Adaptation to a novel host by a seed beetle (Coleoptera: Chrysomelidae: Bruchinae): effect of source population.
Geographic populations of a widespread species can differ in their ability to adapt to a novel environment because they possess different amounts of the requisite genetic variation. We compared responses to the same novel host in ecologically and genetically divergent populations of the seed beetle Callosobruchus maculatus (F.). Populations from Africa and Asia had been derived from and maintained on different legume hosts. In preselection assays, both populations exhibited lower survival, slower development, and smaller size on a third host (adzuki bean), and the difference in performance between the ancestral and novel hosts was especially high for the African population. Replicate lines of each population were switched to adzuki bean or maintained on the ancestral host, and beetle performance was measured on both hosts after 12 generations. Survival on adzuki bean increased substantially in the adzuki-bean lines of the African population, but improved only slightly in the Asian lines. Similarly, only the African adzuki-bean lines exhibited significantly faster development on adzuki bean. Improved performance on adzuki bean did not simultaneously reduce performance on the ancestral host. Together with previous studies, these results confirm that populations of C. maculatus often possess sufficient standing genetic variation for rapid adaptation to a novel host, but the magnitude of the response may depend on the source population. Although international trade in grain legumes can expand beetle host ranges and produce unusual biotypes, the consistent absence of strong genetic trade-offs in larval performance or adult oviposition across hosts makes it unlikely that this insect would form distinct host races.


Utilizing paramedics for in-patient critical care surge capacity.
While many hospitals have developed preliminary emergency department and in-patient surge plans, the ability to surge is often limited by critical resources. The resource which is often the most limited is usually the human resource and within this category the limiting factor is almost universally nursing. As a result, nursing shortages can result in an inability of a hospital or emergency department to create surge capacity to deal with large numbers of ill or injured patients. Utilizing paramedics in acute-care hospitals or at alternate care sites could serve as expansion staff to supplement existing nursing staff allowing fewer nurses to care for a larger numbers of patients during a disaster, act of terrorism, or public health emergency. While the procedures performed for nursing do vary from hospital to hospital, there are national certifications for both emergency nursing (CEN) and critical care nursing (CCRN) that can be used to establish a standard for comparison. A detailed review and curriculum mapping of the specific educational objectives and competencies of the U.S. Department of Transportation National Standard Curriculum for the Emergency Medical Technician-Paramedic as well as the competencies and criteria for board certification as a Certified Emergency Nurse (CEN) and Critical Care Registered Nurse (CCRN) was performed. Approximately 90 percent of the CEN and CCRN knowledge skills and competencies are met or exceeded by the National Standard Paramedic Curriculum. With appropriate training and orientation, paramedics may be used in an in-patient setting to augment emergency and critical care nursing staff during a disaster, act of terrorism, or public health emergency.


Dispelling myths about emergency department use: majority of Medicaid visits are for urgent or more serious symptoms.
Contrary to conventional wisdom that Medicaid patients often use hospital emergency departments (EDs) for routine care, the majority of ED visits by nonelderly Medicaid patients are for symptoms suggesting urgent or more serious medical problems, according to a new national study by the Center for Studying Health System Change (HSC). About 10 percent of nonelderly Medicaid patient ED visits are for nonurgent symptoms, compared with about 7 percent for privately insured nonelderly people. Nonetheless, there are clearly opportunities to develop less-costly care options than emergency departments for both nonelderly Medicaid and privately insured patients. To reduce ED use, policy makers might consider how to encourage development of care settings that can quickly handle a high volume of potentially urgent medical problems. Policy makers may want to focus initially on conditions that account for high ED volume that could likely be treated in less resource-intensive settings. For example, diagnoses of acute respiratory and other common infections in children and injuries together account for about 53 percent of ED visits by children aged 0 to 12 covered by Medicaid and almost 60 percent of ED visits by privately insured children aged 0 to 12. While some infections and injuries will be too serious to treat elsewhere, lower-cost settings that can provide a moderate intensity of care and urgent response time likely could reduce emergency department use.


Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases.
Cell secreted exosomes (30-100nm vesicles) play a major role in intercellular communication due to their ability to transfer proteins and nucleic acids from one cell to another. Depending on the originating cell type and the cargo, exosomes can have immunosuppressive or immunostimulatory effects, which have potential application as immunotherapies for cancer and autoimmune diseases. Cellular components shed from tumor cells or antigen presenting cells (APCs), such as dendritic cells, macrophages and B cells, have been shown to be efficiently packaged in exosomes. In this review, we focus on the application of exosomes as nanocarriers and immunological agents for cancer and autoimmune immunotherapy. APC-derived exosomes demonstrate effective therapeutic efficacy for the treatment of cancer and experimental autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In addition to their intrinsic immunomodulating activity, exosomes have many advantages over conventional nanocarriers for drug and gene delivery.


A photoreactive small-molecule probe for 2-oxoglutarate oxygenases.
2-oxoglutarate (2-OG)-dependent oxygenases have diverse roles in human biology. The inhibition of several 2-OG oxygenases is being targeted for therapeutic intervention, including for cancer, anemia, and ischemic diseases. We report a small-molecule probe for 2-OG oxygenases that employs a hydroxyquinoline template coupled to a photoactivable crosslinking group and an affinity-purification tag. Following studies with recombinant proteins, the probe was shown to crosslink to 2-OG oxygenases in human crude cell extracts, including to proteins at endogenous levels. This approach is useful for inhibitor profiling, as demonstrated by crosslinking to the histone demethylase FBXL11 (KDM2A) in HEK293T nuclear extracts. The results also suggest that small-molecule probes may be suitable for substrate identification studies.


Suboptimal Larval Habitats Modulate Oviposition of the Malaria Vector Mosquito Anopheles coluzzii.
Selection of oviposition sites by gravid females is a critical behavioral step in the reproductive cycle of Anopheles coluzzii, which is one of the principal Afrotropical malaria vector mosquitoes. Several studies suggest this decision is mediated by semiochemicals associated with potential oviposition sites. To better understand the chemosensory basis of this behavior and identify compounds that can modulate oviposition, we examined the generally held hypothesis that suboptimal larval habitats give rise to semiochemicals that negatively influence the oviposition preference of gravid females. Dual-choice bioassays indicated that oviposition sites conditioned in this manner do indeed foster significant and concentration dependent aversive effects on the oviposition site selection of gravid females. Headspace analyses derived from aversive habitats consistently noted the presence of dimethyl disulfide (DMDS), dimethyl trisulfide (DMTS) and 6-methyl-5-hepten-2-one (sulcatone) each of which unitarily affected An. coluzzii oviposition preference. Electrophysiological assays across the antennae, maxillary palp, and labellum of gravid An. coluzzii revealed differential responses to these semiochemicals. Taken together, these findings validate the hypothesis in question and suggest that suboptimal environments for An. coluzzii larval development results in the release of DMDS, DMTS and sulcatone that impact the response valence of gravid females.


Evaluation of a critical pathway for stroke.
The diagnosis of stroke, which is diagnosis-related group (DRG) 014, is the fourth most frequent discharge DRG at Macomb Hospital Center, Warren, Michigan. The length of stay for stroke was 7.52 days before intervention. Quality improvement techniques identified areas of delay that presented opportunities for improvement. After the initiation of a critical pathway that begins its interventions in the Emergency Department, the length of stay decreased to 6.33 days. Quality of care was also improved in delivery time of carotid artery ultrasound examinations, as well as in timeliness of obtaining head computed tomography scans and reports. This article describes the development, implementation, and results of a stroke critical pathway that was implemented to address excessive length of stay.


Marginal cost of the calving interval in beef cows is not uniform.
To understand the profitability of reproduction management measures, an economic assessment based on a beef cow life simulation was proposed. It accounted for the discounted feeding costs of the dam and its calves for the different periods of their lives up to their sale and for the overall production from calves adjusted by mortality and culling. The calibration was proposed for various combinations of typical French and European situations. The maximal cash flow was observed for the lowest calving interval, corresponding to the maximal number of calves produced. The marginal cost of the calving interval was not uniform: on average, it was twice as high at a calving interval of 360 days (€1/day) as at 500 days (€0.5/day). It was also higher when age at first calving was lower and when culling was late or the replacement rate was low. The results were sensitive to the costs of the calves' diets and to the market prices for calves. These assessments may assist the evaluation of the profitability of various measures taken in the field when faced with deteriorating calving intervals in beef production.


Single-cell analysis of murine fibroblasts identifies neonatal to adult switching that regulates cardiomyocyte maturation.
Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. By integrating single-cell RNA-sequencing data of mouse hearts at multiple postnatal stages, we construct cellular interactomes and regulatory signaling networks. Here we report switching of fibroblast subtypes from a neonatal to adult state and this drives cardiomyocyte maturation. Molecular and functional maturation of neonatal mouse cardiomyocytes and human embryonic stem cell-derived cardiomyocytes are considerably enhanced upon co-culture with corresponding adult cardiac fibroblasts. Further, single-cell analysis of in vivo and in vitro cardiomyocyte maturation trajectories identify highly conserved signaling pathways, pharmacological targeting of which substantially delays cardiomyocyte maturation in postnatal hearts, and markedly enhances cardiomyocyte proliferation and improves cardiac function in infarcted hearts. Together, we identify cardiac fibroblasts as a key constituent in the microenvironment promoting cardiomyocyte maturation, providing insights into how the manipulation of cardiomyocyte maturity may impact on disease development and regeneration.


