated feed-forward loop canalizes morphogenesis during Drosophila dorsal closure.
Development is robust because nature has selected various mechanisms to buffer the deleterious effects of environmental and genetic variations to deliver phenotypic stability. Robustness relies on smart network motifs such as feed-forward loops (FFLs) that ensure the reliable interpretation of developmental signals. In this paper, we show that Decapentaplegic (DPP) and JNK form a coherent FFL that controls the specification and differentiation of leading edge cells during Drosophila melanogaster dorsal closure (DC). We provide molecular evidence that through repression by Brinker (Brk), the DPP branch of the FFL filters unwanted JNK activity. High-throughput live imaging revealed that this DPP/Brk branch is dispensable for DC under normal conditions but is required when embryos are subjected to thermal stress. Our results indicate that the wiring of DPP signaling buffers against environmental challenges and canalizes cell identity. We propose that the main function of DPP pathway during Drosophila DC is to ensure robust morphogenesis, a distinct function from its well-established ability to spread spatial information.


Phagocytosis of mastitis isolates of Staphylococcus aureus and expression of type 5 capsular polysaccharide are influenced by growth in the presence of milk.
Phagocytosis by bovine polymorphonuclear granulocytes of seven capsular polysaccharide type 5 Staphylococcus aureus strains isolated from mastitis [corrected] was investigated by means of luminol-dependent chemiluminescence. Bacteria were grown on four different agar media (brain heart infusion, Columbia broth, modified staphylococcus medium 110, and skim milk) and were opsonized by normal bovine serum. When compared to growth on brain heart infusion agar, Columbia agar, and modified staphylococcus medium 110 agar, growth on skim milk agar rendered five of the strains more resistant to opsonization. The other two strains were resistant in all culture media used. Short periods of incubation in milk after growth on brain heart infusion agar did not augment resistance to phagocytosis, indicating that mere adsorption of milk components on bacteria was not responsible. The variability of the chemiluminescence response of polymorphonuclear leukocytes was pronounced among strains with each growth medium except milk. Growth on modified staphylococcus medium 110 and on milk agar favored the masking of teichoic acid, as shown by inagglutinability with rabbit antiserum. Interestingly, agglutination by a monoclonal antibody to capsular polysaccharide type 5 was optimal when bacteria were grown on skim milk agar. This suggests that capsular polysaccharide participated in the masking effect. These findings indicate that masking of the bacterial target of most of the naturally acquired opsonins present in normal bovine serum occurred when bacteria grew in the presence of milk, resulting in an increased resistance to phagocytosis by polymorphonuclear leukocytes.


Meta-analysis of cognitive functioning in patients following kidney transplantation.
There is mixed evidence regarding the nature of cognitive function in patients who have undergone renal transplantation. The aim of this meta-analysis was to examine which cognitive domains are impacted following kidney transplantation and how performance compares with non-transplanted patients or healthy controls/normative data. A systematic search was conducted using keywords within three databases (Embase, MEDLINE and PsychINFO), yielding 458 unique studies, 10 of which met the inclusion criteria. Neuropsychological tests were grouped into nine cognitive domains and three separate analyses were undertaken within each domain: (i) within subjects pre- versus post-transplant, (ii) transplanted versus non-transplanted patients and (iii) transplanted versus healthy matched controls and standardized normative data. Transplanted patients showed moderate to large improvements in the domains of general cognitive status (g = 0.526), information and motor speed (g = 0.558), spatial reasoning (g = 0.376), verbal memory (g = 0.759) and visual memory (g = 0.690) when compared with their pre-operative scores. Test scores in the same five domains were significantly better in post-transplanted patients when compared with dialysis-dependant or conservatively managed chronic kidney disease patients. However, post-transplanted patients' performance was significantly low compared with that of healthy controls (and standardized normative data) in the domains of executive functioning (g = -0.283), verbal fluency (g = -0.657) and language (g = -0.573). Two key issues arise from this review. First, domain-specific cognitive improvement occurs in patients after successful transplantation. Nevertheless, transplanted patients still performed significantly below healthy controls in some domains. Second, there are important shortcomings in existing studies; the length of follow-up is typically short and only limited neuropsychological test batteries are employed. These factors are important in order to support the recovery of cognitive function among patients following renal transplant.


