Highly efficient Q-switched Yb:YAG channel waveguide laser with 5.6 W of average output power.
In this Letter, we present high-power continuous wave (CW) and Q-switched femtosecond laser-written Yb:YAG channel waveguide lasers. In Q-switched operation, obtained by a semiconductor saturable absorber mirror (SESAM), as well as in CW operation, the laser generates average output powers of more than 5.6 W and reaches slope efficiencies above 74%. The Q-switched laser operated at a maximum repetition rate of 5.4 MHz with a minimum pulse duration of 11 ns, and with a maximum pulse energy of 1 μJ. This laser has almost an order of magnitude higher average output power than previously reported Q-switched channel waveguide lasers.


CERKL mutations cause an autosomal recessive cone-rod dystrophy with inner retinopathy.
To define the phenotype of the retinal degeneration associated with mutations in the CERKL gene. Six patients (ages, 26-54 years) from three unrelated families with CERKL mutations were studied clinically and by electroretinography, kinetic, and chromatic static perimetry, autofluorescence (AF) imaging, and optical coherence tomography (OCT). Three siblings were homozygotes for p.R257X mutation; two siblings were compound heterozygotes for p.R257X and a novel p.C362X mutation; and one patient had only p.R257X mutation identified to date. There was a spectrum of severity: from mild visual acuity loss to light perception; from full kinetic fields with relative central scotomas to remnant peripheral islands; from reduced ERGs (some with negative waveforms) to nondetectable signals. Maculopathy showed residual foveal islands or extensive central rod and cone scotomas. With AF imaging, there was evidence of hyperautofluorescence at earlier and hypoautofluorescence at later disease stages. Peripheral function was generally less affected than central function. With OCT there were small foveal islands of outer nuclear layer (ONL) in those with preserved acuity. Eccentric to an annular region with no discernible ONL, there could be ONL in the midperiphery. At early disease stages, ganglion cell layer thickness was less affected than ONL. Later disease stages were accompanied by inner nuclear layer and nerve fiber layer abnormalities. CERKL mutations are associated with widespread retinal degeneration with prominent maculopathy. The clinical presentation is that of an autosomal recessive cone-rod dystrophy. Photoreceptor loss appears at all stages of disease and inner laminopathy complicates the phenotype at later stages.


Laparoscopic nephrosplenic space ablation with barbed suture in eight horses.
CASE DESCRIPTION 8 horses (5 geldings and 3 mares) were evaluated for laparoscopic closure of the nephrosplenic space following a history of recurrent left dorsal displacement of the large colon. CLINICAL FINDINGS All horses underwent a physical examination and routine clinicopathologic testing. Transrectal palpation and transabdominal ultrasonography were performed to exclude the presence of organs in the left paralumbar region. TREATMENT AND OUTCOME A left flank laparoscopic approach with the horses standing was used. A continuous suture was placed in a craniocaudal direction between the renal and splenic capsules with unidirectional barbed suture material. This allowed obliteration of the nephrosplenic space without the need for knots to secure the leading and terminal ends of the suture line. In all horses, transrectal palpation was performed 2 months after surgery; at this time, closure of the caudal part of the nephrosplenic space was evident. In 2 horses, follow-up laparoscopy was performed, and complete closure of the nephrosplenic space was confirmed. Telephone follow-up revealed that none of the horses had any signs of recurrent left dorsal displacement of the large colon. CLINICAL RELEVANCE Results suggested that laparoscopic nephrosplenic space closure with unidirectional barbed suture material could be considered as an option for prevention of left dorsal displacement of the large colon in horses. In the horses of this report, barbed suture material allowed secure ablation of the nephrosplenic space and eliminated the need for intracorporeal knot tying.


Longitudinal Study Depicting Differences in Complementary Feeding and Anthropometric Parameters in Late Preterm Infants up to 2 Years of Age.
Ensuring the nutritional demands of preterm (PT) infants during complementary feeding could contribute significantly to the infants' long-term health and development. However, the dietary guidelines for complementary feeding in PT are scarce. Thus, describing dietary intake and identifying nutritional targets for these infants could be of great interest. The aim of this study is to assess the food intake and anthropometric parameters in a Mediterranean infant cohort from 6 to 24 months and to identify nutritional targets especially focused on late preterm infants. This is a longitudinal prospective study analyzing information from administered questionnaires about general characteristics and food frequency consumption in 115 infants (20 PT (32 to 36 gestational weeks), 95 full-term (FT)) at 6, 12 and 24 months of age. Results show that the differences in the prevalence of underweight observed in PT infants vs. FT infants are maintained for up to 6 months of age but disappear at 12 and 24 months. The age of inclusion of new foods and the average intake of the main food groups was not different from that of FTs. Although protein intake at 6 months was directly correlated with weight gain and growth in FT, these associations were not observed in PT. At the nutritional level, the low intake of vitamin D in preterm infants is noteworthy. These findings may be useful when designing new intervention strategies for this population group.


Marine vertebrate zoonoses: an overview of the DAO special issue.
The role of marine birds, mammals, turtles and fish as vectors of infectious agents of potential risk to humans can be examined from a variety of perspectives. The studies in this DAO Special include a broad survey of multiple agents and species, a sequencing study of Giardia intestinalis haplotypes known to be pathogenic to humans, an assessment of risks to humans working with marine mammals, a source tracking study using E. coli ribotypes, studies of regional Salmonella and Brucella epizootiology, a serology survey and a case report of a herpes simplex infection in a dolphin. Additionally, a recently published study (Venn-Watson et al. 2008; Dis Aquat Org 79:87-93) classifying pure cultures of bacteria from a captive dolphin colony also pertains to this theme. These studies raise the following questions: whether the presence of zoonotic agents in marine vertebrates represents a risk to other marine vertebrates, humans, or both; what are the routes by which these marine vertebrate zoonotic infections are acquired and circulated in the marine ecosystem; to what degree are such agents subclinical versus causes of overt disease in marine vertebrates; what are the subsets of the human population most likely to be affected by such infections; and which human health preventive measures would seem reasonable?


Mobile phone-based pattern recognition and data analysis for patients with type 1 diabetes.
Persons with type 1 diabetes who use electronic self-help tools, most commonly blood glucose meters, record a large amount of data about their personal condition. Mobile phones are powerful and ubiquitous computers that have a potential for data analysis, and the purpose of this study is to explore how self-gathered data can help users improve their blood glucose management. Thirty patients with insulin-regulated type 1 diabetes were equipped with a mobile phone application for 3-6 months, recording blood glucose, insulin, dietary information, physical activity, and disease symptoms. The data were analyzed in terms of usage of the different modules and which data processing and visualization tools could be constructed to support the use of these data. Eighteen patients (denoted "adopters") recorded complete data for over 80 consecutive days, up to 247 days. Among those who withdrew or did not use the application extensively, the most common reasons given were outdated or difficult-to-use phone. Data analysis using period finding and scale-space trends was found to yield significant patterns for most adopters. Pattern recognition methods to predict low or high blood glucose were found to be performing poorly. Minimally intrusive mobile applications enable users with type 1 diabetes to record data that can provide data-driven feedback to the user, potentially providing relevant insight into their disease.


Disability life expectancy for the elderly, city of Sao Paulo, Brazil, 2000: gender and educational differences.
There is evidence that 'health life expectancy' (expected number of years to be lived in health) differs by socioeconomic status. Time spent in health or disability plays a critical role in the use of health care services. The objective of this study was to estimate 'disability life expectancy' by age, gender and education attainment for the elderly of the city of São Paulo, Brazil, in the year 2000. Data came from the SABE database, population censuses and mortality statistics (SEADE Foundation). Life expectancy with disability was calculated using Sullivan's method on the basis of the current probability of death and prevalence of disability by educational level. The prevalence of disability increased with age, for both sexes and both levels of educational attainment studied. Men showed a lower prevalence of disability, in general, and persons with lower educational attainment showed a higher prevalence of disability. Regarding life expectancy, women could expect to live longer than men, with and without disability. For both sexes, the percentage of life expectancy lived with disability decreased with increasing educational attainment. With increasing educational attainment, the sex differences in the percentage of remaining years to be lived with disability increased for most ages. Finally, the percentage of remaining years to be lived with disability increased with age for males and females, except for males with high educational attainment between the ages 70-75 and 75-80. The results may serve as a guide for public policies in the country, since health problems faced by older persons, such as disability, are the result of a number of past experiences during their life-times, such as health care, housing conditions, hygiene practices and education. Education influences health behaviours and is related, to some extent, to all these factors. Therefore, improvements in education for the disadvantaged may improve health.


Thin-slice reconstructions of nonenhanced CT images allow for detection of thrombus in acute stroke.
The purpose of this study was to investigate whether thin-slice image reconstructions of cranial nonenhanced CT scans could be used to significantly increase sensitivity for detecting intraluminal thrombus in patients with acute ischemic stroke due to proximal occlusion of the middle cerebral artery. In a prospective case series, the raw data of nonenhanced CT scans from 54 patients presenting with acute ischemic stroke and proven vascular obliteration of the middle cerebral artery were collected along with the same data from patients not having a stroke but the same sex and age. All raw data were reconstructed with a slice thickness of 5 mm and as thin slices with a thickness of 0.625 mm. Three observers independently evaluated the 5-mm nonenhanced CT reconstructions and 5-mm maximum intensity projections of the thin slices and rated the likelihood of a clot obliterating the middle cerebral artery trunk or first-order branches using a 5-point scale. The results were evaluated in comparison with base data using receiver operating curve analysis. Interobserver agreement was measured using Cohen κ for every pair of observers. The area under the curve for the receiver operating curve analysis for the thick slices ranged from 0.63 to 0.67, whereas for the maximum intensity projection images of the thin slice reconstructions, receiver operating curve analysis revealed areas under the curve between 0.94 and 0.97. Interobserver agreement was higher for thin-slice (κ, 0.69-0.83) versus thick-slice nonenhanced CT reconstructions (κ, 0.38-0.45). Thin-slice reconstructions of standard cranial nonenhanced CT raw data allow for more sensitive and reliable detection of clots occluding the proximal middle cerebral artery.