Ethical reflections on the thoughts and lives of Kurosawa's doctors.
The year 2010 marked the centenary of the birth of Akira Kurosawa (1910-1998), whose works have been reassessed favourably in the last couple of years in Japan. During his lifetime, Kurosawa directed and produced three films whose chief characters are medical doctors: Drunken Angel (1948), The Quiet Duel (1949) and Red Beard (1965). This paper discusses these three films and examines the thoughts and lives of the three protagonists from the perspective of modern medical ethics. The films depict contemporary ethical and social problems, and deal with paternalism, a healthy professional life and the proper place for human reason in medicine, all of which still give rise to debate in modern medical settings. They are very impressive in their portrayal of extreme paternalism, excessively professional lives and disproportionate reliance on rationality. The doctors are role models in certain situations and are examples of how not to behave in other situations. On the one hand, they are devoted to helping their patients, with their self-sacrifice firmly based on humanity and medical ethics. On the other hand, they perform unwelcome favours and are unhealthy role models who might harm others through narrow-minded attitudes about human beings, a fixed view of life and inflexible ideas about medicine. In this sense, they can be regarded as a rather mixed blessing. These films provide us with an opportunity to simultaneously recognise the importance of modern ethical principles and the significance of 'old' ethical values.


A source of antihydrogen for in-flight hyperfine spectroscopy.
Antihydrogen, a positron bound to an antiproton, is the simplest antiatom. Its counterpart-hydrogen--is one of the most precisely investigated and best understood systems in physics research. High-resolution comparisons of both systems provide sensitive tests of CPT symmetry, which is the most fundamental symmetry in the Standard Model of elementary particle physics. Any measured difference would point to CPT violation and thus to new physics. Here we report the development of an antihydrogen source using a cusp trap for in-flight spectroscopy. A total of 80 antihydrogen atoms are unambiguously detected 2.7 m downstream of the production region, where perturbing residual magnetic fields are small. This is a major step towards precision spectroscopy of the ground-state hyperfine splitting of antihydrogen using Rabi-like beam spectroscopy.


Different effects of progesterone and estradiol on chimeric and wild type aldosterone synthase in vitro.
Familial hyperaldosteronism type I (FH-I) is caused by the unequal recombination between the 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, resulting in the generation of a CYP11B1/B2 chimeric gene and abnormal adrenal aldosterone production. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Aldosterone levels rise during pregnancy, yet in pregnant women with FH-1, their hypertensive condition either remains unchanged or may even improve. The purpose of this study was to investigate in vitro whether female sex steroids modulate the activity of chimeric (ASCE) or wild type (ASWT) aldosterone synthase enzymes. We designed an in vitro assay using HEK-293 cell line transiently transfected with vectors containing the full ASCE or ASWT cDNAs. Progesterone or estradiol effects on AS enzyme activities were evaluated in transfected cells incubated with deoxycorticosterone (DOC) alone or DOC plus increasing doses of these steroids. In our in vitro model, both enzymes showed similar apparent kinetic parameters (Km = 1.191 microM and Vmax = 27.08 microM/24 h for ASCE and Km = 1.163 microM and Vmax = 36.98 microM/24 h for ASWT; p = ns, Mann-Whitney test). Progesterone inhibited aldosterone production by ASCE- and ASWT-transfected cells, while estradiol demonstrated no effect. Progesterone acted as a competitive inhibitor for both enzymes. Molecular modelling studies and binding affinity estimations indicate that progesterone might bind to the substrate site in both ASCE and ASWT, supporting the idea that this steroid could regulate these enzymatic activities and contribute to the decay of aldosterone synthase activity in chimeric gene-positive patients. Our results show an inhibitory action of progesterone in the aldosterone synthesis by chimeric or wild type aldosterone synthase enzymes. This is a novel regulatory mechanism of progesterone action, which could be involved in protecting pregnant women with FH-1 against hypertension. In vitro, both enzymes showed comparable kinetic parameters, but ASWT was more strongly inhibited than ASCE. This study implicates a new role for progesterone in the regulation of aldosterone levels that could contribute, along with other factors, to the maintenance of an adequate aldosterone-progesterone balance in pregnancy.


Impact and vibration detection in composite materials by using intermodal interference in multimode optical fibers.
An optical fiber sensor based on the intermodal interference principle is integrated in a composite material to detect impacts and vibrations. Six fibers are integrated at the top of a carbon/epoxy composite panel so as to form a grid into the structure. Spectral and temporal responses to impacts and acoustic vibrations of the sensor are compared with a piezoelectric accelerometer. The tests proved the facility of integration and the high sensitivity of the device. The location of impacts is performed with this arrangement by measuring the arrival times of the front waves to the fibers.


Mechanisms of secondary resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumours (Review).
Treatment of patients affected by advanced or inoperable GIST was revolutionized by the use of the tyrosine kinase inhibitors. Despite the fact that most patients have a good durable response of disease, they develop a resistance to treatments after a median time of 24 months. The acquired resistance is an emerging aspect in medical oncology especially in the era of target therapies. The aim of this review is to report all known mechanisms of secondary resistance to tyrosine kinase inhibitors and to highlight their clinical implications. In general, they may be divided in mechanisms related to the acquisition of new molecular abnormalities associated to KIT and PDGFRA receptor signalling pathway, such as the loss of KIT expression, the genomic amplification of KIT, the activation of an alternative downstream signalling pathways such as AKT/mTOR and the acquisition of new receptor mutations, and other mechanisms different to KIT/PDGFRA receptors. Future research perspectives on target therapy and early resistance evaluation are also discussed.


Breaking the silence on abortion: the role of adult community abortion education in fostering resistance to norms.
Meanings of abortion in society are constructed within sociohistorical and gendered spaces and manifested through myriad discourses that impact on the perception and treatment of the issue in that society. In societies with powerful oppressive anti-abortion norms, such as Northern Ireland, little is known as to how these norms are resisted by the adult population. This study uses a Foucauldian feminist approach to show how resistance to religious and patriarchal norms can be fostered through adult community abortion education. This resistance is multi-faceted and bolstered by a lived experience discourse, which does not necessarily involve eschewing religious notions held within society.


Decreasing initial telomere length in humans intergenerationally understates age-associated telomere shortening.
Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father's age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross-sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications.


Survivorship of hip and knee implants in pediatric and young adult populations: analysis of registry and published data.
One of the least researched areas in orthopaedic pediatrics is the safety and effectiveness of joint replacement, in part because it is uncommon and is undertaken for a wide range of conditions not common for adult joint replacement. This study used data from the AOANJRR (Australian Orthopaedic Association National Joint Replacement Registry) to analyze the use of total hip arthroplasty (THA) and total knee arthroplasty (TKA) in the pediatric population and to provide preliminary data on the outcome of these procedures. The AOANJRR, which is part of the ICOR (International Consortium of Orthopaedic Registries), provided information on pediatric procedures reported to the registry by hospitals undertaking arthroplasty procedures in Australia. All THA and TKA procedures reported to the registry from 1999 to 2012 were included. The cumulative percent revision and the hazard ratio from Cox proportional-hazards models were used for analysis. All tests were two-tailed, with a 5% level of significance. Additionally, an overview of the literature is presented to provide a point of reference. Primary conventional THA was performed in 297 patients twenty years of age or younger; the cumulative percent revision at five years was 4.5%. Primary conventional THA was performed in 975 young adults twenty-one to thirty years of age; the cumulative percent revision at five years was 5.4%. Primary THA was performed in 105 patients twenty years of age or younger; the cumulative percent revision at five years was 4.6%. Primary TKA was performed in 159 young adults twenty-one to thirty years of age; the cumulative percent revision at five years was 10.3%. Compared with older adults, pediatric patients and young adults undergoing THA and TKA have very different diagnoses, including a high prevalence of tumor. Although the reported rate of revision surgery is currently similar to that for older patients, the number of reported procedures and the follow-up period remain limited. It is important for registries to continue to collect and analyze data relevant to this cohort and to coordinate these activities in order to better understand the safety and effectiveness of joint arthroplasty in the pediatric population.


Fatty acid composition and antioxidant properties of cold-pressed marionberry, boysenberry, red raspberry, and blueberry seed oils.
Cold-pressed marionberry, boysenberry, red raspberry, and blueberry seed oils were evaluated for their fatty acid composition, carotenoid content, tocopherol profile, total phenolic content (TPC), oxidative stability index (OSI), peroxide value, and antioxidant properties. All tested seed oils contained significant levels of alpha-linolenic acid ranging from 19.6 to 32.4 g per 100 g of oil, along with a low ratio of n-6/n-3 fatty acids (1.64-3.99). The total carotenoid content ranged from 12.5 to 30.0 micromoles per kg oil. Zeaxanthin was the major carotenoid compound in all tested berry seed oils, along with beta-carotene, lutein, and cryptoxanthin. Total tocopherol was 260.6-2276.9 mumoles per kg oil, including alpha-, gamma-, and delta-tocopherols. OSI values were 20.07, 20.30, and 44.76 h for the marionberry, red raspberry, and boysenberry seed oils, respectively. The highest TPC of 2.0 mg gallic acid equivalents per gram of oil was observed in the red raspberry seed oil, while the strongest oxygen radical absorbance capacity was in boysenberry seed oil extract (77.9 micromol trolox equivalents per g oil). All tested berry seed oils directly reacted with and quenched DPPH radicals in a dose- and time-dependent manner. These data suggest that the cold-pressed berry seed oils may serve as potential dietary sources of tocopherols, carotenoids, and natural antioxidants.