Genetic diversity of Cajazeira (Spondias mombin L.) in three geographic regions.
Cajazeira (Spondias mombin L.), of the family Anacardiaceae, is a species of fruit tree found in the Amazon region with fruits that have excellent prospects for commercial use. We aimed to evaluate the genetic diversity within and among natural populations of S. mombin, with natural occurrence in northern Mato Grosso State, by using inter-simple sequence repeat (ISSR) markers. Overall, 126 individuals were evaluated from three populations located Alta Floresta (AFL) 42, Marcelândia (MAR) 41, and Nova Bandeirantes (NBA) 43. The individuals were genotyped with 14 ISSR primers, which amplified 99 fragments. All markers, with the exception of DiGA3'A, presented a polymorphic information content above 0.25, and thus, are recommended for diversity analyses in S. mombin. Genetic diversity of the AFL [Nei's diversity (H) = 0.2430 and Shannon index (I) = 0.3547] and MAR (H = 0.2062 and I = 0.2993) populations was higher when compared to the NBA population, which presented the lowest genetic diversity (H = 0.2002 and I = 0.2957). Analysis of molecular variance showed that 77.38% of the total genetic variation is found within populations while 22.62% is found among populations. AFL and NBA are genetically the most similar populations and also the closest "Structure" revealed genetic diversity among the genotypes of each population. As there is genetic variability in both populations, and there are no genetically identical individuals, both populations can be a source of genotypes for germplasm banks and for future commercial fruitful plantations S. mombin.


Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome.
Intensified immunosuppression in steroid-resistant nephrotic syndrome is broadly applied, with disparate outcomes. This review of patients from the United Kingdom National Study of Nephrotic Syndrome cohort aimed to improve disease stratification by determining, in comprehensively genetically screened patients with steroid-resistant nephrotic syndrome, if there is an association between response to initial intensified immunosuppression and disease progression and/or post-transplant recurrence. Pediatric patients with steroid-resistant nephrotic syndrome were recruited via the UK National Registry of Rare Kidney Diseases. All patients were whole-genome sequenced, whole-exome sequenced, or steroid-resistant nephrotic syndrome gene-panel sequenced. Complete response or partial response within 6 months of starting intensified immunosuppression was ascertained using laboratory data. Response to intensified immunosuppression and outcomes were analyzed according to genetic testing results, pattern of steroid resistance, and first biopsy findings. Of 271 patients, 178 (92 males, median onset age 4.7 years) received intensified immunosuppression with response available. A total of 4% of patients with monogenic disease showed complete response, compared with 25% of genetic-testing-negative patients (P=0.02). None of the former recurred post-transplantation. In genetic-testing-negative patients, 97% with complete response to first intensified immunosuppression did not progress, whereas 44% of nonresponders developed kidney failure with 73% recurrence post-transplant. Secondary steroid resistance had a higher complete response rate than primary/presumed resistance (43% versus 23%; P=0.001). The highest complete response rate in secondary steroid resistance was to rituximab (64%). Biopsy results showed no correlation with intensified immunosuppression response or outcome. Patients with monogenic steroid-resistant nephrotic syndrome had a poor therapeutic response and no post-transplant recurrence. In genetic-testing-negative patients, there was an association between response to first intensified immunosuppression and long-term outcome. Patients with complete response rarely progressed to kidney failure, whereas nonresponders had poor kidney survival and a high post-transplant recurrence rate. Patients with secondary steroid resistance were more likely to respond, particularly to rituximab.


Cognitive tests used in chronic adult human randomised controlled trial micronutrient and phytochemical intervention studies.
In recent years there has been a rapid growth of interest in exploring the relationship between nutritional therapies and the maintenance of cognitive function in adulthood. Emerging evidence reveals an increasingly complex picture with respect to the benefits of various food constituents on learning, memory and psychomotor function in adults. However, to date, there has been little consensus in human studies on the range of cognitive domains to be tested or the particular tests to be employed. To illustrate the potential difficulties that this poses, we conducted a systematic review of existing human adult randomised controlled trial (RCT) studies that have investigated the effects of 24 d to 36 months of supplementation with flavonoids and micronutrients on cognitive performance. There were thirty-nine studies employing a total of 121 different cognitive tasks that met the criteria for inclusion. Results showed that less than half of these studies reported positive effects of treatment, with some important cognitive domains either under-represented or not explored at all. Although there was some evidence of sensitivity to nutritional supplementation in a number of domains (for example, executive function, spatial working memory), interpretation is currently difficult given the prevailing 'scattergun approach' for selecting cognitive tests. Specifically, the practice means that it is often difficult to distinguish between a boundary condition for a particular nutrient and a lack of task sensitivity. We argue that for significant future progress to be made, researchers need to pay much closer attention to existing human RCT and animal data, as well as to more basic issues surrounding task sensitivity, statistical power and type I error.


Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes.
Signaling molecules downstream from the insulin receptor, such as the insulin receptor substrate protein 1 (IRS-1), are also activated by other receptor tyrosine kinases. Here we demonstrate that the non-receptor tyrosine kinases, focal adhesion kinase pp125(FAK) and Src-class kinase pp59(Lyn), after insulin-independent activation by phosphoinositolglycans (PIG), can cross talk to metabolic insulin signaling in rat and 3T3-L1 adipocytes. Introduction by electroporation of neutralizing antibodies against pp59(Lyn) and pp125(FAK) into isolated rat adipocytes blocked IRS-1 tyrosine phosphorylation in response to PIG but not insulin. Introduction of peptides encompassing either the major autophosphorylation site of pp125(FAK), tyrosine 397, or its regulatory loop with the twin tyrosines 576 and 577 inhibited PIG-induced IRS-1 tyrosine phosphorylation and glucose transport. PIG-induced pp59(Lyn) kinase activation and pp125(FAK) tyrosine phosphorylation were impaired by the former and latter peptide, respectively. Up-regulation of pp125(FAK) by integrin clustering diminished PIG-induced IRS-1 tyrosine phosphorylation and glucose transport in nonadherent but not adherent adipocytes. In conclusion, PIG induced IRS-1 tyrosine phosphorylation by causing (integrin antagonized) recruitment of IRS-1 and pp59(Lyn) to the common signaling platform molecule pp125(FAK), where cross talk of PIG-like structures and extracellular matrix proteins to metabolic insulin signaling may converge, possibly for the integration of the demands of glucose metabolism and cell architecture.


Colonisation and transmission of Clostridium difficile in healthy individuals examined by PCR ribotyping and pulsed-field gel electrophoresis.
Healthy adults who had not been exposed to antimicrobial agents for the preceding 4 weeks were examined for intestinal carriage of Clostridium difficile. The 1234 individuals examined were composed of seven groups: three classes of university students, hospital workers at two hospitals, employees of a company and self-defence force personnel at a local station. Overall, 94 (7.6%) individuals were positive for C. difficile by faecal culture but carriage rates among the study groups ranged from 4.2% to 15.3%. Typing by PCR ribotyping and pulsed-field gel electrophoresis demonstrated clusters of carriers colonised by a single type in each of three groups, indicating that cross-transmission of C. difficile can occur in community settings. Follow-up culture was performed on 38 C. difficile-positive individuals and C. difficile was isolated again from 12 (32%) of them 5-7 months after the initial culture; six (50%) of these 12 individuals had a new strain on repeat culture. Two or more family members were C. difficile-positive in five of 22 families examined. C. difficile with an identical type was isolated from persons within a family in only one family. These results suggest that intestinal carriage by healthy adults may play a role as a reservoir for community-acquired C. difficile-associated diarrhoea, but that cross-transmission of C. difficile does not occur frequently among family members at home.


Foreign Language Short Course: Special Operations Clinical Research Fundamentals.
When we do not know a language, we are at the mercy of an interpreter. The same is true for research: Special Operations Forces (SOF) clinicians not actively involved in research initiatives may rely on scientific interpreters, so it is important to speak some of the language personally. For any clinician, using evidence in practice requires a working knowledge of how that evidence was generated from research, which requires an understanding of research science language. Here we review common basics of research science to reinforce concepts and elements of experimental and nonexperimental research.


Design and characterization of a modular membrane protein anchor to functionalize the moss Physcomitrella patens with extracellular catalytic and/or binding activities.
Heterologous enzymes and binding proteins were secreted by the moss Physcomitrella patens or anchored extracellularly on its cell membrane in order to functionalize the apoplast as a biochemical reaction compartment. This modular membrane anchoring system utilizes the signal peptide and the transmembrane segment of the somatic embryogenesis receptor-like kinase (SERK), which were identified in a comprehensive bioinformatic analysis of the P. patens genome. By fusing the soluble enzyme NanoLuc luciferase to the signal peptide, its secretion capability was confirmed in vivo. The membrane localization of hybrid proteins comprising the SERK signal peptide, NanoLuc or other functional modules, the SERK transmembrane anchor, and a C-terminal GFP reporter was demonstrated using fluorescence microscopy as well as site-specific proteolytic release of the extracellular enzyme domain. Our membrane anchoring system enables the expression of various functional proteins in the apoplast of P. patens, empowering this photoautotrophic organism for biotechnological applications.