Simuliid blackflies (Diptera: Simuliidae) and ceratopogonid midges (Diptera: Ceratopogonidae) as vectors of Mansonella ozzardi (Nematoda: Onchocercidae) in northern Argentina.
Mansonella ozzardi, a relatively nonpathogenic filarial parasite of man in Latin America, is transmitted by either ceratopogonid midges or simuliid blackflies. In the only known focus of the disease in north-western Argentina the vectors have never been incriminated. This study investigated the potential vectors of M. ozzardi in this area. The only anthropophilic species of these Diptera families biting man at the time of the investigation were Simulium exiguum, S. dinellii, Culicoides lahillei and C. paraensis. Using experimentally infected flies S. exiguum and both species of Culicoides allowed full development of microfilariae to the infective stage, with C. lahillei being a more competent host than S. exiguum. Based on these data, biting rates and natural infectivity rates it is probable that at the begininning of the wet season C. lahillei is the main vector of M. ozzardi and both C. paraensis and S. exiguum secondary vectors. Additionally, it was found that a single dose of ivermectin was ineffectual in eradicating M. ozzardi from infected individuals in this area.


Quantifying the effects of ecological constraints on trait expression using novel trait-gradient analysis parameters.
Complex processes related to biotic and abiotic forces can impose limitations to assembly and composition of plant communities. Quantifying the effects of these constraints on plant functional traits across environmental gradients, and among communities, remains challenging. We define ecological constraint (Ci ) as the combined, limiting effect of biotic interactions and environmental filtering on trait expression (i.e., the mean value and range of functional traits). Here, we propose a set of novel parameters to quantify this constraint by extending the trait-gradient analysis (TGA) methodology. The key parameter is ecological constraint, which is dimensionless and can be measured at various scales, for example, on population and community levels. It facilitates comparing the effects of ecological constraints on trait expressions across environmental gradients, as well as within and among communities. We illustrate the implementation of the proposed parameters using the bark thickness of 14 woody species along an aridity gradient on granite outcrops in southwestern Australia. We found a positive correlation between increasing environmental stress and strength of ecological constraint on bark thickness expression. Also, plants from more stressful habitats (shrublands on shallow soils and in sun-exposed locations) displayed higher ecological constraint for bark thickness than plants in more benign habitats (woodlands on deep soils and in sheltered locations). The relative ease of calculation and dimensionless nature of Ci allow it to be readily implemented at various scales and make it widely applicable. It therefore has the potential to advance the mechanistic understanding of the ecological processes shaping trait expression. Some future applications of the new parameters could be investigating the patterns of ecological constraints (1) among communities from different regions, (2) on different traits across similar environmental gradients, and (3) for the same trait across different gradient types.


Modeling the intensity and polarization response of planar bolometric detectors.
Far-infrared bolometric detectors are used extensively in ground-based and space-borne astronomy, and thus it is important to understand their optical behavior precisely. We have studied the intensity and polarization response of free-space bolometers and shown that when the size of the absorber is reduced below a wavelength, the response changes from being that of a classical optical detector to that of a few-mode antenna. We have calculated the modal content of the reception patterns and found that for any volumetric detector having a side length of less than a wavelength, three magnetic and three electric dipoles characterize the behavior. The size of the absorber merely determines the relative strengths of the contributions. The same formalism can be applied to thin-film absorbers, where the induced current is forced to flow in a plane. In this case, one magnetic and two electric dipoles characterize the behavior. The ability to model easily the intensity, polarization, and straylight characteristics of electrically small detectors will be of great value when designing high-performance polarimetric imaging arrays.


Reoperation for urinary incontinence: a nationwide cohort study, 1998-2007.
The synthetic midurethral slings were introduced in the 1990s and were rapidly replaced the Burch colposuspension as the gold standard treatment for urinary incontinence. It has been reported that the retropubic midurethral tape has an objective and subjective cure rate of 85% at 5 years of follow-up, but the rate of reoperation after retropubic midurethral tape at the long-term follow-up is less well described. The existing literature specifies an overall lifetime rate of reoperation of about 8-9% after an initial operation for urinary incontinence. There are, however, conflicting statements about the risk of reoperation after specific surgical procedures for urinary incontinence. The objective of the study was to describe the cumulative incidence of reoperation within a 5 year period after different types of surgical procedures for urinary incontinence based on a nationwide population. We used the Danish National Patient Registry to identify women who had surgery for urinary incontinence from 1998 through 2007 and the outcome was a reoperation within 5 years. Kaplan-Meier curves were used to estimate the rate of reoperation for 6 types of surgery for urinary incontinence (retropubic midurethral tape, transobturator tape, urethral injection therapy, Burch colposuspension, pubovaginal slings, and miscellaneous operations). Cox proportional hazard models were used to estimate the hazard ratio (HR) with 95% confidence intervals (CIs), adjusted for factors suspected to be associated with reoperation. A total of 8671 women (mean age, 56.1 years, range 6.7-93.7 years) underwent surgical treatment for urinary incontinence. Among these women, 5820 (67%) received a synthetic midurethral sling at baseline. The cumulative incidence of reoperation after any surgical treatment for urinary incontinence was 10%. The lowest rate of reoperation was observed among women having pubovaginal slings (6%), retropubic midurethral tape (6%) and Burch colposuspension (6%) followed by transobturator tape (9%), and miscellaneous operations (12%), whereas the highest observed risk was for urethral injection therapy (44%). In a Cox proportional hazard model that adjusted for age, department volume, and calendar effect, the transobturator tape carried a 2-fold higher risk of reoperation (HR, 2.1; 95% CI, 1.5-2.9), and urethral injection therapy carried a 12 fold-higher risk (HR, 11.5; 95% CI, 9.3-14.3) compared with retropubic midurethral tape. This nationwide cohort study provides physicians with a representative evaluation of the rate of reoperations after surgical procedures for urinary incontinence. Pubovaginal slings, Burch colposuspension, and retropubic midurethral tape had a similar risk of reoperation (6%). Women who were operated with transobturator tape had a significantly higher risk of reoperation compared with retropubic midurethral tape.


3D structure determination of STARP peptides implicated in P. falciparum invasion of hepatic cells.
To block the different stages of Plasmodium falciparum invasion into human hepatocytes and red blood cells, we have focused on those proteins belonging to the pre-erythrocytic stage. One of these proteins is Sporozoite Threonine and Asparagine Rich Protein (STARP), which is a ligand used by P. falciparum parasites to bind Hepatic cells (HepG2). Previous studies on this protein identified two conserved peptides binding with high activity to HepG2 cells (namely 20546 and 20570) with corresponding critical hepatic-cell binding residues and determined an important role for these two peptides in the invasion process. This study shows the results of immunization trials in Aotus monkeys with native STARP peptides and analogues modified in critical hepatic-cell binding residues. The results show that native peptides are not immunogenic but can induce high-antibody titers when their critical residues are replaced by other with similar volume and mass but different polarity. Nuclear Magnetic Resonance ((1)H NMR) studies revealed that native peptides (non-immunogenic) displayed shorter alpha-helical regions compared to their highly immunogenic modified analogues. Binding assays with HLA-DRbeta1* molecules showed that 20546 modified peptides inducing high-antibody titers (24972, 24320 and 24486) bound to HLA-DRbeta1*0301 molecules, while the 20570 modified analogue (24322) bound to HLA-DRbeta1*0101. The results support including these high-immunogenic STARP-derived modified peptides as pre-erythrocytic candidates to be included in the design of a synthetic antimalarial vaccine.


Burnout and use of HIV services among health care workers in Lusaka District, Zambia: a cross-sectional study.
Well-documented shortages of health care workers in sub-Saharan Africa are exacerbated by the increased human resource demands of rapidly expanding HIV care and treatment programmes. The successful continuation of existing programmes is threatened by health care worker burnout and HIV-related illness. From March to June 2007, we studied occupational burnout and utilization of HIV services among health providers in the Lusaka public health sector. Providers from 13 public clinics were given a 36-item, self-administered questionnaire and invited for focus group discussions and key-informant interviews. Some 483 active clinical staff completed the questionnaire (84% response rate), 50 staff participated in six focus groups, and four individuals gave interviews. Focus group participants described burnout as feeling overworked, stressed and tired. In the survey, 51% reported occupational burnout. Risk factors were having another job (RR 1.4 95% CI 1.2-1.6) and knowing a co-worker who left in the last year (RR 1.6 95% CI 1.3-2.2). Reasons for co-worker attrition included: better pay (40%), feeling overworked or stressed (21%), moving away (16%), death (8%) and illness (5%). When asked about HIV testing, 370 of 456 (81%) reported having tested; 240 (50%) tested in the last year. In contrast, discussion groups perceived low testing rates. Both discussion groups and survey respondents identified confidentiality as the prime reason for not undergoing HIV testing. In Lusaka primary care clinics, overwork, illness and death were common reasons for attrition. Programmes to improve access, acceptability and confidentiality of health care services for clinical providers and to reduce workplace stress could substantially affect workforce stability.


Early, Prehospital Activation of the Walking Blood Bank Based on Mechanism of Injury Improves Time to Fresh Whole Blood Transfusion.
Balanced component therapy (BCT) remains the mainstay in trauma resuscitation of the critically battle injured. In austere medical environments, access to packed red blood cells, apheresis platelets, and fresh frozen plasma is often limited. Transfusion of warm, fresh whole blood (FWB) has been used to augment limited access to full BCT in these settings. The main limitation of FWB is that it is not readily available for transfusion on casualty arrival. This small case series evaluates the impact early, mechanism-of-injury (MOI)-based, preactivation of the walking blood bank has on time to transfusion. We report an average time of 18 minutes to FWB transfusion from patient arrival. Early activation of the walking blood bank based on prehospital MOI may further reduce the time to FWB transfusion.