Regional approach to building operational level capacity for disaster planning: the case of the Eastern Africa region.
The Eastern Africa region is regularly affected by a variety of disasters ranging from drought, to human conflict and population displacement. The magnitude of emergencies and response capacities is similar across the region. In order to strengthen public health disaster management capacities at the operational level in six countries of the Eastern Africa region, the USAID-funded leadership project worked through the HEALTH Alliance, a network of seven schools of public health from six countries in the region to train district-level teams. To develop a sustainable regional approach to building operational level capacity for disaster planning. This project was implemented through a higher education leadership initiative. Project activities were spear-headed by a network of Deans and Directors of public health schools within local universities in the Eastern Africa region. The leadership team envisioned a district-oriented systems change strategy. Pre-service and in-service curricula were developed regionally and district teams were formed to attend short training courses. Project activities began with a situational analysis of the disaster management capacity at national and operational levels. The next steps were chronologically the formation of country training teams and training of trainers, the development of a regional disaster management training curriculum and training materials, the cascading of training activities in the region, and the incorporation of emerging issues into the training curriculum. An evaluation model included the analysis of preparedness impact of the training program. The output from the district teams was the creation of individual district-level disaster plans and their implementation. This 4-year project focused on building operational level public health emergency response capacity, which had not previously been part of any national program. Use of the all-hazard approach rather than a scenario-based contingency planning led to the development of a standardized curriculum for training both in-service and pre-service personnel. Materials developed during the implementation phases of the project have been incorporated into public health graduate curricula in the seven schools. This systems-based strategy resulted in demonstrable outcomes related to district preparedness and university engagement in disaster management. University partnerships are an effective method to build district-level disaster planning capacity. Use of a regional network created a standardized approach across six countries.


Removal of lead contaminated dusts from hard surfaces.
Government guidelines have widely recommended trisodium phosphate (TSP) or "lead-specific" cleaning detergents for removal of lead-contaminated dust (LCD) from hard surfaces, such as floors and window areas. The purpose of this study was to determine if low-phosphate, non-lead-specific cleaners could be used to efficiently remove LCD from 3 types of surfaces (vinyl flooring, wood, and wallpaper). Laboratory methods were developed and validated for simulating the doping, embedding, and sponge cleaning of the 3 surface types with 4 categories of cleaners: lead-specific detergents, nonionic cleaners, anionic cleaners, and trisodium phosphate (TSP). Vinyl flooring and wood were worn using artificial means. Materials were ashed, followed by ultrasound extraction, and anodic stripping voltammetry (ASV). One-way analysis of variance approach was used to evaluate the surface and detergent effects. Surface type was found to be a significant factor in removal of lead (p < 0.001). Vinyl flooring cleaned better than wallpaper by over 14% and wood cleaned better than wallpaper by 13%. There was no difference between the cleaning action of vinyl flooring and wood. No evidence was found to support the use of TSP or lead-specific detergents over all-purpose cleaning detergents for removal of lead-contaminated dusts. No-phosphate, non-lead-specific detergents are effective in sponge cleaning of lead-contaminated hard surfaces and childhood lead prevention programs should consider recommending all-purpose household detergents for removal of lead-contaminated dust after appropriate vacuuming.


Differential Evolution With Event-Triggered Impulsive Control.
Differential evolution (DE) is a simple but powerful evolutionary algorithm, which has been widely and successfully used in various areas. In this paper, an event-triggered impulsive (ETI) control scheme is introduced to improve the performance of DE. Impulsive control (IPC), the concept of which derives from control theory, aims at regulating the states of a network by instantly adjusting the states of a fraction of nodes at certain instants, and these instants are determined by event-triggered mechanism (ETM). By introducing IPC and ETM into DE, we hope to change the search performance of the population in a positive way after revising the positions of some individuals at certain moments. At the end of each generation, the IPC operation is triggered when the update rate of the population declines or equals to zero. In detail, inspired by the concepts of IPC, two types of impulses are presented within the framework of DE in this paper: 1) stabilizing impulses and 2) destabilizing impulses. Stabilizing impulses help the individuals with lower rankings instantly move to a desired state determined by the individuals with better fitness values. Destabilizing impulses randomly alter the positions of inferior individuals within the range of the current population. By means of intelligently modifying the positions of a part of individuals with these two kinds of impulses, both exploitation and exploration abilities of the whole population can be meliorated. In addition, the proposed ETI is flexible to be incorporated into several state-of-the-art DE variants. Experimental results over the IEEE Congress on Evolutionary Computation (CEC) 2014 benchmark functions exhibit that the developed scheme is simple yet effective, which significantly improves the performance of the considered DE algorithms.


Oral mucosal lesions in skin diseased patients attending a dermatologic clinic: a cross-sectional study in Sudan.
So far there have been no studies focusing on the prevalence of a wide spectrum of oral mucosal lesions (OML) in patients with dermatologic diseases. This is noteworthy as skin lesions are strongly associated with oral lesions and could easily be neglected by dentists. This study aimed to estimate the frequency and socio-behavioural correlates of OML in skin diseased patients attending outpatient's facility of Khartoum Teaching Hospital - Dermatology Clinic, Sudan. A cross-sectional hospital-based study was conducted in Khartoum from October 2008 to January 2009. A total of 588 patients (mean age 37.2 ± 16 years, 50.3% females) completed an oral examination and a personal interview of which 544 patients (mean age 37.1 ± 15.9 years, 50% females) with confirmed skin disease diagnosis were included for further analyses. OML were recorded using the World Health Organization criteria (WHO). Biopsy and smear were used as adjuvant techniques for confirmation. Data were analysed using the Statistical Package for Social Science (Version 15.0.1). Cross tabulation and Chi-square with Fisher's exact test were used. A total of 438 OML were registered in 315 (57.9%, males: 54.6% versus females: 45.6%, p < 0.05) skin diseased patients. Thus, a certain number of patients had more than one type of OML. Tongue lesions were the most frequently diagnosed OML (23.3%), followed in descending order by white lesions (19.1%), red and blue lesions (11%) and vesiculobullous diseases (6%). OML in various skin diseases were; vesiculobullous reaction pattern (72.2%), lichenoid reaction pattern (60.5%), infectious lesions (56.5%), psoriasiform reaction pattern (56.7%), and spongiotic reaction pattern (46.8%). Presence of OML in skin diseased patients was most frequent in older age groups (62.4% older versus 52.7% younger, p < 0.05), in males (63.2% males versus 52.6% females, p < 0.05), patients with a systemic disease (65.2% with systemic versus 51.9% without systemic disease, p < 0.05) and among current users of smokeless tobacco (toombak) (77% current use versus 54.8% no use, p < 0.00). OML were frequently diagnosed in skin diseased patients and varied systematically with age, gender, systemic condition and use of toombak. The high prevalence of OML emphasizes the importance of routine examination of oral mucosa in a dermatology clinic.


Characterization of inositolpolyphosphate binding to myocardial membranes.
Although it is well-accepted that the phosphatidylinositol signalling transduction pathway, producing inositol-1,4,5-P3 (InsP3) and inositol-1,3,4,5-P4 (InsP4) as second messengers, functions in heart muscle, virtually nothing is known about the roles of the higher inositol polyphosphates such as inositolhexakisphosphate (InsP6). This study demonstrates that InsP6 has the ability to bind intracellularly, with different binding characteristics, to different myocardial membranes. Binding to purified sarcoplasmic reticulum (SR) membranes, purified sarcolemmal (SL) membranes as well as to viable mitochondria were characterized. Binding to all these membranes display high as well as low affinity binding sites, with differing affinities. Kd values of binding to SR were 32 and 383 nM, to SL 61 and 1312 nM, while those of mitochondrial binding were 230 and 2200 nM respectively. InsP4 binding was also investigated and displayed the following characteristics: to SR, one low affinity binding site (Kd = 203 nM) and to SL, a high as well as a low affinity binding site with Kd values of 41 and 2075 nM respectively. Presence of InsP3, the second messenger for SR calcium release, at concentrations of 1 nM, elevated the binding of InsP4 to SR and SL by a mean of 30% and 20% respectively. Fractionation of SR and SL membranes on sucrose density gradients, after solubilization with CHAPS, indicated that InsP6 bound to two separate protein peaks in both these membranes, while InsP4 bound to only one. In SR membranes, InsP4 bound preferentially to a protein separating at high sucrose density while it bound to a protein separating at low sucrose density in SL membranes.


No Effect of a Self-Help Book for Insomnia in Patients With Obstructive Sleep Apnea and Comorbid Chronic Insomnia - A Randomized Controlled Trial.
Objective: To compare the effects of a self-help book for insomnia to that of sleep hygiene advice in a randomized controlled trial with follow-up after about 3 months among patients who were diagnosed with obstructive sleep apnea (OSA) and comorbid chronic insomnia, and who were concurrently initiating treatment with continuous positive airway pressure (CPAP). Methods: In all, 164 patients were included. OSA was diagnosed and categorized based on a standard respiratory polygraphic sleep study using a type 3 portable monitor. The self-help book focused on cognitive behavioral therapy for insomnia. The main outcome measure was insomnia severity assessed with the Bergen Insomnia Scale (BIS) and the Insomnia Severity Index (ISI). Results: The scores on the BIS improved significantly from pre-treatment to follow-up in the sleep hygiene advice group (26.8 vs. 21.8) and in the self-help book group (26.3 vs. 22.4). Similarly, the ISI scores were significantly improved in both conditions (sleep hygiene: 17.0 vs. 14.1; self-help book: 16.6 vs. 13.6). No time × condition interaction effects were detected, suggesting that the self-help book did not improve insomnia symptoms more than the sleep hygiene advice. Conclusion: In this randomized controlled trial among patients with OSA and comorbid insomnia who were initiating CPAP treatment, concurrently treating their insomnia with a self-help book did not improve sleep more than sleep hygiene advice. The statistically significant improved sleep at follow-up in both groups is most likely explained by the CPAP treatment.


Nitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activity.
3-Nitro-1H-1,2,4-triazole-based acetamides bearing a biphenyl- or a phenoxyphenyl moiety have shown remarkable antichagasic activity both in vitro and in an acute murine model, as well as substantial in vitro antileishmanial activity but lacked activity against human African trypanosomiasis. We have shown now that by inserting a methylene group in the linkage to obtain the corresponding propanamides, both antichagasic and in particular anti-human African trypanosomiasis potency was increased. Therefore, IC50 values at low nM concentrations against both T. cruzi and T. b. rhodesiense, along with huge selectivity indices were obtained. Although several propanamides were active against Leishmania donovani, they were slightly less potent than their corresponding acetamides. There was a good correlation between lipophilicity (clogP value) and trypanocidal activity, for all new compounds. Type I nitroreductase, an enzyme absent from the human host, played a role in the activation of the new compounds, which may function as prodrugs. Antichagasic activity in vivo was also demonstrated with representative propanamides.