Altered Gut Microbiome Profile in Patients With Pulmonary Arterial Hypertension.
Pulmonary arterial hypertension (PAH) is considered a disease of the pulmonary vasculature. Limited progress has been made in preventing or arresting progression of PAH despite extensive efforts. Our previous studies indicated that PAH could be considered a systemic disease since its pathology involves interplay of multiple organs. This, coupled with increasing implication of the gut and its microbiome in chronic diseases, led us to hypothesize that patients with PAH exhibit a distinct gut microbiome that contributes to, and predicts, the disease. Fecal microbiome of 18 type 1 PAH patients (mean pulmonary arterial pressure, 57.4, SD 16.7 mm Hg) and 13 reference subjects were compared by shotgun metagenomics to evaluate this hypothesis. Significant taxonomic and functional changes in microbial communities in the PAH cohort were observed. Pathways for the synthesis of arginine, proline, and ornithine were increased in PAH cohort compared with reference cohort. Additionally, groups of bacterial communities associated with trimethylamine/ trimethylamine N-oxide and purine metabolism were increased in PAH cohort. In contrast, butyrate-and propionate-producing bacteria such as Coprococcus, Butyrivibrio, Lachnospiraceae, Eubacterium, Akkermansia, and Bacteroides were increased in reference cohort. A random forest model predicted PAH from the composition of the gut microbiome with 83% accuracy. Finally, virome analysis showed enrichment of Enterococcal and relative depletion of Lactococcal phages in the PAH cohort. In conclusion, patients with PAH exhibit a unique microbiome profile that has the high predictive potential for PAH. This highlights previously unknown roles of gut bacteria in this disease and could lead to new therapeutic, diagnostic, or management paradigms for PAH.


Workplace violence towards workers in the emergency departments of Palestinian hospitals: a cross-sectional study.
Workplace violence (WPV) in hospital emergency departments (EDs) is a common problem. The objective of this study was to assess the characteristics (level and type), associated risk factors, causes, and consequences of WPV against workers in Palestinian EDs. A cross-sectional study was conducted in 14 out of the available 39 EDs in Palestine: 8 from the West Bank and 6 from the Gaza Strip. Data were collected using a self-administered questionnaire between July-September 2013. Multivariate logistic regression models were used to examine risk factors associated with exposure to WPV. A total of 444 participants (response rate 74.5%): 161 (32.0%) nurses, 142 (32%) physicians, and 141 (31.7%) administrative personnel. The majority (76.1%) experienced a type of WPV in the past 12 months: 35.6% exposed to physical and 71.2% to non-physical assaults (69.8% verbal abuses, 48.4% threats, and 8.6% sexual harassments). Perpetrators of physical and non-physical violence were mainly patients' families/visitors (85.4% and 79.5%, respectively). Waiting time, lack of prevention measures, and unmet expectations of patients and their families are the main reasons for WPV. The multivariate regression analysis showed that younger personnel (OR = 2.29 CI 95% 1.309-4.036), clinicians (nurses and physicians) (OR = 1.65 CI 95% 0.979-2.797) comparing with administrative, and less experienced ED personnel (OR = 2.39 CI 95% 1.141-5.006) are significantly at higher risk of exposure to WPV (P < 0.05). Low level (40%) of violence reporting is evident, largely attributed to not enough actions being taken and fear of consequences. Violence has been shown to have considerable consequences for workers' well-being, patient care, and job retention. Violence against workers in Palestinian EDs is highly common. The effects of violence are considerable. Multiple factors cause violence; however, EDs' internal-system-related factors are the most amenable to change. Attention should be given to strengthening violence prevention policy and measures and improving incident-reporting system.


Increasing prevalence of ESBL production among Irish clinical Enterobacteriaceae from 2004 to 2008: an observational study.
Extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae infections are associated with delayed initiation of appropriate treatment, poor outcomes and increased hospital stay and expense. Although initially associated with healthcare settings, more recent international reports have shown increasing isolation of ESBLs in the community. Both hospital and community ESBL epidemiology in Ireland are poorly defined. This report describes clinical and laboratory data from three hospitals over 4.5 years. All significant isolates of Enterobacteriaceae were subjected to standardized antimicrobial susceptibility testing and screening for ESBL production. Available patient data from hospital databases were reviewed. The database included 974 ESBL producing organisms from 464 patients. Urine and blood isolates represented 84% and 3% of isolates respectively. E. coli predominated (90.9%) followed by K. pneumoniae (5.6%). The majority of patients (n = 246, 53.0%) had been admitted to at least one of the study hospitals in the year prior to first isolation of ESBL. The overall 30-day all-cause mortality from the date of culture positivity was 9.7% and the 1 year mortality was 61.4%. A Cox regression analysis showed age over 60, male gender and previous hospital admissions were significant risk factors for death within 30 days of ESBL isolation. Numbers of ESBL-producing E. coli isolated from urine and blood cultures increased during the study. Urine isolates were more susceptible than blood isolates. Co-resistance to other classes of antimicrobial agents was more common in ESBL producers from residents of long stay facilities (LSF) compared with hospital inpatients who lived at home. This work demonstrates a progressively increasing prevalence of ESBL Enterobacteriaceae in hospital, LSF and community specimens in a defined catchment area over a long time period . These results will improve clinician awareness of this problem and guide the development of empiric antimicrobial regimens for community acquired bloodstream and urinary tract infections.