Preliminary Validation of a High Docosahexaenoic Acid (DHA) and α-Linolenic Acid (ALA) Dietary Oil Blend: Tissue Fatty Acid Composition and Liver Proteome Response in Atlantic Salmon (Salmo salar) Smolts.
Marine oils are important to human nutrition as the major source of docosahexaenoic acid (DHA), a key omega-3 long-chain (≥C20) polyunsaturated fatty acid (n-3 LC-PUFA) that is low or lacking in terrestrial plant or animal oils. The inclusion of fish oil as main source of n-3 LC-PUFA in aquafeeds is mostly limited by the increasing price and decreasing availability. Fish oil replacement with cheaper terrestrial plant and animal oils has considerably reduced the content of n-3 LC-PUFA in flesh of farmed Atlantic salmon. Novel DHA-enriched oils with high alpha-linolenic acid (ALA) content will be available from transgenic oilseeds plants in the near future as an alternative for dietary fish oil replacement in aquafeeds. As a preliminary validation, we formulated an oil blend (TOFX) with high DHA and ALA content using tuna oil (TO) high in DHA and the flaxseed oil (FX) high in ALA, and assessed its ability to achieve fish oil-like n-3 LC-PUFA tissue composition in Atlantic salmon smolts. We applied proteomics as an exploratory approach to understand the effects of nutritional changes on the fish liver. Comparisons were made between fish fed a fish oil-based diet (FO) and a commercial-like oil blend diet (fish oil + poultry oil, FOPO) over 89 days. Growth and feed efficiency ratio were lower on the TOFX diet. Fish muscle concentration of n-3 LC-PUFA was significantly higher for TOFX than for FOPO fish, but not higher than for FO fish, while retention efficiency of n-3 LC-PUFA was promoted by TOFX relative to FO. Proteomics analysis revealed an oxidative stress response indicative of the main adaptive physiological mechanism in TOFX fish. While specific dietary fatty acid concentrations and balances and antioxidant supplementation may need further attention, the use of an oil with a high content of DHA and ALA can enhance tissue deposition of n-3 LC-PUFA in relation to a commercially used oil blend.


Bridging the gap to advance the care of individuals with cancer: collaboration and partnership in the Cardiology Oncology Innovation Network (COIN).
Cardiovascular diseases and cancer continue to be the two leading causes of death in the United States. While innovations in artificial intelligence, digital health, and telemedicine may revolutionize cardio-oncology clinical practice, barriers to widespread adoption continue to exist. The most effective way to advance these technologies is through a broad range of stakeholders sharing a common vision. Additionally, as we enter the digital era in healthcare, we must help lead this charge for the benefit of our cardiology and oncology patients. Bolstering collaborations in cardiology and oncology is key, in partnership with technology firms, industry, academia, and private practice, with an emphasis on various forms of innovation. The ultimate goal is to connect our patients and their health to informatics-based opportunities to advance cardiovascular disease prevention in cancer patients. We have established the Cardiology Oncology Innovation Network in accordance with this vision, to develop new care delivery options through the use of innovative technological strategies. Our tripartite mission - innovation, collaboration, and education - aims to increase access to and expertise in digital transformation to prevent cardiovascular diseases in cancer patients. Here we describe network initiatives, early accomplishments, and future milestones.


Structure and dynamics of solvent molecules inside the polytheonamide B channel in different environments: a molecular dynamics study.
The β6.3-helical channel of the marine cytotoxic peptide, polytheonamide B (pTB), is examined in water, the POPC bilayer, and a 1 : 1 chloroform/methanol mixture using all-atom molecular dynamics simulations. The structures and fluctuations of the β6.3-helix of pTB are investigated in the three environments. The average structure of pTB calculated in the mixed solvent is in good agreement with the NMR-resolved structure in the mixed solvent, indicating the validity of the parameters used for the non-standard groups in pTB. The configuration and dynamics of solvent molecules inside the pore are examined in detail. It is found that the motions of methanol molecules inside the pore are not correlated because of the absence of strong hydrogen bonds (HBs) between adjacent methanol molecules. On the other hand, the motions of water molecules inside the pore are highly correlated, both translationally and orientationally, due to the strong HBs between neighboring water molecules. It is suggested that the collective behavior of water molecules inside the pore in the membrane is crucial for the permeation of ions through the pTB channel.


Innate immune homeostasis by the homeobox gene caudal and commensal-gut mutualism in Drosophila.
Although commensalism with gut microbiota exists in all metazoans, the host factors that maintain this homeostatic relationship remain largely unknown. We show that the intestinal homeobox gene Caudal regulates the commensal-gut mutualism by repressing nuclear factor kappa B-dependent antimicrobial peptide genes. Inhibition of Caudal expression in flies via RNA interference led to overexpression of antimicrobial peptides, which in turn altered the commensal population within the intestine. In particular, the dominance of one gut microbe, Gluconobacter sp. strain EW707, eventually led to gut cell apoptosis and host mortality. However, restoration of a healthy microbiota community and normal host survival in the Caudal-RNAi flies was achieved by reintroduction of the Caudal gene. These results reveal that a specific genetic deficiency within a host can profoundly influence the gut commensal microbial community and host physiology.


The multiple tasks test. Strategies in Parkinson's disease.
The clinical balance tests presently used cannot predict falls in Parkinson's disease (PD), perhaps because they probe fairly isolated "components" of postural control. The Multiple Tasks Test (MTT) is a new balance test that simultaneously assesses multiple components of postural control. We investigated whether this MTT can detect postural abnormalities in PD patients. Fifty young controls (mean age 27.6 years), 20 elderly controls (mean age 62.5 years), and 20 PD patients (mean age 61.8 years, mean Hoehn and Yahr stage 2.2) participated. The MTT consisted of eight separate tasks of increasing complexity, which were executed sequentially. These tasks were composed of several motor components (standing up, walking, avoiding obstacles, touching the floor, turning around, and sitting down) and one cognitive component (answering serial questions). Four additional components included carrying an empty or loaded tray, wearing slippery shoes, and reduced illumination. All components within each task had to be performed simultaneously or directly sequentially. Errors were defined as Hesitations (slowed performance) or Blocks (complete cessation), which were scored separately for execution of the motor and cognitive components. Speed of performance was not stressed, but we did measure the time taken to complete all tasks. The complete MTT was performed by all subjects, except for a subgroup of seven patients and seven elderly controls who performed a shortened version, with only three of the eight sequential tasks (simple, intermediate, and most difficult). The number of subjects that produced Hesitations or Blocks for the motor components differed between the three groups [two-way repeated measures MANOVA, F(2.7) = 20.56; P < 0.001], patients making more errors than young and elderly controls. Furthermore, the number of subjects that made motor errors increased as the tasks became more complex [F(2.7) = 6.69; P < 0.001]. This increase differed across the three groups [significant interaction effect; F(2.7) = 3.31; P < 0.001] because particularly patients produced motor errors during the more complex tasks. In both control groups, 62% performed all eight consecutive tasks without errors in the motor components. In contrast, only 8% of the patients completed all tasks without motor errors (log rank test, P < 0.0001). This difference between patients and controls disappeared if the cognitive component was also scored, because more controls made cognitive errors during complex tasks than patients. Controls apparently gave priority to execution of the motor components, which they performed significantly faster than the patients. Both patients and controls made more errors during the shortened MTT, suggesting that learning effects (gain in performance through practice) influenced performance on the complete test. The MTT is a new balance test that clearly discriminates between healthy subjects and PD patients. Unlike controls, PD patients lend less priority to motor tasks over cognitive tasks. In addition, impaired motor learning may partially explain the higher error rate in PD. Future studies must determine if impaired MTT performance can predict actual falls in daily life.


Synthetic inositol phosphate analogs reveal that PPIP5K2 has a surface-mounted substrate capture site that is a target for drug discovery.
Diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) is one of the mammalian PPIP5K isoforms responsible for synthesis of diphosphoinositol polyphosphates (inositol pyrophosphates; PP-InsPs), regulatory molecules that function at the interface of cell signaling and organismic homeostasis. The development of drugs that inhibit PPIP5K2 could have both experimental and therapeutic applications. Here, we describe a synthetic strategy for producing naturally occurring 5-PP-InsP4, as well as several inositol polyphosphate analogs, and we study their interactions with PPIP5K2 using biochemical and structural approaches. These experiments uncover an additional ligand-binding site on the surface of PPIP5K2, adjacent to the catalytic pocket. This site facilitates substrate capture from the bulk phase, prior to transfer into the catalytic pocket. In addition to demonstrating a "catch-and-pass" reaction mechanism in a small molecule kinase, we demonstrate that binding of our analogs to the substrate capture site inhibits PPIP5K2. This work suggests that the substrate-binding site offers new opportunities for targeted drug design.


Retroviral insertions in the murine His-1 locus activate the expression of a novel RNA that lacks an extensive open reading frame.
The His-1 locus is a common site of viral insertion in murine myeloid leukemias induced by the wild mouse ecotropic retrovirus, CasBrM. In this report, we describe the cloning of a novel gene at the His-1 locus and show that His-1 expression is associated with the transformed phenotype. Northern (RNA) blot analysis identified His-1 transcripts in four transformed myeloid cell lines but in no normal tissues examined. Two of these cell lines were derived from retrovirus-induced myeloid leukemias that harbor integrated proviruses which drive His-1 gene expression by promoter insertion. The two other cell lines expressed a discrete 3-kb His-1 RNA that is derived from a novel gene consisting of three exons that span 6 kb on mouse chromosome 2. The His-1 gene is conserved as a single-copy sequence in multiple vertebrate species and is expressed as a spliced and polyadenylated RNA. A protein-coding region is not evident from analysis of the His-1 sequence because of the presence of multiple small open reading frames, none of which are greater than 219 bp. This lack of an extensive open reading frame is an unusual feature that is shared by other RNA molecules believed to function in the absence of translation.


Factors associated with concomitant psychotropic drug use in the treatment of major depression: a STAR*D Report.
Concomitant psychotropic medication (CPM) treatment is common in persons with major depression (MDD). However, relationships with patient characteristics and response to treatment are unclear. Participants with nonpsychotic MDD (N=2682) were treated with citalopram, 20-60 mg/day. Sociodemographic, clinical, and treatment outcome characteristics were compared between those using CPMs at study entry or during up to 14 weeks of citalopram treatment, and non-users. About 35% of participants used a CPM. Insomnia was the predominant indication (70.3%). CPM users were more likely to be seen in primary care settings (69.3% versus 30.7%), be white, of non-Hispanic ethnicity, married, and have a higher income, private insurance, and certain comorbid disorders. CPM users had greater depressive severity, poorer physical and mental functioning, and poorer quality of life than non-users. Response and remission rates were also lower. CPM users were more likely to achieve >50 mg/day of citalopram, to report greater side effect intensity, and to have serious adverse events, but less likely to be intolerant of citalopram. CPMs are associated with greater illness burden, more Axis I comorbidities (especially anxiety disorders), and lower treatment effectiveness. This suggests that CPM use may identify a more difficult to treat population that needs more aggressive treatment.