Displacement of the surface membrane bound calcium of the skeletal muscle fibers of the frog: effects of lanthanum and opioids.
Three opioids, viz. methadone, morphine and meperidine, were tested separately for their effects on the rate of 45Ca++ efflux from frog toe muscles. The experimental procedures were designed to provide reliable measurements of the displacement of 45Ca++ from surface binding sites using the thin and light toe muscle. La (2 mM) was used to test the ability of the experimental procedure to detect the displacement of calcium bound superficially to the muscle fiber membrane. La not only enhances the rate of efflux of 45Ca++ from surface membrane superficial stores but also inhibits the efflux of intracellular calcium. Of the opioids tested, only methadone (10(-4) or 10(-3) M) caused a slight but significant increase in the rate of 45Ca++ efflux from the surface bound (i.e., the La -displaceable) store of calcium of the muscle. The "calcium-displacement" effect of methadone was much weaker than that seen with La . Morphine (10(-4) or 10(-3) M) or meperidine (10(-4) or 10(-3) M) did not show any such effect on the bound 45Ca++ desaturation rate even under experimental conditions modified to enable the detection of the displacement of even small amounts of 45Ca++ from superficial binding sites on the muscles.


Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes.
Exposure to plasticizers di(n-butyl) phthalate (DBP) and diethylhexyl phthalate (DEHP) during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal male rat, these two phthalate esters decrease testosterone (T) production and insulin-like peptide 3 (insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that coadministered DBP and DEHP would act in a cumulative dose-additive fashion to induce reproductive malformations, inhibit fetal steroid hormone production, and suppress the expression of insl3 and genes responsible for steroid production. Pregnant Sprague Dawley rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or a combination of DBP and DEHP (500 mg/kg each chemical; DBP+DEHP); the dose of each individual phthalate was one-half of the effective dose predicted to cause a 50% incidence of epididymal agenesis. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 testes were incubated for T production and processed for gene expression by quantitative real-time PCR. The DBP+DEHP dose increased the incidence of many reproductive malformations by >or=50%, including epididymal agenesis, and reduced androgen-dependent organ weights in cumulative, dose-additive manner. Fetal T and expression of insl3 and cyp11a were cumulatively decreased by the DBP+DEHP dose. These data indicate that individual phthalates with a similar mechanism of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit dose-additive effects when administered as a mixture.


The biosynthesis of sulfoquinovosyldiacylglycerol: studies with groundnut (Arachis hypogaea) leaves.
The biosynthetic pathway of sulfoquinovosyldiacylglycerol (SQDG) was investigated using groundnut (Arachis hypogaea) leaf discs and 35S-labeled precursors. [35S]SO4(2-) was actively taken up by the leaf discs and rapidly incorporated into SQDG. After 2 h, 1.5% of the [35S]SO4(2-) added to the incubation medium was taken up, of which 28% was incorporated into SQDG. The methanol-water phases of the lipid extracts of the leaf discs were analyzed for the 35S-labeled intermediates. Up to 2 h of incubation, cysteic acid, 3-sulfopyruvate, 3-sulfolactate, 3-sulfolactaldehyde, and sulfoquinovose (SQ) which have been proposed as intermediates [Davies et al. (1966) Biochem. J. 98, 369-373] were not labeled. Only a negligible amount of radioactivity was observed in these compounds after incubation for 4 h and more. Addition of sodium molybdate inhibited the uptake of [35S]SO4(2-) as well as its incorporation into SQDG by the leaf discs, suggesting that 3'-phosphoadenosine-5'-phosphosulfate may be involved in the biosynthesis of SQDG. Addition of unlabeled cysteic acid to the incubation medium enhanced the uptake of [35S]SO4(2-) but did not affect its incorporation into SQDG. 35S-labeled cysteic acid was taken up by the leaf discs and metabolized to sulfoacetic acid but not incorporated into SQ or SQDG. These results show that cysteic acid is not an intermediate in SQDG biosynthesis. [35S]SQ was taken up by the leaf discs and incorporated into SQDG in a time-dependent manner. [35S]Sulfoquinovosylglycerol was also taken up by the leaf discs but not incorporated into SQDG. It is concluded that SQDG is not biosynthesized by the proposed sulfoglycolytic pathway in higher plants. Though [35S]SQ was converted to SQDG, the rates are much lower compared to [35S]SO4(2-) incorporation, which suggests that a more direct pathway involving sulfonation of a lipid precursor may exist in higher plants.


Antidiabetic and antihyperlipidemic activity of p-coumaric acid in diabetic rats, role of pancreatic GLUT 2: In vivo approach.
P-coumaric acid (p-CA, 3-[4-hydroxyphenyl]-2-propenoic acid), the major component widely found in nutritious plant foods, has various antioxidant, antiinflammatory and anticancer property. To evaluate the antidiabetic and antihyperlipidemic mechanisms, via the effects on carbohydrate, lipids and lipoproteins responses in adult male albino Wistar rats were examined by treated with p-CA. Rats were injected with streptozotocin (STZ, 40mg/kg b.w.) by intraperitonially (i.p.) 30days for the induction of experimental diabetes mellitus. Diabetic rats were treated with p-CA orally at a dose of 100mg/kg b.w. The potential defending character of p-CA against diabetic rats was evaluated by performing the various biochemical parameters and glucose transporter such as GLUT2 mRNA expression of pancreas. Administration of p-CA significantly lowers the blood glucose level, gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase whereas increases the activities of hexokinase, glucose-6 phosphatase dehydrogenase and GSH via by increasing level of insulin. p-CA reduces the total cholesterol and triglycerides in both plasma and tissues i.e. liver and kidney. p-CA also decreases the LDL-C, VLDL-C and it considerably increase the level of HDL-C. A significant decreased expression of GLUT 2 mRNA in the pancreas was recorded in the supplementation of p-CA treated groups. Taken together, these results suggest that p-CA modulates glucose and lipid metabolism via GLUT 2 activation in the pancreatic and has potentially beneficial effects in improving or treating metabolic disorders.


New tools for optimizing fluid resuscitation in acute pancreatitis.
Acute pancreatitis (AP) is a frequent disease with degrees of increasing severity responsible for high morbidity. Despite continuous improvement in care, mortality remains significant. Because hypovolemia, together with microcirculatory dysfunction lead to poor outcome, fluid therapy remains a cornerstone of the supportive treatment. However, poor clinical evidence actually support the aggressive fluid therapy recommended in recent guidelines since available data are controversial. Fluid management remains unclear and leads to current heterogeneous practice. Different strategies may help to improve fluid resuscitation in AP. On one hand, integration of fluid therapy in a global hemodynamic resuscitation has been demonstrated to improve outcome in surgical or septic patients. Tailored fluid administration after early identification of patients with high-risk of poor outcome presenting inadequate tissue oxygenation is a major part of this strategy. On the other hand, new decision parameters have been developed recently to improve safety and efficiency of fluid therapy in critically ill patients. In this review, we propose a personalized strategy integrating these new concepts in the early fluid management of AP. This new approach paves the way to a wide range of clinical studies in the field of AP.


Quantifying position-dependent codon usage bias.
Although the mapping of codon to amino acid is conserved across nearly all species, the frequency at which synonymous codons are used varies both between organisms and between genes from the same organism. This variation affects diverse cellular processes including protein expression, regulation, and folding. Here, we mathematically model an additional layer of complexity and show that individual codon usage biases follow a position-dependent exponential decay model with unique parameter fits for each codon. We use this methodology to perform an in-depth analysis on codon usage bias in the model organism Escherichia coli. Our methodology shows that lowly and highly expressed genes are more similar in their codon usage patterns in the 5'-gene regions, but that these preferences diverge at distal sites resulting in greater positional dependency (pD, which we mathematically define later) for highly expressed genes. We show that position-dependent codon usage bias is partially explained by the structural requirements of mRNAs that results in increased usage of A/T rich codons shortly after the gene start. However, we also show that the pD of 4- and 6-fold degenerate codons is partially related to the gene copy number of cognate-tRNAs supporting existing hypotheses that posit benefits to a region of slow translation in the beginning of coding sequences. Lastly, we demonstrate that viewing codon usage bias through a position-dependent framework has practical utility by improving accuracy of gene expression prediction when incorporating positional dependencies into the Codon Adaptation Index model.


Computational methods for microRNA target prediction.
The discovery of microRNAs (miRNAs) has introduced a new paradigm into gene regulatory systems. Large numbers of miRNAs have been identified in a wide range of species, and most of them are known to downregulate translation of messenger RNAs (mRNAs) via imperfect binding of the miRNA to a specific site or sites in the 3' untranslated region (UTR) of the mRNA. Identification of genes targeted by miRNAs is widely believed to be an important step toward understanding the role of miRNAs in gene regulatory networks. As part of the effort to understand interactions between miRNAs and their targets, computational algorithms have been developed based on observed rules for features such as the degree of hybridization between the two RNA molecules. These in silico approaches provide important tools for miRNA target detection, and together with experimental validation, help to reveal regulated targets of miRNAs. Here, we summarize the knowledge that has been accumulated about the principles of target recognition by miRNAs and the currently available computational methodologies for prediction of miRNA target genes.


Misleading presentation of breast cancer in popular magazines.
Women commonly misunderstand their risk for breast cancer, overestimating both their risk for developing the disease at a young age and their lifetime risk. To determine whether age bias occurs in popular media coverage of breast cancer. SELECTION STRATEGY: The search term breast cancer was used to identify 389 articles in U.S. magazines with a circulation of at least 500,000 published between January 1, 1993, and June 30, 1997. Presence of age-related themes and age of patients with breast cancer who were described in vignettes. Age-related themes included breast cancer as a cause of premature death, breast cancer in mothers of young children, and the impact of a breast cancer diagnosis on dating and marriage. Factual information about age as a risk factor for breast cancer was presented in only 14% of articles, and age was often included in vignettes describing a woman with breast cancer. Thirty-four percent of the articles included one or more breast cancer vignettes. These articles included 172 unique vignettes in which patient age was described. In 84% of the vignettes (144 of 172), women were diagnosed with breast cancer before 50 years of age; in 47% (80 of 172), women were diagnosed before 40 years of age. On the basis of the age-specific incidence of breast cancer in the United States, the expected percentages would be 16% and 3.6%, respectively. Stories about breast cancer in popular U.S. magazines misrepresent the age distribution of the disease, emphasizing atypical cases of early-onset breast cancer and their social consequences. This presentation of breast cancer may contribute to women's fears of breast cancer and to overestimates of personal risk.


GT198 Splice Variants Display Dominant-Negative Activities and Are Induced by Inactivating Mutations.
Alternative pre-mRNA splicing yields functionally distinct splice variants in regulating normal cell differentiation as well as cancer development. The putative tumor suppressor gene GT198 (PSMC3IP), encoding a protein also known as TBPIP and Hop2, has been shown to regulate steroid hormone receptor-mediated transcription and to stimulate homologous recombination in DNA repair. Here, we have identified 6 distinct GT198 splice variant transcripts generated by alternative promoter usage or alternative splicing. Various splice variant transcripts preserve a common open reading frame, which encodes the DNA binding domain of GT198. The splice variants act as dominant negatives to counteract wild-type GT198 activity in transcription and to abolish Rad51 foci formation during radiation-induced DNA damage. In fallopian tube cancer, we have identified 44 point mutations in GT198 clustered in 2 mutation hotspot sequences. The mutation hotspots coincide with the regulatory sequences responsible for alternative splicing, strongly supporting that imbalanced alternative splicing is a selected consequence in cancer. In addition, splice variant-associated cytoplasmic expression is found in tumors carrying germline or somatic GT198 mutations. An altered alternative splicing pattern with increased variants is also present in lymphoblastoid cells derived from familial breast cancer patients carrying GT198 germline mutations. Furthermore, GT198 and its variant are reciprocally expressed during mouse stem cell differentiation. The constitutive expression of the GT198 variant but not the wild type induces tumor growth in nude mice. Our results collectively suggest that mutations in the GT198 gene deregulate alternative splicing. Defective alternative splicing promotes antagonizing variants and in turn induces a loss of the wild type in tumorigenesis. The study highlights the role of alternative splicing in tumor suppressor gene inactivation.


Genetics of Cholesterol-Related Genes in Metabolic Syndrome: A Review of Current Evidence.
Metabolic syndrome (MetS) refers to a cluster of metabolic dysregulations, which include insulin resistance, obesity, atherogenic dyslipidemia and hypertension. The complex pathogenesis of MetS encompasses the interplay between environmental and genetic factors. Environmental factors such as excessive nutrients and sedentary lifestyle are modifiable and could be improved by lifestyle modification. However, genetic susceptibility to MetS, a non-modifiable factor, has attracted the attention of researchers, which could act as the basis for future diagnosis, prognosis, and therapy for MetS. Several cholesterol-related genes associated with each characteristic of MetS have been identified, such as apolipoprotein, lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and adiponectin. This review aims to summarize the genetic information of cholesterol-related genes in MetS, which may potentially serve as biomarkers for early prevention and management of MetS.


Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination.
MK5 (mitogen-activated protein kinase [MAPK]-activated protein kinase 5), also designated PRAK (p38-regulated and -activated kinase), was deleted from mice by homologous recombination. Although no MK5 full-length protein and kinase activity was detected in the MK5 knockout mice, the animals were viable and fertile and did not display abnormalities in tissue morphology or behavior. In addition, these mice did not show increased resistance to endotoxic shock or decreased lipopolysaccharide-induced cytokine production. Hence, MK5 deletion resulted in a phenotype very different from the complex inflammation-impaired phenotype of mice deficient in MK2, although MK2 and MK5 exhibit evolutional, structural, and apparent extensive functional similarities. To explain this discrepancy, we used wild-type cells and embryonic fibroblasts from both MK2 and MK5 knockout mice as controls to reexamine the mechanism of activation, the interaction with endogenous p38 MAPK, and the substrate specificity of both enzymes. In contrast to MK2, which shows interaction with and chaperoning properties for p38 MAPK and which is activated by extracellular stresses such as arsenite or sorbitol treatment, endogenous MK5 did not show these properties. Furthermore, endogenous MK5 is not able to phosphorylate Hsp27 in vitro and in vivo. We conclude that the differences between the phenotypes of MK5- and MK2-deficient mice result from clearly different functional properties of both enzymes.


Location of a single beta-tubulin gene product in both cytoskeletal and mitotic-spindle microtubules in Physarum polycephalum.
In the mutant BEN210 of Physarum polycephalum several beta-tubulins are detectable. beta 1-tubulin is unique to the myxamoeba, beta 2-tubulin is unique to the plasmodium, and the mutant beta 1-210 tubulin encoded by the benD210 allele is present in both cell types. In order to analyse the subcellular distribution of the beta 1-210 polypeptide, we prepared cytoskeletons from myxamoebae and mitotic spindles from plasmodia, and examined the tubulin polypeptide composition of these microtubular organelles by two-dimensional gel electrophoresis and immunoblotting. The results show that the beta 1-210 tubulin is present in microtubules of both the cytoskeleton and the intranuclear mitotic spindle. Thus a single beta-tubulin gene product can participate in multiple microtubular organelles in distinct cellular compartments.


Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.
Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.


Antithrombotic Therapy and Device-Related Thrombosis Following Endovascular Left Atrial Appendage Closure.
The aim of this study is to review the evidence on the use of antithrombotic therapy and risk of device-related thrombosis after left atrial appendage closure. Left atrial appendage closure (LAAC) is increasingly performed for stroke prevention in patients with nonvalvular atrial fibrillation, especially those who cannot tolerate or are ineligible for oral anticoagulation. After device implantation for LAAC, different antithrombotic regimens with varying duration of therapy are currently used. Such selection depends on patients' risk for bleeding and physicians' choice. Device-related thrombosis remains an Achilles' heel of LAAC, and the etiology remains incompletely understood. Dual-antiplatelet therapy, and direct oral anticoagulation may have similar safety and device-related thrombosis occurrence in real-world LAAC registries compared with warfarin and aspirin. Device imaging surveillance should be routinely performed to assess for device-related thrombosis, which if diagnosed should be treated aggressively, as it is associated with higher thromboembolic risks. Given the uncertainties and therapeutic dilemma, the authors provide an in-depth discussion of the options and rationale for antithrombotic therapy post-LAAC.


Changes in Axial Length and Progression of Visual Field Damage in Glaucoma.
To investigate the relationship between axial length (AL) elongation and progression of primary open-angle glaucoma (POAG). AL was measured twice over a 5.1 ± 0.76 (mean ± standard deviation: SD) year period in 125 eyes of 72 patients with POAG. The eyes were divided into not long (AL < 26 mm, 80 eyes) and long (>26 mm, 45 eyes) groups. During this period, patients' visual fields (VFs) were measured with the Humphrey Field Analyzer 12.4 ± 7.5 times and intraocular pressure (IOP) was measured with Goldmann applanation tonometry 27.0 ± 7.5 times. The relationship between the mean total deviation (mTD) progression rates in the whole field and superior and inferior hemifield, as well as in 10 VF sectors, and the variables of age, mean IOP, SD of IOP, AL, difference in AL (△AL), and mTD value at baseline was examined. There was a significant difference between AL at baseline and AL at repeat measurement (P < 0.0001). △AL was 0.035 ± 0.10 mm. An increase in △AL was significantly related to AL at baseline (P = 0.027), but not to age, mean IOP, and SD of IOP. △AL was related to the progression of mTD in the inferior hemifield (slower mTD progression was associated with increased △AL), but not in the whole field or superior hemifield. Increased △AL was related to slower progression rates in 2 of 10 sectors, both in the inferior hemifield. The main finding was that an increase in AL was significantly related to slower VF progression in the inferior hemifield.


Epidemiology of Skeletal Health in Type 1 Diabetes.
The skeleton is adversely affected by type 1 diabetes (T1D). Patients with T1D of both sexes have an increased risk of fracture that begins in childhood and extends across the entire lifespan. T1D is characterized by mild to modest deficits in bone density, structure, and microarchitecture. Current evidence suggests that the observed bone deficits in T1D are the result of impaired bone formation rather than increased bone resorption. There is emerging data that bone quality is impaired in T1D, which may explain the findings that fracture risk is elevated out of proportion to the degree of bone mineral deficit. In this review, we summarize the current knowledge regarding the epidemiology of skeletal health in T1D. Given the high individual and societal burden of osteoporotic fracture, there is an urgent need to better understand the etiology of T1D-related bone disease so that clinical strategies to prevent fracture can be developed.


How I treat paroxysmal nocturnal hemoglobinuria.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal blood disorder that manifests with hemolytic anemia, bone marrow failure, and thrombosis. Many of the clinical manifestations of the disease result from complement-mediated intravascular hemolysis. Allogeneic bone marrow transplantation is the only curative therapy for PNH. Eculizumab, a monoclonal antibody that blocks terminal complement activation, is highly effective in reducing hemolysis, improving quality of life, and reducing the risk for thrombosis in PNH patients. Insights into the relevance of detecting PNH cells in PNH and other bone marrow failure disorders are highlighted, and indications for treating PNH patients with bone marrow transplantation and eculizumab are explored.