Expression of galanin and its receptors are perturbed in a rodent model of mild, blast-induced traumatic brain injury.
The symptomatology, mood and cognitive disturbances seen in post-traumatic stress disorder (PTSD) and mild blast-induced traumatic brain injury (mbTBI) overlap considerably. However the pathological mechanisms underlying the two conditions are currently unknown. The neuropeptide galanin has been suggested to play a role in the development of stress and mood disorders. Here we applied bio- and histochemical methods with the aim to elucidate the nature of any changes in the expression of galanin and its receptors in a rodent model of mbTBI. In situ hybridization and quantitative polymerase chain reaction studies revealed significant, injury-induced changes, in some cases lasting at least for one week, in the mRNA levels of galanin and/or its three receptors, galanin receptor 1-3 (GalR1-3). Such changes were seen in several forebrain regions, and the locus coeruleus. In the ventral periaqueductal gray GalR1 mRNA levels were increased, while GalR2 were decreased. Analysis of galanin peptide levels using radioimmunoassay demonstrated an increase in several brain regions including the locus coeruleus, dorsal hippocampal formation and amygdala. These findings suggest a role for the galanin system in the endogenous response to mbTBI, and that pharmacological studies of the effects of activation or inhibition of different galanin receptors in combination with functional assays of behavioral recovery may reveal promising targets for new therapeutic strategies in mbTBI.


Pisa syndrome in Parkinson disease: An observational multicenter Italian study.
To estimate the prevalence of Pisa syndrome (PS) in patients with Parkinson disease (PD) and to assess the association between PS and demographic and clinical variables. In this multicenter cross-sectional study, consecutive outpatients with PD attending 21 movement disorders Italian tertiary centers were enrolled and underwent standardized clinical evaluation. PS was defined as trunk lateral deviation ≥10°. Patients with PD were compared according to the presence of PS for several demographic and clinical variables. Among 1,631 enrolled patients with PD, PS was detected in 143 patients (8.8%, 95% confidence interval 7.4%-10.3%). Patients with PS were older, had lower body mass index, longer disease duration, higher disease stages, and poorer quality of life. Falls were more frequent in the PS group as well as occurrence of "veering gait" (i.e., the progressive deviation toward one side when patient walked forward and backward with eyes closed). Patients with PS received higher daily levodopa equivalent daily dose and were more likely to be treated with combination of levodopa and dopamine agonists. Osteoporosis and arthrosis were significantly the most frequent associated medical conditions in patients with PS. Multiple explanatory variable logistic regression models confirmed the association of PS with the following variables: Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, associated medical conditions, and presence of veering gait. Our results suggest that PS is a relatively frequent and often disabling complication in PD, especially in the advanced disease stages. The association is dependent on a number of potentially relevant demographic and clinical variables.


A proposal to standardize dyspnoea measurement in clinical trials of acute heart failure syndromes: the need for a uniform approach.
Dyspnoea is the most common presenting symptom amongst patients with acute heart failure syndromes (AHFS). It is distressing to patients and therefore an important target for treatment in clinical practice, clinical trials, and for regulatory approval of novel agents. Despite its importance as a treatment target, no consensus exists on how to assess dyspnoea in this setting. There is a considerable uncertainty about the reproducibility of the various instruments used to measure dyspnoea, their ability to reflect changes in symptoms and whether they accurately reflect the patient's experience. Little attempt has been made to ensure consistent implementation with respect to patients' posture during assessment or timing in relationship to therapy. There is also limited understanding of how rapidly and completely dyspnoea responds to standard therapy. A standardized method with which to assess dyspnoea is required for clinical trials of AHFS in order to ensure uniform collection of data on a key endpoint. We propose the Provocative Dyspnoea Assessment, a method of measurement that combines sequential dyspnoea provocation by positioning and walking with a dyspnoea self assessment using a five-point Likert scale, to yield a final Dyspnoea Severity Score. This proposed tool requires detailed validation but has face validity for the uniform assessment of dyspnoea.


Counterion binding alters surfactant self-assembly in deep eutectic solvents.
Micellisation of surfactants in deep eutectic solvents has been recently demonstrated to provide a controllable way to modify micelle morphology. Ion-pair interactions between the solvent and the surfactant headgroup were identified as affecting the micellisation by modifying the charge density of the micelle. Here we explore the micellisation of dodecylsulfate surfactants with different counterions (Li+, Cs+, Mg2+, Bmim+, Emim+, cholinium+) dissolved in two deep eutectic solvents: choline chloride:urea and choline chloride:glycerol. Surface tension results show a solvent and counterion dependence of the CMC of the surfactants. Small-angle neutron scattering was subsequently used to investigate the morphology of the micelles formed. The results show that the elongation of the micelles is strongly dependent on the solvent, showing more elongated aggregates in choline chloride:urea than in choline chloride:glycerol. The morphology of micelles in DES was also found to depend on the counterion, where the affinity of binding showed similarities to that in water.


MRI study of subconjunctival and intravitreal injections.
Previous magnetic resonance imaging (MRI) studies to investigate the routes of penetration and barriers in ocular delivery have provided insights into the mechanisms of transscleral and intraocular drug delivery. The objective of the present study was to investigate ocular penetration and clearance after subconjunctival and intravitreal injections using a contrast agent at concentrations higher than those in the previous studies. This high concentration approach was hypothesized to allow the visualization of the contrast agent in the eye that could not be achieved previously. Subconjunctival and intravitreal injections of contrast agent Magnevist, a model hydrophililc probe, were performed in rabbits, and the distribution and clearance of the probe after the injections were examined by MRI. After subconjunctival injection in vivo, significant contrast agent penetration into the anterior chamber was observed but not into the vitreous. A clearance pathway of the hydrophilic probe from the subconjunctival depot to the regions near the periocular fat behind the eye was found. After intravitreal injection in vivo, the contrast agent was observed in the anterior chamber, optic nerve, and tissues surrounding the eye during clearance. MRI continues to provide insights into the transport barriers and clearance pathways of hydrophilic molecules in ocular delivery.


Placebo-controlled trial of potassium supplements in black patients with mild essential hypertension.
Forty-eight black patients with mildly increased blood pressure (BP) that had not yet been subjected to treatment took part in a double-blind clinical trial of the efficacy and tolerability of oral potassium supplements (64 mmol daily) versus a matching placebo (made of starch with coating) in a 16-week study. Potassium supplements produced a significant decrease in mean supine and standing BP within 4 weeks after treatment inception. Urinary potassium excretion increased significantly in the 24 patients who received potassium supplements (p less than 0.001). No significant changes occurred in plasma sodium and potassium concentrations or in urinary excretion of sodium during the study. All patients completed the trial without experiencing any notable untoward effects. These results are consistent with the premise that oral potassium supplements may exert hypotensive effects of clinically significant degree in patients with mild hypertension.


An expert-novice comparison of lifeguard specific vigilance performance.
Lifeguards must maintain alertness and monitor an aquatic space across extended periods. However, lifeguard research has yet to investigate a lifeguard's ability to maintain performance over time and whether this is influenced by years of certified experience or the detection difficulty of a drowning incident. The aim of this study was to examine whether lifeguard experience, drowning duration, bather number, and time on task influences drowning detection performance. A total of 30 participants took part in nine 60-minute lifeguard specific tasks that included 11 drowning events occurring at five-minute intervals. Each task had manipulated conditions that acted as the independent variables, including bather number and drowning duration. The experienced group detected a greater number of drowning events per task, compared to novice and naïve groups. Findings further highlighted that time, bather number, and drowning duration has a substantial influence on lifeguard specific drowning detection performance. It is hoped that the outcome of the study will have applied application in highlighting the critical need for lifeguard organizations to be aware of a lifeguard's capacity to sustain attention, and for researchers to explore methods for minimizing any decrement in vigilance performance.


Neuroradiologic Imaging of Neurologic and Neuro-Ophthalmic Complications of Coronavirus-19 Infection.
To review the literature and provide a summary of COVID-19-related neurologic and neuro-ophthalmic complications. The currently available literature was reviewed on PubMed and Google Scholar using the following keywords for searches: CNS, Neuro-Ophthalmology, COVID-19, SARS-CoV-2, coronavirus, optic neuritis, pseudotumor cerebri, Acute Disseminated Encephalomyelitis, posterior reversible encephalopathy syndrome (PRES), meningitis, encephalitis, acute necrotizing hemorrhagic encephalopathy, and Guillain-Barré and Miller Fisher syndromes. Neuroradiologic findings of neurologic and neuro-ophthalmologic complications in relationship to COVID-19 infection were reviewed. Afferent visual pathway-related disorders with relevant imaging manifestations included fundus nodules on MRI, papilledema and pseudotumor cerebri syndrome, optic neuritis, Acute Disseminated Encephalomyelitis, vascular injury with thromboembolism and infarct, leukoencephalopathy, gray matter hypoxic injury, hemorrhage, infectious meningitis/encephalitis, acute necrotizing hemorrhagic encephalopathy, and PRES. Efferent visual pathway-related complications with relevant imaging manifestations were also reviewed, including orbital abnormalities, cranial neuropathy, Guillain-Barré and Miller Fisher syndromes, and nystagmus and other eye movement abnormalities related to rhombencephalitis. COVID-19 can cause central and peripheral nervous system disease, including along both the afferent and efferent components of visual axis. Manifestations of disease and long-term sequela continue to be studied and described. Familiarity with the wide variety of neurologic, ophthalmic, and neuroradiologic presentations can promote prompt and appropriate treatment and continue building a framework to understand the underlying mechanism of disease.