Developmental dyslexia: the visual attention span deficit hypothesis.
The visual attention (VA) span is defined as the amount of distinct visual elements which can be processed in parallel in a multi-element array. Both recent empirical data and theoretical accounts suggest that a VA span deficit might contribute to developmental dyslexia, independently of a phonological disorder. In this study, this hypothesis was assessed in two large samples of French and British dyslexic children whose performance was compared to that of chronological-age matched control children. Results of the French study show that the VA span capacities account for a substantial amount of unique variance in reading, as do phonological skills. The British study replicates this finding and further reveals that the contribution of the VA span to reading performance remains even after controlling IQ, verbal fluency, vocabulary and single letter identification skills, in addition to phoneme awareness. In both studies, most dyslexic children exhibit a selective phonological or VA span disorder. Overall, these findings support a multi-factorial view of developmental dyslexia. In many cases, developmental reading disorders do not seem to be due to phonological disorders. We propose that a VA span deficit is a likely alternative underlying cognitive deficit in dyslexia.


Allergic and pseudoallergic reactions induced by glucocorticoids: a review.
Glucocorticoids (GCs) represent the most effective treatment for autoimmune and allergic diseases, even if collateral effects are not rare, especially endocrine and immunosuppressive manifestations. Moreover, these drugs can develop adverse immunological reactions of I, III or IV type. Though immediate adverse reactions caused by systemic therapy with GCs are not very frequent, the possible beginning of anaphylactic and pseudo-anaphylactic manifestations in patients undergoing therapy with these drugs has to be considered. It has been observed that immediate adverse reactions usually are happened in asthmatic patients and in patients obliged to assume GCs again and again because of their pathology (e.g, kidney transplant). Other risk factors resulted to be female sex and hypersensibility to acetylsalicylic acid (ASA). Both in the cases of pseudo-allergic and allergic reactions, the pharmacological principle is hardly the responsible agent for the reaction; instead the excipients in drugs are often implicated (succinate salt, sulphites and carboxy-methyl-cellulose). It is possible that the IgE-response is highly specific for a fixed GC molecule as well depending on the way of administration and its salification. Moreover, it has been hypothesized that in patients with a first type allergic reaction to GCs there is a fourth type, sensitization to GCs, which is not usually diagnosed and even comes before IgE sensitization. Third type hypersensibility reactions may occur, too. Since GCs are large-scale drugs, also in emergency medicine and reanimation, allergic sensitization towards them, although infrequent, gives many interventionist problems. In the light of this feature, it seems of crucial importance to verify the tolerance toward other GC molecules. And in particular, it has been noted that patients presenting immediate reactions to hydrocortisone (HC) and methylprednisolone (MP) could tolerate prednisone and prednisolone per os and second-generation GCs, such as desamathazone and betamethazone. Nevertheless, second-generation GCs must not be considered safe; in fact, the beginning of allergic manifestations has been pointed out even towards them.


Screening for fecal carriage of MCR-producing Enterobacteriaceae in healthy humans and primary care patients.
The extent of the occurrence of the plasmid-encoded colistin resistance genes mcr-1 and mcr-2 among humans is currently sparsely studied in Western Europe. To determine the occurrence of MCR-producing Enterobacteriaceae in fecal samples of healthy humans with high occupational exposure to food and primary care patients in Switzerland. Stool samples from 1091 healthy individuals and fecal swabs from 53 primary care patients were screened for polymyxin-resistant Enterobacteriaceae using LB agar containing 4 mg/L colistin. Minimal inhibitory concentrations (MICs) of colistin were determined for non-intrinsic colistin-resistant isolates. Isolates were screened by PCR for the presence of mcr-1 and mcr-2 genes. The fecal carriage rate of colistin resistant (MIC value >2 mg/l) Enterobacteriaceae was 1.5% for healthy people and 3.8% for primary care patients. Isolates included Hafnia alvei (n = 9), Escherichia coli (n = 3), Enterobacter cloacae (n = 4), Klebsiella pneumoniae (n = 1) and Raoultella ornithinolytica (n = 1). None of the isolates harbored the mcr-1 or mcr-2 genes. There is no evidence for the presence of MCR-producers in the fecal flora of healthy people or primary care patients. Therefore, the risk of transfer of mcr genes from animals, food or the environment to humans is likely to be low in Switzerland.


Predictions of children's emotionality from evolutionary and epigenetic hypotheses.
Sex-dependent effects of mismatched prenatal-postnatal maternal conditions are predicted by combining two evolutionary hypotheses: that foetal conditions provide a forecast of likely postnatal environments (Predictive Adaptive Response), and that the female foetus is better adapted than the male to maternal adversity (Trivers-Willard hypothesis). Animal studies have implicated glucocorticoid mechanisms modifiable by effects of postnatal tactile stimulation on glucocorticoid receptor gene expression. In this study we examined behavioural predictions in humans based on these evolutionary and epigenetic models. Mothers in a general population cohort provided self-reported anxiety scores at 20 weeks pregnancy, and at 9 weeks, 14 months and 3.5 years postpartum, and frequency of infant stroking at 9 weeks. Mothers and teachers reported child symptoms at 7 years. SEM models with maximum-likelihood estimates made use of data from 887 participants. There was a three-way interaction between prenatal and postnatal anxiety and maternal stroking in the prediction of irritability, seen only in girls. This arose because lower maternal stroking was associated with higher irritability, only in the mismatched, low-high and high-low maternal anxiety groups. We provide evidence that mechanisms likely to have evolved well before the emergence of humans, contribute to the development of children's emotionality and risk for depression.


Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs: a randomized controlled trial.
It is estimated that half of unintended pregnancies could be averted if emergency contraception (EC) were easily accessible and used. To evaluate the effect of direct access to EC through pharmacies and advance provision on reproductive health outcomes. A randomized, single-blind, controlled trial (July 2001-June 2003) of 2117 women, ages 15 to 24 years, attending 4 California clinics providing family planning services, who were not desiring pregnancy, using long-term hormonal contraception or requesting EC. Participants were assigned to 1 of the following groups: (1) pharmacy access to EC; (2) advance provision of 3 packs of levonorgestrel EC; or (3) clinic access (control). Primary outcomes were use of EC, pregnancies, and sexually transmitted infections (STIs) assessed at 6 months; secondary outcomes were changes in contraceptive and condom use and sexual behavior. Women in the pharmacy access group were no more likely to use EC (24.2%) than controls (21.0%) (P = .25). Women in the advance provision group (37.4%) were almost twice as likely to use EC than controls (21.0%) (P<.001) even though the frequency of unprotected intercourse was similar (39.8% vs 41.0%, respectively, P = .46). Only half (46.7%) of study participants who had unprotected intercourse used EC over the study period. Eight percent of participants became pregnant and 12% acquired an STI; compared with controls, women in the pharmacy access and advance provision groups did not experience a significant reduction in pregnancy rate (pharmacy access group: adjusted odds ratio [OR], 0.98; 95% confidence interval [CI], 0.58-1.64; P = .93; advance provision group: OR, 1.10; 95% CI, 0.66-1.84, P = .71) or increase in STIs (pharmacy access group: adjusted OR, 1.08, 95% CI, 0.71-1.63, P = .73; advance provision group: OR, 0.94, 95% CI, 0.62-1.44, P = .79). There were no differences in patterns of contraceptive or condom use or sexual behaviors by study group. While removing the requirement to go through pharmacists or clinics to obtain EC increases use, the public health impact may be negligible because of high rates of unprotected intercourse and relative underutilization of the method. Given that there is clear evidence that neither pharmacy access nor advance provision compromises contraceptive or sexual behavior, it seems unreasonable to restrict access to EC to clinics.


Lack of association between TNF-308 polymorphism and the clinical and immunological characteristics of systemic lupus erythematosus and primary Sjögren's syndrome.
To investigate the previously reported association of tumor necrosis factor alpha (TNF) -308 single nucleotide polymorphism (SNP) with the clinical course and immunological features in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). The studied group consisted of 113 consecutive SLE and 65 pSS patients. TNF -308 SNP was determined by the polymerase chain reaction-restriction fragment length polymorphism technique. Clinical and immunological characteristics were assessed according to a standard protocol that included disease activity (SLEDAI) and damage (SLICC Damage Index). Serum TNFalpha levels were measured in samples collected from 32 patients with SLE and 16 with pSS by enzyme-linked immunosorbent assay. The TNF2 allele (A) was observed in 46% and 54% of SLE and pSS patients, respectively. We failed to find any significant association between the -308 SNP and disease manifestations, the presence of autoantibodies or cytokine levels in either group. TNF -308 SNP (TNF2) does not exhibit a significant influence on the disease course or immunological response in SLE and pSS. Other genetic and/or environmental factors seem to be required and to be more important than TNF2 allele for the progression of these diseases.


Import of biopolymers into Escherichia coli: nucleotide sequences of the exbB and exbD genes are homologous to those of the tolQ and tolR genes, respectively.
Escherichia coli with mutations in the exb region are impaired in outer membrane receptor-dependent uptake processes. They are resistant to the antibiotic albomycin and exhibit reduced sensitivity to group B colicins. A 2.2-kilobase-pair DNA fragment of the exb locus was sequenced. It contained two open reading frames, designated exbB and exbD, which encoded polypeptides of 244 and 141 amino acids, respectively. Both proteins were found in the cytoplasmic membrane. They showed strong homologies to the TolQ and TolR proteins, respectively, which are involved in uptake of group A colicins and infection by filamentous bacteriophages. exbB and exbD were required to complement exb mutations. Osmotic shock treatment rendered exb mutants sensitive to colicin M, which was taken as evidence that the ExbB and ExbD proteins are involved in transport processes across the outer membrane. It is concluded that the exb- and tol-dependent systems originate from a common uptake system for biopolymers.


Purification and characterization of human H-ras proteins expressed in Escherichia coli.
The full-length normal and T24 mutant human H-ras proteins and two truncated derivatives of the T24 mutant were expressed efficiently in Escherichia coli. The proteins accumulated to 1 to 5% of total cellular protein, and each was specifically recognized by anti-ras monoclonal antibodies. The two full-length proteins as well as a carboxyl-terminal truncated derivative (deleted for 23 amino acid residues) were soluble upon cell lysis and were purified to 90% homogeneity without the use of denaturants. In contrast, an amino-terminal truncated ras derivative (deleted for 22 amino acid residues) required treatment with urea for its solubilization. The guanine nucleotide binding activity of these four proteins was assessed by a combination of ligand binding on proteins blots, immunoprecipitation, and standard filter binding procedures. The full-length proteins showed similar binding kinetics and a stoichiometry approaching 1 mol of GTP bound per mol of protein. The showed similar binding kinetics and a stoichiometry approaching 1 mol of GTP bound per mol of protein. The carboxyl-terminal truncated protein also bound GTP, but to a reduced extent, whereas the amino-terminal truncated protein did not have binding activity. Apparently, the carboxyl-terminal domain of ras, although important for transforming function, does not play a critical role in GTP binding.


Ion-channel properties of mastoparan, a 14-residue peptide from wasp venom, and of MP3, a 12-residue analogue.
Mastoparan, a 14-residue peptide, has been investigated with respect to its ability to form ion channels in planar lipid bilayers. In the presence of 0.3-3.0 microM mastoparan, two types of activity are seen. Type I activity is characterized by discrete channel openings, exhibiting multiple conductance levels in the range 15-700 pS. Type II activity is characterized by transient increases in bilayer conductance, up to a maximum of about 650 pS. Both type I and type II activities are voltage dependent. Channel activation occurs if the compartment containing mastoparan is held at a positive potential; channel inactivation if the same compartment is held at a negative potential. Channel formation is dependent on ionic strength; channel openings are only observed at KCl concentrations of 0.3 M or above. Furthermore, raising the concentration of KCl to 3.0 M stabilizes the open form of the channel. Mastoparan channels are weakly cation selective, PK/Cl approximately 2. A 12-residue analogue, des-Ile1,Asn2-mastoparan, preferentially forms type I channels. The ion channels formed by these short peptides may be modelled in terms of bundles of transmembrane alpha-helices.


[Diagnosis and management of haemoptysis].
Haemoptysis is defined as the expectoration of blood or bloody streaking of the sputum. The list of possible underlying differential diagnoses is broad, and the cause of haemoptysis depends on the origin of the individual patient. Patients with minor haemoptysis can often be managed in the outpatient setting. In contrast, patients with major haemoptysis require immediate in-hospital diagnostic workup and therapy. Patients with major haemoptysis should be managed by a multidisciplinary team consisting of Pulmonologists, Critical Care Physicians/Anaesthesiologists, Interventional Radiologists, and Thoracic Surgeons. In major haemoptysis, airway maintenance, adequate gas exchange, and haemodynamic stabilization are mandatory. In this article, the recommended diagnostic and therapeutic steps in patients with major haemoptysis (particularly computed tomography, laboratory analyses, bronchoscopy, and bronchial artery embolization) are presented and discussed.


Nonadrenergic inhibitory nerves attenuate neurally mediated contraction in cat bronchi.
Effects of nonadrenergic and noncholinergic (NANC) inhibitory nerves on cholinergic neurotransmission were examined in isolated bronchial segments from cats in the presence of propranolol (10(-6) M) and indomethacin (10(-6) M) by use of electrical field stimulation (EFS) techniques. EFS caused contraction alone in tissues at the baseline tension and biphasic responses (contraction and relaxation) in tissues precontracted with 5-hydroxytryptamine. Contraction was abolished by atropine (10(-6) M), and relaxation was abolished by tetrodotoxin (10(-6) M). At the baseline tension, EFS at frequencies greater than 10 Hz inhibited the subsequent (4 min later) contraction induced by EFS at 1-5 Hz. EFS-induced inhibition was stimulus frequency dependent and reached maximum at 20 Hz. However, EFS at 20 Hz did not inhibit the subsequent contractile response to acetylcholine (10(-7) to 10(-3) M). Exogenously applied vasoactive intestinal peptide mimicked EFS-induced inhibitory effects, but substance P and calcitonin gene-related peptide did not. The inhibitory effect of EFS at 20 Hz was not altered by pyrilamine, cimetidine, naloxone, methysergide, phentolamine, BW755C, AF-DX 116, or removal of epithelium. These results imply that the NANC transmitter acts via presynaptic cholinergic receptors.


Unusual treatment of bimaxillary dentoalveolar protrusion via miniscrews and molar extraction.
This case report describes the treatment of a Saudi female patient, aged 13 years 8 months at the start of treatment, with a Class I bimaxillary dentoalveolar protrusion and extracted maxillary first molars. Miniscrews were placed bilaterally in the interdental space between both the upper and the lower posterior teeth. The treatment plan consisted of extraction of both lower first permanent molars, distalization of upper and lower premolars using miniscrews followed by en masse retraction of the upper and lower six anterior teeth. The active treatment period was 2 years 8 months. Arch retention was done using upper wrap-around retainer and lower fixed 3-3 retainer. The use of miniscrews helped to resolve the bimaxillary protrusion regardless of extraction pattern used.


Gap Gene Regulatory Dynamics Evolve along a Genotype Network.
Developmental gene networks implement the dynamic regulatory mechanisms that pattern and shape the organism. Over evolutionary time, the wiring of these networks changes, yet the patterning outcome is often preserved, a phenomenon known as "system drift." System drift is illustrated by the gap gene network-involved in segmental patterning-in dipteran insects. In the classic model organism Drosophila melanogaster and the nonmodel scuttle fly Megaselia abdita, early activation and placement of gap gene expression domains show significant quantitative differences, yet the final patterning output of the system is essentially identical in both species. In this detailed modeling analysis of system drift, we use gene circuits which are fit to quantitative gap gene expression data in M. abdita and compare them with an equivalent set of models from D. melanogaster. The results of this comparative analysis show precisely how compensatory regulatory mechanisms achieve equivalent final patterns in both species. We discuss the larger implications of the work in terms of "genotype networks" and the ways in which the structure of regulatory networks can influence patterns of evolutionary change (evolvability).


Do Hypertensive Men Spy With an Angry Little Eye? Anger Recognition in Men With Essential Hypertension - Cross-sectional and Prospective Findings.
Higher trait anger has inconsistently been associated with hypertension and hypertension development, but social context in terms of recognition of other persons' anger has been neglected in this context. Here, we investigated anger recognition of facial affect and trait anger in essential hypertensive and normotensive men in addition to prospective associations with blood pressure (BP) increases. Baseline assessment comprised a total of 145 participants including 57 essential hypertensive and 65 normotensive men who were otherwise healthy and medication-free. Seventy-two eligible participants additionally completed follow-up assessment 3.1 (±0.08 SEM) years later to analyze BP changes over time. We assessed emotion recognition of facial affect with a paradigm displaying mixed facial affect of two morphed basic emotions including anger, fear, sadness, and happiness. Trait anger was assessed with the Spielberger trait anger scale. Cross-sectionally, we found that with increasing BP, hypertensive men overrated anger displayed in facial expressions of mixed emotions as compared to normotensive men (ps ≤ .019) while there were no differences in trait anger (p = .16). Prospectively, the interaction between mean anger recognition and trait anger independently predicted BP increases from baseline to follow-up (ps ≤ .043), in that overrating displayed anger predicted future BP increases only if trait anger was high. Our findings indicate an anger recognition bias in men with essential hypertension and that overrating displayed anger in combination with higher trait anger seems to predict future BP increases. This might be of clinical relevance for the development and progression of hypertension and cardiovascular disease.


Estimation of broadband surface emissivity from narrowband emissivities.
This work analyzed and addressed the estimate of the broadband emissivities for the spectral domains 3-14μm (ε(3-14)) and 3-∞μm (ε(3-∞). Two linear narrow-to-broadband conversion models were proposed to estimate broadband emissivities ε(3-14) and ε(3-∞) using the Moderate Resolution Imaging Spectroradiometer (MODIS) derived emissivities in three thermal infrared channels 29 (8.4-8.7μm), 31 (10.78-11.28μm) and 32 (11.77-12.27μm). Two independent spectral libraries, the Advanced Spaceborne Thermal Emission Reflection Radiometer (ASTER) spectral library and the MODIS UCSB (University of California, Santa Barbara) emissivity library, were used to calibrate and validate the proposed models. Comparisons of the estimated broadband emissivities using the proposed models and the calculated values from the spectral libraries, showed that the proposed method of estimation of broadband emissivity has potential accuracy and the Root Mean Square Error (RMSE) between estimated and calculated broadband emissivities is less than 0.01 for both ε(3-14) and ε(3-∞).


Praising others differently: neuroanatomical correlates to individual differences in trait gratitude and elevation.
Differing from basic emotions such as happiness, gratitude and elevation are important other-praising emotions. Previous behavioral studies have established that these complex emotions differ from each other; however, it remains under-investigated whether proneness to these emotions have common or distinct neuroanatomical correlates. Here we used voxel-based morphometry to identify the common and distinct neuroanatomical correlates of trait (i.e. proneness to) gratitude and elevation. We used the Gratitude Questionnaire-6 and the trait elevation scale to measure these affective traits. We demonstrated that trait gratitude was positively correlated with gray matter volume (GMV) in the left cerebellum extending to fusiform gyrus, and also the right middle occipital gyrus (MOG) extending to posterior superior temporal sulcus (pSTS) and temporoparietal junction (TPJ), while trait elevation was negatively correlated with GMV in the left dorsolateral prefrontal cortex. While controlling each other, all the regions still held significant, except the right MOG and pSTS/TPJ. The results indicate that there are distinct neuroanatomical correlates for proneness to gratitude and elevation, while the evidence is mixed that pSTS/TPJ may be the common correlates for them. The implications of these findings are discussed.