Just who is at risk? The ethics of environmental regulation.
The willingness to view risk as part of daily life has vanished. A risk-averse mindset among environmental regulators engenders confusion between the ethics of intention and the ethics of consequence, leading to the elevation of the precautionary principle with unintended and often unfortunate outcomes. Environmental risk assessment is conservative, but the actual level of conservatism cannot be determined. High-end exposure assumptions and current toxicity criteria from the USEPA, based on linear extrapolation for carcinogens and default uncertainty factors for systemic toxicants, obscure the degree of conservatism in risk assessments. Ideally, one could choose a percentile of the target population to include within environmental standards, but this choice is complicated by the food, pharmaceutical and advertising industries, whose activities, inadvertent or not, often promote maladaptive and unhealthy lifestyle choices. There has lately been much discussion about background exposures and disease processes and their potential to increase the risk from environmental chemicals. Should these background exposures or disease processes, especially those associated with maladaptive individual choices, be included as part of a regulatory risk evaluation? A significant ethical question is whether environmental regulation should protect those pursuing a self-destructive lifestyle that may add to or synergize with otherwise innocuous environmental exposures. Choosing a target percentile of protection would provide an increased level of transparency and the flexibility to choose a higher or lower percentile if such a choice is warranted. Transparency and flexibility will lead to more responsive environmental regulation that balances protection of public health and the stewardship of societal resources.


Handedness is related to neural mechanisms underlying hemispheric lateralization of face processing.
While the right-hemispheric lateralization of the face perception network is well established, recent evidence suggests that handedness affects the cerebral lateralization of face processing at the hierarchical level of the fusiform face area (FFA). However, the neural mechanisms underlying differential hemispheric lateralization of face perception in right- and left-handers are largely unknown. Using dynamic causal modeling (DCM) for fMRI, we aimed to unravel the putative processes that mediate handedness-related differences by investigating the effective connectivity in the bilateral core face perception network. Our results reveal an enhanced recruitment of the left FFA in left-handers compared to right-handers, as evidenced by more pronounced face-specific modulatory influences on both intra- and interhemispheric connections. As structural and physiological correlates of handedness-related differences in face processing, right- and left-handers varied with regard to their gray matter volume in the left fusiform gyrus and their pupil responses to face stimuli. Overall, these results describe how handedness is related to the lateralization of the core face perception network, and point to different neural mechanisms underlying face processing in right- and left-handers. In a wider context, this demonstrates the entanglement of structurally and functionally remote brain networks, suggesting a broader underlying process regulating brain lateralization.


Management of Black Spot of Rose with Winter Fungicide Treatment.
Fungicides were evaluated for their efficacy against black spot of rose, caused by Diplocarpon rosae, when applied during winter months to hybrid tea rose plants in two studies. One study, conducted at two Auburn University campus sites, consisted of applications of horticultural oil, chlorothalonil plus an antitranspirant, and cyproconazole, along with nontreated plants; one site included triforine applications. Rose canes were treated two and three times between late October and February in 1996-97 and 1997-98, respectively; then plants were examined every 2 to 4 days beginning in mid-February for onset of symptoms of black spot. In both years, winter applications of fungicides (chlorothalonil, cyproconazole, and triforine) delayed disease onset compared with treatments without fungicides (nontreated and oil applications). Decreased plant defoliation, as well as improved plant vigor, were observed through the 1998 growing season following fungicidal winter treatments at campus sites; winter treatments with oil did not suppress disease compared with no treatment. In a second study started in November 1997, at a site near Shorter, AL, three systemic fungicides (myclobutanil, cyproconazole, and triforine) were applied to rose canes during the winter; nontreated plants were included. Decreased disease symptoms and defoliation of rose plants were observed early in the 1998 and 1999 seasons following winter applications of cyproconazole and triforine compared with myclobutanil or nontreated plants. Winter treatments with these fungicides did not consistently provide season-long reduction of black spot. However, season-long plant vigor and flower production on plants were improved at the Shorter site following winter applications of any of the above systemic fungicides compared with nontreated plants.


Diagnosis and management of Alzheimer disease.
Alzheimer disease afflicts millions of older Americans, with an estimated cost to society approaching $100 million annually. Family physicians will care for an increasing number of patients with Alzheimer disease as well as their caregivers and families. A comprehensive and systematic review of the literature published between 1985 and 1998 about diagnosing and treating Alzheimer disease was conducted, using "dementia," "Alzheimer's disease," and "treatment" as search strategy key words. Data and information that reported significant conclusions were critically reviewed. Potentially important new data about new agents that might be of benefit when caring for patients with Alzheimer disease are discussed. The primary goals when treating Alzheimer disease patients are enhancing autonomy and functional abilities and maintaining quality of life for patients and caregivers. In addition to diagnostic and pharmacologic treatment, primary care physicians will be called upon to provide nonpharmacologic support to assist with behavioral, social, and living environment problems faced by these patients and their families. The most common pharmacologic treatment is cholinesterase inhibition. Two cholinesterase inhibitors, tacrine and donepezil, are effective in treating cognitive and global function. Newer cholinesterase inhibitors should soon be available that might offer safety advantages as well as efficacy in treating behavioral and psychiatric symptoms related to Alzheimer disease. Other agents, including vitamin E, nonsteroidal anti-inflammatory drugs, estrogen, and Ginkgo biloba, are under investigation. Nonpharmacologic measures are important components in the management of Alzheimer disease. Support groups can help to diminish behavioral problems, maintain the patient's independence, and provide relief for caregivers and families.


Scanning electron microscopic study of Piper betle L. leaves extract effect against Streptococcus mutans ATCC 25175.
Previous studies have shown that Piper betle L. leaves extract inhibits the adherence of Streptococcus mutans to glass surface, suggesting its potential role in controlling dental plaque development. In this study, the effect of the Piper betle L. extract towards S. mutans (with/without sucrose) using scanning electron microscopy (SEM) and on partially purified cell-associated glucosyltransferase activity were determined. S. mutans were allowed to adhere to glass beads suspended in 6 different Brain Heart Infusion broths [without sucrose; with sucrose; without sucrose containing the extract (2 mg mL(-1) and 4 mg mL(-1)); with sucrose containing the extract (2 mg mL(-1) and 4 mg mL(-1))]. Positive control was 0.12% chlorhexidine. The glass beads were later processed for SEM viewing. Cell surface area and appearance and, cell population of S. mutans adhering to the glass beads were determined upon viewing using the SEM. The glucosyltransferase activity (with/without extract) was also determined. One- and two-way ANOVA were used accordingly. It was found that sucrose increased adherence and cell surface area of S. mutans (p<0.001). S. mutans adhering to 100 µm² glass surfaces (with/without sucrose) exhibited reduced cell surface area, fluffy extracellular appearance and cell population in the presence of the Piper betle L. leaves extract. It was also found that the extract inhibited glucosyltransferase activity and its inhibition at 2.5 mg mL(-1) corresponded to that of 0.12% chlorhexidine. At 4 mg mL(-1) of the extract, the glucosyltransferase activity was undetectable and despite that, bacterial cells still demonstrated adherence capacity. The SEM analysis confirmed the inhibitory effects of the Piper betle L. leaves extract towards cell adherence, cell growth and extracellular polysaccharide formation of S. mutans visually. In bacterial cell adherence, other factors besides glucosyltransferase are involved.


Update on the epidemiology of pulmonary nontuberculous mycobacterial infections.
For decades, the incidence of pulmonary nontuberculous mycobacteria (NTM) has been reported to be increasing, yet formal epidemiological evaluation of this notion has been lacking until recently. Defining the epidemiology of NTM has been more challenging than with Mycobacterium tuberculosis (MTB). Unlike MTB, NTM are soil and water organisms, and infection is thought to be acquired from the environment rather than transmitted from person-to-person, with very rare exceptions. Due to their nearly ubiquitous presence in municipal water supplies, exposure to NTM is common. Further, NTM can colonize the respiratory tract without causing disease. NTM disease is not reportable to public health authorities; therefore, epidemiological and surveillance data are not readily available. Nonetheless, the prevalence of pulmonary NTM disease has increased dramatically in the United States and globally over the past 3 decades. Mycobacterium avium complex (MAC) accounts for the majority of NTM infections worldwide, but there is significant regional variability of various species. Additionally, novel species have been implicated in several countries in NTM pulmonary disease.


Infection stage-dependent modulation of macrophage activation in Trypanosoma congolense-resistant and -susceptible mice.
The contribution of cytokines and chemokines to resistance and susceptibility to African trypanosomiasis remains controversial. In the present study, the levels of type I and type II cytokines and of the MCP-1 chemokine were compared during the early and late stages of Trypanosoma congolense infection in susceptible BALB/c and resistant C57BL/6 mice. Moreover, the status of macrophage activation was compared in these animals by analyzing the inducible nitric oxide synthase-arginase balance, tumor necrosis factor secretion, and expression of the FIZZ1 and YM genes. Data show that changing from a predominant type I cytokine environment in the early stage of infection to a predominant type II cytokine environment and an enhanced MCP-1 secretion in the late stage of infection correlates with resistance to T. congolense. Concomitantly, macrophage activation evolves from a classical to a predominant alternative phenotype. We further confirmed that the simultaneous occurrence of type I/type II cytokines in the early stage of infection in susceptible BALB/c mice, reflected by the presence of macrophages exhibiting a mixed classical/alternative activation phenotype, is associated with uncontrolled parasite growth and early death. Interleukin-4 (IL-4) and IL-13 signaling did not influence the susceptibility of BALB/c mice to T. congolense infection and interestingly were not the main trigger to alternative macrophage activation. In T. congolense-resistant C57BL/6 mice, our results corroborated the induction of FIZZ1 and YM gene expressions with the alternative pathway of macrophage activation. In susceptible BALB/c mice, however, YM but not FIZZ1 induction reflected the emergence of alternatively activated macrophages. Hence, the FIZZ1 and YM genes may be useful markers to discriminate between distinct populations of alternatively activated macrophages.