Multisite phosphorylation of the alpha subunit of transducin by the insulin receptor kinase and protein kinase C.
The GDP-bound alpha subunit of transducin, but not the guanosine 5'-[gamma-thio]triphosphate-bound one, undergoes phosphorylation on tyrosine residues by the insulin receptor kinase and on serine residues by protein kinase C. Holotransducin is poorly phosphorylated by the insulin receptor kinase and is not phosphorylated by protein kinase C. Neither holotransducin nor any of its subunits were phosphorylated by the cAMP-dependent protein kinase. That a given subunit of transducin undergoes multisite phosphorylation depending on the type of nucleotide bound to it or the nature of the kinase suggests that hormone-dependent phosphorylation could provide a versatile mode for regulation of guanine nucleotide-binding protein (G protein) function. In particular, the findings that certain G proteins serve as substrates for both the insulin receptor kinase and protein kinase C implicate G proteins in playing a key role in mediating the action of insulin and ligands that act to activate protein kinase C.


Incidence of juvenile idiopathic arthritis in the Nordic countries. A population based study with special reference to the validity of the ILAR and EULAR criteria.
To find the incidence of juvenile arthritis according to the ILAR and EULAR criteria within defined areas in the Nordic countries, and to study the validity of the ILAR and EULAR criteria from this perspective. A longitudinal, prospective, population based study with patients enrolled according to the ILAR and EULAR criteria. Twenty doctors in Iceland, Norway, Sweden, Denmark, and Finland collected data from the incidence cases within their catchment areas over a period of 1.5 years, beginning July 1, 1997. Clinical and serological data from the first year of the disease were collected. In the whole group of 315 patients, the incidence rate was 15 per 100,000 children/year (95% CI 13-17) according to the ILAR criteria, varying from 7 (1-13) in Iceland, 19 (7-31) and 23 (10-36) from 2 different regions in Norway, and 9 (5-12) and 16 (9-23) from 2 different areas in Denmark, to 15 (12-18) in Sweden and 21/100,000/year (15-26) in the Helsinki region in Finland. An early peak in distribution for age of onset was found in girls but not in boys. The number of antinuclear antibody (ANA) positive children in the whole group, made up of children who had undergone at least one analyzed ANA test, was 123/315 (39%). Girls were ANA positive in 83/197 (42%) and boys in 40/118 (34%). Uveitis developed in 27/315 (8.6%) children during the first 6 months of the disease. Incidence rates of juvenile arthritis for areas within the Nordic countries were in accord with previous data. The ILAR criteria present slightly higher incidence rates, with a shorter disease duration for inclusion, compared to the EULAR criteria. Patients in one subgroup in either of the criteria sets do not necessarily belong to the expected subgroup in the other set of criteria; e.g., for juvenile ankylosing spondylitis (EULAR) and enthesitis related arthritis (ILAR). Our epidemiological findings are a reminder to be aware of possible new subgroups in children with juvenile arthritis.


Small-conductance calcium-activated K+ channels are expressed in pancreatic islets and regulate glucose responses.
Glucose-stimulated insulin secretion is associated with transients of intracellular Ca(2+) concentration [Ca(2+)](i) in the pancreatic beta-cell. We identified the expression and function of specific small-conductance Ca(2+)-activated K(+) (SK) channel genes in insulin-secreting cells. The presence of mRNA for SK1, -2, -3, and -4 (intermediate-conductance Ca(2+)-activated K(+) 1 [IK1]) channels was demonstrated by RT-PCR in rodent islets and insulinoma cells. SK2 and -3 proteins in mouse islets were detected by immunoblot and immunocytochemistry. In the tTA-SK3 tet-off mouse, a normal amount of SK3 protein was present in islets, but it became undetectable after exposure to doxycycline (DOX), which inhibits the transcription of the tTA-SK3 gene. The SK/IK channel-blockers apamin, dequalinium, and charybdotoxin caused increases in average [Ca(2+)](i) levels and in frequency of [Ca(2+)](i) oscillations in wild-type mouse islets. In SK3-tTA tet-off mice, the addition of apamin with glucose and tetraethylammonium (TEA) caused a similar elevation in [Ca(2+)](i), which was greatly diminished after DOX suppression of SK3 expression. We conclude that SK1, -2, -3, and IK1 (SK4) are expressed in islet cells and insulin-secreting cells and are able to influence glucose-induced calcium responses, thereby regulating insulin secretion.


Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.
It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.


Does inability to allocate attention contribute to balance constraints during gait in older adults?
Recent research has explored dual-task deficits during locomotion in older adults, yet the mechanisms underlying these deficits are poorly understood. In the current study, we examined one possible factor contributing to these deficits, the inability to flexibly allocate attention between two tasks. Twelve healthy young adults and 12 healthy elderly adults performed obstacle avoidance while walking and an auditory Stroop task either alone or simultaneously. Using an attentional allocation index (AAI) to compare performance of healthy young and older adults and to measure the flexibility of allocation of attention, results showed a tendency in older adults toward a decreased ability to flexibly allocate their attention between the two tasks, with small AAI values. The decreased ability to allocate attention in older adults was found to be more prominent in the auditory Stroop task performance than in the obstacle avoidance task. This study suggests that an important factor contributing to decreased dual-task performance in older adults when simultaneously performing a postural and secondary cognitive task is a reduced ability to flexibly allocate attention between the two tasks, with the general ability to switch attention flexibly being predictive of the ability to adhere to a prioritized focus.


The effects of adrenaline in out of hospital cardiac arrest with shockable and non-shockable rhythms: Findings from the PACA and PARAMEDIC-2 randomised controlled trials.
Previous research suggests there may be differences in the effects of adrenaline related to the initial cardiac arrest rhythm. The aim of this study was to assess the effect of adrenaline compared with placebo according to whether the initial cardiac arrest rhythm was shockable or non-shockable. Return of spontaneous circulation (ROSC), survival and neurological outcomes according to the initial arrest rhythm were compared amongst patients enrolled in the PARAMEDIC-2 randomised, placebo controlled trial. The results of the PARAMEDIC-2 and PACA out of hospital cardiac arrest trials were combined and meta-analysed. The initial rhythm was known for 3929 (98.2%) in the placebo arm and 3919 (97.6%) in the adrenaline arm. The effect on the rate of ROSC of adrenaline relative to placebo was greater in patients with non-shockable cardiac rhythms (1002/3003 (33.4%) versus 222/3005 (7.4%), adjusted OR: 6.5, (95% CI 5.6-7.6)) compared with shockable rhythms 349/716 (48.7%) versus (208/702 (29.6%), adjusted OR: 2.3, 95%CI: 1.9-2.9)). The adjusted odds ratio for survival at discharge for non-shockable rhythms was 2.5 (1.3, 4.8) and 1.3 (0.9, 1.8) for shockable rhythms (P value for interaction 0.065) and 1.8 (0.8-4.1) and 1.1 (0.8-1.6) respectively for neurological outcome at discharge (P value for interaction 0.295). Meta-analysis found similar results. Relative to placebo, the effects of adrenaline ROSC are greater for patients with an initially non-shockable rhythm than those with a shockable rhythms. Similar patterns are observed for longer term survival outcomes and favourable neurological outcomes, although the differences in effects are less pronounced. ISRCTN73485024.


The genetics of aerotolerant growth in an alphaproteobacterium with a naturally reduced genome.
Reduced genome bacteria are genetically simplified systems that facilitate biological study and industrial use. The free-living alphaproteobacterium Zymomonas mobilis has a naturally reduced genome containing fewer than 2,000 protein-coding genes. Despite its small genome, Z. mobilis thrives in diverse conditions including the presence or absence of atmospheric oxygen. However, insufficient characterization of essential and conditionally essential genes has limited broader adoption of Z. mobilis as a model alphaproteobacterium. Here, we use genome-scale CRISPRi-seq (clustered regularly interspaced short palindromic repeats interference sequencing) to systematically identify and characterize Z. mobilis genes that are conditionally essential for aerotolerant or anaerobic growth or are generally essential across both conditions. Comparative genomics revealed that the essentiality of most "generally essential" genes was shared between Z. mobilis and other Alphaproteobacteria, validating Z. mobilis as a reduced genome model. Among conditionally essential genes, we found that the DNA repair gene, recJ, was critical only for aerobic growth but reduced the mutation rate under both conditions. Further, we show that genes encoding the F1FO ATP synthase and Rhodobacter nitrogen fixation (Rnf) respiratory complex are required for the anaerobic growth of Z. mobilis. Combining CRISPRi partial knockdowns with metabolomics and membrane potential measurements, we determined that the ATP synthase generates membrane potential that is consumed by Rnf to power downstream processes. Rnf knockdown strains accumulated isoprenoid biosynthesis intermediates, suggesting a key role for Rnf in powering essential biosynthetic reactions. Our work establishes Z. mobilis as a streamlined model for alphaproteobacterial genetics, has broad implications in bacterial energy coupling, and informs Z. mobilis genome manipulation for optimized production of valuable isoprenoid-based bioproducts. IMPORTANCE The inherent complexity of biological systems is a major barrier to our understanding of cellular physiology. Bacteria with markedly fewer genes than their close relatives, or reduced genome bacteria, are promising biological models with less complexity. Reduced genome bacteria can also have superior properties for industrial use, provided the reduction does not overly restrict strain robustness. Naturally reduced genome bacteria, such as the alphaproteobacterium Zymomonas mobilis, have fewer genes but remain environmentally robust. In this study, we show that Z. mobilis is a simplified genetic model for Alphaproteobacteria, a class with important impacts on the environment, human health, and industry. We also identify genes that are only required in the absence of atmospheric oxygen, uncovering players that maintain and utilize the cellular energy state. Our findings have broad implications for the genetics of Alphaproteobacteria and industrial use of Z. mobilis to create biofuels and bioproducts.