Complementary and conventional medicine use among youth with recurrent headaches.
To identify prevalence and patterns of complementary and alternative medicine (CAM) use among youth with recurrent headaches (HA) and evaluate associations with co-occurring health problems and limitations as well as with the use and expenditures for conventional medical care. Variables were constructed for youth aged 10 to 17 by using linked data from the 2007 National Health Interview Survey and the 2008 Medical Expenditures Panel Survey. Bivariate, logistic, and 2-part regression analyses were used. Of the 10.6% of youth experiencing HA, 29.6% used CAM, rising to 41% for the many HA sufferers who also experienced difficulties with emotions, concentration, behavior, school attendance, or daily activities. Biologically based products (16.2%) and mind-body therapies (13.3%) were most commonly used, especially by the 86.4% of youth with HA experiencing at least 1 other chronic condition. Compared with non-CAM users, youth with HA who used CAM also had higher expenditures for and use of most types of conventional care. CAM use is most common among youth with HA experiencing multiple chronic conditions and difficulties in daily functioning. Associations among CAM use, multiple chronic conditions, and higher use of conventional care highlight the need for medical providers to routinely ask about CAM use to meet the complex health needs of their patients and facilitate the optimal integration of care. Research is needed to identify models for coordinating complementary and conventional care within a medical home and to understand the health benefits or risks associated with CAM use in conjunction with conventional treatments for patients with HA.


[Metallic Elemental Analysis of Tibetan Herbal Medicines and Tibetan Medicine Preparations by Synchrotron Radiation X-Ray Fluorescence].
To discuss the relationship between metallic element and disease through determine the elementals in Tibetan Herbal Medicines and Tibetan Medicine Preparations that have obvious effect on hepatobiliary diseases by Synchrotron Radiation X-ray Source, then to reveal the substance foundation of pharmacological action. The results show that all the Tibetan Herbal Medicines used in the experiment have the 9 kinds of metallic elements of potassium(K), calcium(Ca), titanium(Ti), vanadium(V), chromium(Cr), manganese(Mn), ferrum(Fe), zinc(Zn) and lead(Pb), the content of the elements are in the ppb or ppm level though the element constitute and the content have obvious difference. Tibetan Medicine Preparations have another 6 kinds of metallic elements of nickel(Ni), copper(Cu), rubidium(Rb), mercury(Hg), cobalt(Co), gallium(Ga) and 1 kind of nonmetallic elements of arsenic(As) when compare with Herbal Medicines, and the element constitute and the content also have obvious difference. Take advantage of SR-XRF, the test gets the basic data of elements of Tibetan Herbal Medicines and Preparations, supply the scientific support to discuss the interaction of pharmacological mechanism and the metallic elements, and find the suitability of the technique for the metallic elements detection in Tibetan Medicines.


Hydrogels from Amorphous Calcium Carbonate and Polyacrylic Acid: Bio-Inspired Materials for "Mineral Plastics".
Given increasing environmental issues due to the large usage of non-biodegradable plastics based on petroleum, new plastic materials, which are economic, environmentally friendly, and recyclable are in high demand. One feasible strategy is the bio-inspired synthesis of mineral-based hybrid materials. Herein we report a facile route for an amorphous CaCO3 (ACC)-based hydrogel consisting of very small ACC nanoparticles physically cross-linked by poly(acrylic acid). The hydrogel is shapeable, stretchable, and self-healable. Upon drying, the hydrogel forms free-standing, rigid, and transparent objects with remarkable mechanical performance. By swelling in water, the material can completely recover the initial hydrogel state. As a matrix, thermochromism can also be easily introduced. The present hybrid hydrogel may represent a new class of plastic materials, the "mineral plastics".


Short-term Outcomes and Pregnancy Rate After Laparoscopic Fertility-Sparing Surgery for Borderline Ovarian Tumors: A Single-Institute Experience.
We investigated the short-term outcomes and pregnancy rate after a laparoscopic approach to fertility preservation in patients with borderline ovarian tumors (BOTs). Clinic-pathologic variants of patients with BOTs who underwent conservative surgery at the Tianjin Central Hospital of Obstetrics and Gynecology between January 2009 and July 2015 were retrospectively analyzed. Among 211 patients with BOTs, 74 (35.1%) received conservative surgery (44 cases using a laparoscopic approach and 30 cases using a laparotomy approach). The mean age of the laparotomy group was significantly younger than that of the laparoscopic group (P = 0.024). The maximal longitude of the tumor in the laparotomy group was significantly longer than that in the laparoscopic group (P < 0.001). The number of incomplete surgery cases in the laparoscopic group was significantly greater than that in the laparotomy group (P < 0.001). The 2 groups showed no significant differences in gravidity and parity before surgery, abnormality of serum tumor makers, tumor lateralities, ascites, histology, duration of follow-up, pregnancy rate after surgery, or postoperative recurrence. Total recurrent rate was 6.7% (5/74). Two cases in laparotomy group and 3 cases in laparoscopic group relapsed respectively. There was no significant difference of recurrent rate between the 2 groups. The total pregnant rate was 33.8% (25/74). Nine patients (30%) in the laparotomy group and 16 patients (36.4%) in the laparoscopic group became pregnant during follow-up respectively. There were no significant differences in the postoperative durations of pregnancy, pregnancy type, age at pregnancy, tumor lateralities, ascites, or type of pathology between 2 groups. The pregnancy rate of incomplete surgery cases in laparoscopic group was significantly higher than that of laparotomy group (P = 0.011). No recurrence occurred among the pregnant cases. A comprehensive laparoscopic surgery was not performed in incomplete surgery patients undergoing complete exploration. Good short-term outcomes and pregnancy were observed in patients receiving conservative laparoscopic surgery for BOTs, especially in patients receiving incomplete conservative laparoscopic surgery.


Vaccination delays Maedi-Visna lentivirus infection in a naturally-infected sheep flock.
The Maedi-Visna (MV) lentivirus causes two slowly progressive eventually fatal diseases of sheep, Maedi, a progressive interstitial pneumonia, and Visna, a progressive demyelinating disease of the central nervous system. Other lentiviruses also cause fatal slow infections in their natural hosts, e.g. the HIV virus in humans. Results of experimental vaccination against any lentivirus where vaccinees are challenged by natural routes, may therefore be of general interest. From 1991-1998 experiments with formalin-inactivated whole Maedi-Visna virus vaccine were carried out in the Department of Microbiology at the University of Iceland. Western Blot tests showed good immune response to all major proteins of the virus. When aluminium hydroxide was added to the vaccine all vaccinees developed neutralizing antibodies to the vaccine strain at titers 1/8 - 1/256. After housing 5 twin pairs, one twin in each pair vaccinated, the other unvaccinated, with infected sheep for 4 years, all the unvaccinated twins became infected, but only 2 of their vaccinated siblings as confirmed by virus cultivation experiments on tissues from their lungs spleens lymph nodes and choroid plexuses. One twin in each of 40 female twin pairs, born into a Maedi-Visna-infected sheep flock and kept under natural farming conditions in Cyprus, was vaccinated at birth, 3 weeks and 3 months, with formalin-inactivated whole Maedi-Visna lentivirus vaccine adjuvanted with aluminium hydroxide. 17 mothers of the twins were seronegative, 13 seroconverting and 10 had old infection. Of 17 vaccinees born to seronegative mothers 9 were uninfected at 28 months, but only 2 of their unvaccinated siblings. Of 13 unvaccinated twins born to seroconverting mothers, 12 caught infection during their first 10 weeks, but only 4 of their vaccinated siblings. Vaccination had no effects on 10 vaccinees born to mothers with long-standing Maedi-Visna infections and broad andibody response at birth of their lambs. Compared with their unvaccinated siblings, natural infection was delayed in significant number of vaccinated twins born by seronegative and seroconverting mothers and vaccinated at birth, 3 weeks and 3 months with formalin inactivated whole MV vaccine adjuvanted with aluminium hydroxide. Maternal antibodies interfered with vaccination so early in life if the mother had old infection.


Animal genomics and infectious disease resistance in poultry.
Avian pathogens are responsible for major costs to society, both in terms of huge economic losses to the poultry industry and their implications for human health. The health and welfare of millions of birds is under continued threat from many infectious diseases, some of which are increasing in virulence and thus becoming harder to control, such as Marek's disease virus and avian influenza viruses. The current era in animal genomics has seen huge developments in both technologies and resources, which means that researchers have never been in a better position to investigate the genetics of disease resistance and determine the underlying genes/mutations which make birds susceptible or resistant to infection. Avian genomics has reached a point where the biological mechanisms of infectious diseases can be investigated and understood in poultry and other avian species. Knowledge of genes conferring disease resistance can be used in selective breeding programmes or to develop vaccines which help to control the effects of these pathogens, which have such a major impact on birds and humans alike.


Metabolic syndrome and the risk of placental dysfunction.
Placental dysfunction (PD), which may manifest partly as the hypertensive disorders of pregnancy and abruption or infarction of the placenta, occurs more commonly in women with obesity, chronic hypertension, diabetes mellitus, and dyslipidemia-each a major feature of the metabolic syndrome. However, the relationship between the metabolic syndrome and the future risk of PD or fetal demise is unknown. We completed a retrospective cohort study of 1.03 million women who had a first documented delivery in the province of Ontario between 1990 and 2002. Using linked administrative databases, we categorized women as having zero, one, two, or three to four features of the metabolic syndrome up to 24 months before their index delivery hospitalization. Women were considered to have placental dysfunction if they had a diagnosis of preeclampsia, gestational hypertension, placental abruption, or placental infarction during their first hospitalization for delivery in the period of study. At the time of delivery, 75 380 women (7.3%) were diagnosed as having PD. There was a progressive increase in the risk of PD in women with one (adjusted odds ratio [OR] 3.1; 95% confidence interval [CI] 3.0-3.1), two (OR 5.5; 95% CI 5.2-5.8), or three to four (OR 7.7; 95% CI 6.7-8.9) features of the metabolic syndrome, compared with none. A similar gradient effect was seen for the combined outcome of PD with poor fetal growth, or of PD with concomitant fetal death. Women who exhibit features of the metabolic syndrome before pregnancy have a higher graded risk of PD and fetal demise. Studies are needed to determine whether modifying a woman's metabolic profile before pregnancy, through modest caloric restriction and increased physical activity, can lower her future risk of PD.


Combined kinematic cup alignment reduces the rate of impingement and edge loading compared to mechanical and anatomical alignment. An in-vitro case-control study.
In recent years, different alignments have been described for acetabular components in total hip arthroplasty (THA), to reduce the risk of impingement and edge loading. Currently there are 3 main options: mechanical (40° inclination/15° anteversion relative to the anterior pelvic plane), anatomic (40° inclination/anteversion parallel to the transverse ligament) and combined kinematic (according to spinal-pelvic parameters). There are no studies comparing all three in terms of impingement and edge loading. We therefore performed a retrospective case-control in-vitro study comparing risk of impingement and edge loading between the three alignments. The study hypothesis was that combined kinematic alignment incurs significantly less risk of impingement and edge loading than do the other two types of alignment. Using a THA planning system, we simulated the 3 alignments for 90 patients undergoing THA with a ceramic-on-ceramic bearing between November 2019 and January 2022; for each simulation, we recorded any prosthetic impingement or edge loading. The study endpoint was the rate of prosthetic impingement or edge loading between the 3 alignments. With the mechanical alignment, 31% of patients (28/90) showed risk of impingement and 22% (20/90) risk of edge loading. With the anatomic alignment, 31% of patients (28/90) showed risk of impingement and 23.3% (21/90) risk of edge loading. With the combined kinematic alignment, 12.2% of patients (11/90) showed risk of impingement and 8.9% (8/90) risk of edge loading. Pairwise comparison showed that the combined kinematic alignment was associated with significantly less impingement and edge loading than the mechanical alignment (respectively, p=0.03 and p=0.022) or the anatomic alignment (respectively, p=0.03 and p=0.014), while the mechanical and anatomic alignments did not differ. A combined kinematic cup alignment in THA significantly reduced the risk of impingement and edge loading compared to mechanical and anatomic alignments. III, retrospective case-control study.


Prevalence of type 2 diabetes and impaired glucose regulation with associated cardiometabolic risk factors and depression in an urbanizing rural community in bangladesh: a population-based cross-sectional study.
To determine the prevalence of type 2 diabetes (T2DM) and impaired glucose regulation (impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]) in an urbanizing rural population of Bangladesh and associated cardiometabolic risk indicators and depression. A total of 2,293 subjects aged ≥20 years in an urbanizing rural Bangladeshi community were investigated. Socio-demographic and anthropometric details, blood pressure, fasting plasma glucose (FPG), 2 hours after 75 g plasma glucose (2hPG), glycosylated hemoglobin, fasting serum insulin and lipid profiles were studied. Presence of depressive symptoms using Montogomery-Asberg Depression Rating Scale was also assessed. The prevalence of IFG, IGT, IFG+IGT, and T2DM were 3.4%, 4.0%, 1.2%, and 7.9%, respectively. The prevalence of T2DM and impaired glucose regulation differed between males and females, but, both increased with age in both sexes. FPG and 2hPG had positive correlation. Employing logistic regression, it was found that increased age, waist to hip ratio, systolic blood pressure, total cholesterol, triglycerides, and depression were independent risk indicators for diabetes. Both insulin resistance and β-cell deficiency were significantly related for causation of diabetes. Among the study population, 26.2% had general obesity, 39.8% central obesity, 15.5% hypertension, 28.7% dyslipidemia, 17.6% family history of diabetes, and 15.3% had depression. Physical inactivity and smoking habits were significantly higher in male. Rising prevalence of diabetes and impaired glucose regulation in this urbanizing rural population exist as a significant but hidden public health problem. Depression and other cardiometabolic risk indicators including obesity, hypertension, and dyslipdemia were also prevalent in this population.


Repeatability of muscle synergies within and between days for typically developing children and children with cerebral palsy.
Muscle synergies are typically calculated from electromyographic (EMG) signals using nonnegative matrix factorization. Synergies identify weighted groups of muscles that are commonly activated together during a task, such as walking. Synergy analysis has become an emerging tool to evaluate neuromuscular control; however, the repeatability of synergies between trials and days has not been evaluated. The goal of this study was to evaluate the repeatability of synergy complexity and structure in unimpaired individuals and individuals with cerebral palsy (CP). EMG data were collected from eight lower-limb muscles during gait for six typically developing (TD) children and five children with CP on two separate days, over three walking speeds. To evaluate synergy complexity, we calculated the total variance accounted for by one synergy (tVAF1). On a given day, the average range in tVAF1 between gait cycles was 18.2% for TD and 19.1% for CP. The average standard deviation in tVAF1 between gait cycles was 4.9% for TD and 5.0% for CP. Average tVAF1 calculated across gait cycles was not significantly different between days for TD or CP participants. Comparing synergy structure, the average (standard deviation) within day correlation coefficients of synergy weights for two or more synergies were 0.89 (0.15) for TD and 0.88 (0.15) for CP. Between days, the average correlation coefficient of synergy weights for two or more synergies was greater than 0.89 for TD and 0.74 for CP. These results demonstrate that synergy complexity and structure averaged over multiple gait cycles are repeatable between days in both TD and CP groups.


Defective microglial development in the hippocampus of Cx3cr1 deficient mice.
Microglial cells participate in brain development and influence neuronal loss and synaptic maturation. Fractalkine is an important neuronal chemokine whose expression increases during development and that can influence microglia function via the fractalkine receptor, CX3CR1. Mice lacking Cx3cr1 show a variety of neuronal defects thought to be the result of deficient microglia function. Activation of CX3CR1 is important for the proper migration of microglia to sites of injury and into the brain during development. However, little is known about how fractalkine modulates microglial properties during development. Here we examined microglial morphology, response to ATP, and K(+) current properties in acute brain slices from Cx3cr1 knockout mice across postnatal hippocampal development. We found that fractalkine signaling is necessary for the development of several morphological and physiological features of microglia. Specifically, we found that the occurrence of an outward rectifying K(+) current, typical of activated microglia, that peaked during the second and third postnatal week, was reduced in Cx3cr1 knockout mice. Fractalkine signaling also influenced microglial morphology and ability to extend processes in response to ATP following its focal application to the slice. Our results reveal the developmental profile of several morphological and physiological properties of microglia and demonstrate that these processes are modulated by fractalkine signaling.


Effect of zilpaterol hydrochloride supplementation on cutability and subprimal yield of beef steer carcasses.
Beef steers (n = 11,877) from 7 studies were fed zilpaterol hydrochloride (ZH) for 0 or 20 to 40 d before slaughter to determine the effects of ZH on subprimal weight and yield. Carcasses were selected based on mean HCW of treatment groups for fabrication into boneless, closely trimmed, or denuded subprimals, lean, fat, and bone. Data from the 7 trials were pooled for statistical analysis. Feeding ZH increased (P < 0.05) weights of all major subprimals compared with steers not supplemented with ZH. Also, subprimals from the hindquarter, including valuable cuts like the tenderloin, strip loin, and top sirloin butt, increased (P < 0.05) as a percentage of cold carcass weight from steers fed ZH. The tenderloin was 0.06 percentage units greater (P < 0.05), the strip loin was 0.08 percentage units greater (P < 0.05), and the top sirloin butt was 0.11 percentage units greater (P < 0.05) in ZH-fed steers when compared with steers not fed ZH. Supplementation of ZH greatly increased (P < 0.05) total saleable carcass yield by 1.76 percentage units, whereas ZH inclusion decreased (P < 0.05) the percentage of fat trim and bone by 0.58 and 1.10 percentage units, respectively. Therefore, ZH can be utilized by the beef industry to improve red meat yield efficiency throughout the beef production chain.


A microfluidic device that forms and redirects pheromone gradients to study chemotropism in yeast.
Chemotropism, or directed cell growth in response to a chemical gradient, is integral to many biological processes. The mating response of the budding yeast, Saccharomyces cerevisiae, is a well studied model chemotropic system. Yeast cells of opposite mating type signal their positions by secreting soluble mating pheromones. The mutual exchange of pheromones induces the cells to grow towards one another, resulting in mating projections or "shmoos." Yeast cells exhibit a remarkable ability to orient their growth toward the nearest potential mating partner, and to reorient (i.e., bend their mating projections) in response to a change in the direction of the pheromone gradient. Although a number of microfluidic devices have been used to generate linear pheromone gradients and to measure initial orientation, none of them have the capability to change the direction of the gradient, other than to invert it. We have developed a microfluidic device that can produce stable pheromone gradients and rapidly rotate them in 90° increments, mimicking the dynamic gradients yeast are exposed to in situ, and allowing for the study of reorientation as well as initial orientation. The mean angle of orientation exhibited by gradient-stimulated yeast cells in this device was 56.9°. In control experiments, cells subjected to pheromone coming from all four directions showed no evidence of orientation. Switching the direction of the pheromone source by 90° induced 83.6% of the polarized cells to change their direction of growth. Of these, 85.2% bent their mating projections toward the second source, demonstrating the utility of this device in the study of reorientation with specifically controlled gradients.


Acute Abdominal Pain Assessment in the Emergency Department: The Experience of a Greek University Hospital.
Acute abdominal pain (AAP) is a common symptom in the emergency department (ED). Because abdominal pain can be caused by a wide spectrum of underlying pathology, evaluation of abdominal pain in the ED requires a comprehensive approach, based on patient history, physical examination, laboratory tests and imaging studies. The aim of this study was to investigate predictive factors for admission to the hospital in patients who presented to the ED with AAP as the main symptom. This prospective observational study enrolled 125 patients who presented with AAP in the ED of the Patras University Hospital in western Greece. The sample of patients who enrolled in the study was representative of patients who receive care in this academic institution. All patients underwent clinical examination, laboratory testing and radiological assessment. Clinical and laboratory data were analyzed in an attempt to identify clinical or laboratory factors predicting hospital admission. Based on clinical, laboratory and radiologic evaluation, 37.6% of patients enrolled in the study were admitted to the hospital, whereas 62.4% were not admitted. Compared to patients who were not admitted, patients admitted to the hospital had higher age and significantly higher inflammatory markers, white blood count and C-reactive protein (CRP). Binary logistic regression analysis showed that abnormal imaging findings (odds ratio (OR) = 6.47, 95% confidence interval (CI): 2.11 - 19.77, P < 0.001) and elevated serum CRP levels (OR = 6.24, 95% CI: 2.16 - 18.03, P < 0.001) were significant predictive factors for hospital admission. Assessment of AAP remains a challenging problem in the ED. Comprehensive history combined with detailed clinical examination, appropriate laboratory testing and radiologic imaging facilitates effective assessment of patients who present in the ED with AAP and guides the decision to admit patients to the hospital for further care.


Postpartum contraceptive use among adolescent mothers in seven states.
To describe postpartum contraceptive use among adolescent mothers and assess the hypothesis that receipt of prenatal contraceptive counseling or a postpartum checkup is associated with the use of more effective methods. Data are from the Pregnancy Risk Assessment and Monitoring System for seven states and the city of New York for the years 2006-2008. The sample comprises 3,207 adolescent mothers aged 15-19 years. We conducted descriptive and multinomial logistic regression analyses. The outcome measure was the type of contraceptive method used at the time of the survey. Nineteen percent of adolescent mothers, more than half of whom were sexually active, were using no contraception at the time of the survey. The remaining 81% were using a contraceptive method. Use of long-acting reversible contraception (LARC) was low-11% were using an intrauterine device, and only 1% were using an implant. Receipt of prenatal contraceptive counseling and receipt of a postpartum checkup were both associated with a decreased likelihood of having sex without contraception. A postpartum checkup was also associated with an increased likelihood of using medium-acting contraceptives (injectables, ring, or patch) and a decreased likelihood of relying on condoms. Prenatal contraceptive counseling was also associated with an increased likelihood of pill use. Given the demonstrated association between LARC use and decreased rates of rapid repeat pregnancy, efforts should be made to increase adolescent mothers' access to LARC. Enhancing the scope and quality of prenatal contraceptive counseling and increasing the proportion of adolescent mothers who return for a postpartum checkup may also improve postpartum contraceptive use.


Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital.
Very few data exist on risk factors for developing biofilm-forming Candida bloodstream infection (CBSI) or on variables associated with the outcome of patients treated for this infection. We identified 207 patients with CBSI, from whom 84 biofilm-forming and 123 non biofilm-forming Candida isolates were recovered. A case-case-control study to identify risk factors and a cohort study to analyze outcomes were conducted. In addition, two sub-groups of case patients were analyzed after matching for age, sex, APACHE III score, and receipt of adequate antifungal therapy. Independent predictors of biofilm-forming CBSI were presence of central venous catheter (odds ratio [OR], 6.44; 95% confidence interval [95% CI], 3.21-12.92) or urinary catheter (OR, 2.40; 95% CI, 1.18-4.91), use of total parenteral nutrition (OR, 5.21; 95% CI, 2.59-10.48), and diabetes mellitus (OR, 4.47; 95% CI, 2.03-9.83). Hospital mortality, post-CBSI hospital length of stay (LOS) (calculated only among survivors), and costs of antifungal therapy were significantly greater among patients infected by biofilm-forming isolates than those infected by non-biofilm-forming isolates. Among biofilm-forming CBSI patients receiving adequate antifungal therapy, those treated with highly active anti-biofilm (HAAB) agents (e.g., caspofungin) had significantly shorter post-CBSI hospital LOS than those treated with non-HAAB antifungal agents (e.g., fluconazole); this difference was confirmed when this analysis was conducted only among survivors. After matching, all the outcomes were still favorable for patients with non-biofilm-forming CBSI. Furthermore, the biofilm-forming CBSI was significantly associated with a matched excess risk for hospital death of 1.77 compared to non-biofilm-forming CBSI. Our data show that biofilm growth by Candida has an adverse impact on clinical and economic outcomes of CBSI. Of note, better outcomes were seen for those CBSI patients who received HAAB antifungal therapy.


Ion channel gene therapy for smooth muscle disorders: relaxing smooth muscles to treat erectile dysfunction.
The promise of gene therapy to treat diseases remains largely unfulfilled. Past setbacks and the complexity of the delivery systems used, in terms of both targeting the appropriate cells and inducing expression of products at therapeutic levels, thus far have prevented significant success for gene therapy. Smooth muscle disorders represent a unique target for gene therapy. In many cases, smooth muscle is readily accessible and, to induce a therapeutic effect, will not require very high levels of gene product expression. This allows a lower efficiency of gene transfer to be successful. With these important features in mind, we believe that naked DNA transfer of potassium ion channels represents a novel and successful way to treat smooth muscle disorders. Herein, we present a rationale for treating erectile dysfunction, a smooth muscle disorder of the cavernosal bodies of the penis, with naked DNA gene transfer therapy. By inserting the hSlo gene, which codes for Maxipotassium channels, into smooth muscle cells, we can improve smooth muscle relaxation in the corporal bodies and thus improve erectile function. This method of gene transfer has proven to be safe and effective for erectile dysfunction, and human trials are ongoing.


Important messages in the 'post': recent discoveries in 5-HT neurone feedback control.
The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) mediates important brain functions and contributes to the pathophysiology and successful drug treatment of many common psychiatric disorders, especially depression. It is established that a key mechanism involved in the control of 5-HT neurones is feedback inhibition by presynaptic 5-HT autoreceptors, which are located on 5-HT cell bodies and nerve terminals. However, recent experiments have discovered an unexpected complexity of 5-HT neurone control, specifically in the form of postsynaptic 5-HT feedback mechanisms. These mechanisms have the physiological effects of 5-HT autoreceptors but use additional 5-HT receptor subtypes and operate through neural inputs to 5-HT neurones. A postsynaptic feedback system that excites 5-HT neurones has also been reported. This article discusses current knowledge of the pharmacology and physiology of these new found 5-HT feedback mechanisms and considers their possible contribution to depression pathophysiology and utility as a resource of novel antidepressant drug strategies.


Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.
Alpha herpesvirus genomes encode the capacity to establish quiescent infections (i.e. latency) in the peripheral nervous system for the life of their hosts. Multiple times during latency, viral genomes can reactivate to start a productive infection, enabling spread of progeny virions to other hosts. Replication of alpha herpesviruses is well studied in cultured cells and many aspects of productive replication have been identified. However, many questions remain concerning how a productive or a quiescent infection is established. While infections in vivo often result in latency, infections of dissociated neuronal cultures in vitro result in a productive infection unless lytic viral replication is suppressed by DNA polymerase inhibitors or interferon. Using primary peripheral nervous system neurons cultured in modified Campenot tri-chambers, we previously reported that reactivateable, quiescent infections by pseudorabies virus (PRV) can be established in the absence of any inhibitor. Such infections were established in cell bodies only when physically isolated axons were infected at a very low multiplicity of infection (MOI). In this report, we developed a complementation assay in compartmented neuronal cultures to investigate host and viral factors in cell bodies that prevent establishment of quiescent infection and promote productive replication of axonally delivered genomes (i.e. escape from silencing). Stimulating protein kinase A (PKA) signaling pathways in isolated cell bodies, or superinfecting cell bodies with either UV-inactivated PRV or viral light particles (LP) promoted escape from genome silencing and prevented establishment of quiescent infection but with different molecular mechanisms. Activation of PKA in cell bodies triggers a slow escape from silencing in a cJun N-terminal kinase (JNK) dependent manner. However, escape from silencing is induced rapidly by infection with UVPRV or LP in a PKA- and JNK-independent manner. We suggest that viral tegument proteins delivered to cell bodies engage multiple signaling pathways that block silencing of viral genomes delivered by low MOI axonal infection.


Plasmodium vivax and Plasmodium falciparum infection dynamics: re-infections, recrudescences and relapses.
In malaria endemic populations, complex patterns of Plasmodium vivax and Plasmodium falciparum blood-stage infection dynamics may be observed. Genotyping samples from longitudinal cohort studies for merozoite surface protein (msp) variants increases the information available in the data, allowing multiple infecting parasite clones in a single individual to be identified. msp genotyped samples from two longitudinal cohorts in Papua New Guinea (PNG) and Thailand were analysed using a statistical model where the times of acquisition and clearance of each clone in every individual were estimated using a process of data augmentation. For the populations analysed, the duration of blood-stage P. falciparum infection was estimated as 36 (95% Credible Interval (CrI): 29, 44) days in PNG, and 135 (95% CrI 94, 191) days in Thailand. Experiments on simulated data indicated that it was not possible to accurately estimate the duration of blood-stage P. vivax infections due to the lack of identifiability between a single blood-stage infection and multiple, sequential blood-stage infections caused by relapses. Despite this limitation, the method and data point towards short duration of blood-stage P. vivax infection with a lower bound of 24 days in PNG, and 29 days in Thailand. On an individual level, P. vivax recurrences cannot be definitively classified into re-infections, recrudescences or relapses, but a probabilistic relapse phenotype can be assigned to each P. vivax sample, allowing investigation of the association between epidemiological covariates and the incidence of relapses. The statistical model developed here provides a useful new tool for in-depth analysis of malaria data from longitudinal cohort studies, and future application to data sets with multi-locus genotyping will allow more detailed investigation of infection dynamics.


Mutational analysis of the sbo-alb locus of Bacillus subtilis: identification of genes required for subtilosin production and immunity.
The Bacillus subtilis 168 derivative JH642 produces a bacteriocin, subtilosin, which possesses activity against Listeria monocytogenes. Inspection of the amino acid sequence of the presubtilosin polypeptide encoded by the gene sboA and sequence data from analysis of mature subtilosin indicate that the precursor subtilosin peptide undergoes several unique and unusual chemical modifications during its maturation process. The genes of the sbo-alb operon are believed to function in the synthesis and maturation of subtilosin. Nonpolar mutations introduced into each of the alb genes resulted in loss or reduction of subtilosin production. sboA, albA, and albF mutants showed no antilisterial activity, indicating that the products of these genes are critical for the production of active subtilosin. Mutations in albB, -C, and -D resulted in reduction of antilisterial activity and decreased immunity to subtilosin, particularly under anaerobic conditions. A new gene, sboX, encoding another bacteriocin-like product was discovered residing in a sequence overlapping the coding region of sboA. Construction of an sboX-lacZ translational fusion and analysis of its expression indicate that sboX is induced in stationary phase of anaerobic cultures of JH642. An in-frame deletion of the sboX coding sequence did not affect the antilisterial activity or production of or immunity to subtilosin. The results of this investigation show that the sbo-alb genes are required for the mechanisms of subtilosin synthesis and immunity.