Validation of a bovine rectal palpation simulator for training veterinary students.
Bovine rectal palpation is a necessary skill for a veterinary student to learn. However, lack of resources and welfare issues currently restrict the amount of training available to students in this procedure. Here we present a virtual reality based teaching tool -- the Bovine Rectal Palpation Simulator -- that has been developed as a supplement to existing training methods. When using the simulator, the student palpates virtual objects representing the bovine reproductive tract, receiving feedback from a PHANToM haptic device (inside a fibreglass model of a cow), while the teacher follows the student's actions on the monitor and gives instruction. We present a validation experiment that compares the performance of a group of traditionally trained students with a group whose training was supplemented with a simulator training session. The subsequent performance in the real task, when examining cows for the first time, was assessed with the results showing a significantly better performance for the simulator group.


Racial and ethnic differences in breast cancer survival: how much is explained by screening, tumor severity, biology, treatment, comorbidities, and demographics?
The reasons for race/ethnicity (R/E) differences in breast cancer survival have been difficult to disentangle. Surveillance, Epidemiology, and End Results (SEER)-Medicare data were used to identify 41,020 women aged > or =68 years with incident breast cancer between 1994-1999 including African American (2479), Hispanic (1172), Asian/Pacific Island (1086), and white women (35,878). A Cox proportional hazards model assessed overall and stage-specific (0/I, II/III, and IV) R/E differences in breast cancer survival after adjusting for mammography screening, tumor characteristics at diagnosis, biologic markers, treatment, comorbidity, and demographics. African American women had worse survival than white women, although controlling for predictor variables reduced this difference among all stage breast cancer (hazards ratio [HR], 1.08; 95% confidence interval [95% CI], 0.97-1.20). Adjustment for predictors reduced, but did not eliminate, disparities in the analysis limited to women diagnosed with stage II/III disease (HR, 1.30; 95% CI, 1.10-1.54). Screening mammography, tumor characteristics at diagnosis, biologic markers, and treatment each produced a similar reduction in HRs for women with stage II/III cancers. Asian and Pacific Island women had better survival than white women before and after accounting for all predictors (adjusted all stages HR, 0.61 [95% CI, 0.47-0.79]; adjusted stage II/III HR, 0.61 [95% CI, 0.47-0.79]). Hispanic women had better survival than white women in all and stage II/III analysis (all stage HR, 0.88; 95% CI, 0.75-1.04) and stage II/III analysis (HR, 0.88; 95% CI, 0.75-1.04), although these findings did not reach statistical significance. There was no significant difference in survival by R/E noted among women diagnosed with stage IV disease. Predictor variables contribute to, but do not fully explain, R/E differences in breast cancer survival for elderly American women. Future analyses should further investigate the role of biology, demographics, and disparities in quality of care.


Molecular phylogeny of Chloropseidae and Irenidae - cryptic species and biogeography.
Chloropseidae (Leafbirds) and Irenidae (Fairy-bluebirds) are colourful Oriental birds, which have been placed as a deep (old) branch in the radiation of passeroid songbirds. We present a densely sampled molecular phylogeny of the two families based on two nuclear introns (GAPDH and ODC) and two mitochondrial genes (ND3 and cyt-b) largely stemming from old museum specimens. Our results show that several subspecies within both Chloropseidae and Irenidae are genetically distinct and separated in the Miocene some 10-11Million years ago (Mya), indicating a substantial underestimation of species numbers within the two families. Based on our molecular findings, plumage distinctiveness and contemporary distributions we propose that several subspecies be recognised at the species level. Furthermore, we use the molecular data to examine biogeographical patterns of the two families in the light of historical geological re-arrangements in the region. The results indicate that the Philippines were colonised in the Pliocene and that colonisation probably progressed via the Sulu islands from Borneo and not via Palawan, which was first colonised in the Pleistocene.


The fecal viral flora of wild rodents.
The frequent interactions of rodents with humans make them a common source of zoonotic infections. To obtain an initial unbiased measure of the viral diversity in the enteric tract of wild rodents we sequenced partially purified, randomly amplified viral RNA and DNA in the feces of 105 wild rodents (mouse, vole, and rat) collected in California and Virginia. We identified in decreasing frequency sequences related to the mammalian viruses families Circoviridae, Picobirnaviridae, Picornaviridae, Astroviridae, Parvoviridae, Papillomaviridae, Adenoviridae, and Coronaviridae. Seventeen small circular DNA genomes containing one or two replicase genes distantly related to the Circoviridae representing several potentially new viral families were characterized. In the Picornaviridae family two new candidate genera as well as a close genetic relative of the human pathogen Aichi virus were characterized. Fragments of the first mouse sapelovirus and picobirnaviruses were identified and the first murine astrovirus genome was characterized. A mouse papillomavirus genome and fragments of a novel adenovirus and adenovirus-associated virus were also sequenced. The next largest fraction of the rodent fecal virome was related to insect viruses of the Densoviridae, Iridoviridae, Polydnaviridae, Dicistroviriade, Bromoviridae, and Virgaviridae families followed by plant virus-related sequences in the Nanoviridae, Geminiviridae, Phycodnaviridae, Secoviridae, Partitiviridae, Tymoviridae, Alphaflexiviridae, and Tombusviridae families reflecting the largely insect and plant rodent diet. Phylogenetic analyses of full and partial viral genomes therefore revealed many previously unreported viral species, genera, and families. The close genetic similarities noted between some rodent and human viruses might reflect past zoonoses. This study increases our understanding of the viral diversity in wild rodents and highlights the large number of still uncharacterized viruses in mammals.


Bee Pollen Extracts Modulate Serum Metabolism in Lipopolysaccharide-Induced Acute Lung Injury Mice with Anti-Inflammatory Effects.
Bee pollen (BP) collected from different floras possesses various potential bioactivities, but the mechanism-related research on anti-inflammatory effects is limited. Here, three types of BP originating from Camellia sinensis L. (BP-Cs), Nelumbo nucifera Gaertn. (BP-Nn), and Brassica campestris L. (BP-Bc) were assessed using molecular and metabolomics methods to determine their anti-inflammatory effects. The differences in polyphenolic abundance of three types of BP extracts were determined by HPLC-DAD/Q-TOF-MS. In vitro anti-inflammatory effects of three BP extracts were evaluated in a lipopolysaccharide (LPS)-induced RAW 264.7 cells model. BP-Cs extract with the most abundant polyphenols was found to be the most effective in reducing inflammation by downregulating inflammatory-related genes expression and blocking the activation of MAPK and NF-κB signaling pathways. Polyphenol-rich BP-Cs was further evaluated for their in vivo anti-inflammatory effect in a LPS-induced acute lung injury mouse model. An UPLC-Q-TOF/MS-based metabolomics approach was applied to analyze metabolite changes in mouse serum. Weshowed that the pretreated BP-Cs extract alleviated inflammation and regulated glycerophospholipid metabolism significantly. Our findings provide a foundation for developing and justifying BP as a potential anti-inflammatory ingredient in functional foods or nutraceutical formulations.


Nucleotide sequences specific for Tn1545-like conjugative transposons in pneumococci and staphylococci resistant to tetracycline.
The distributions of tet(M) and conjugative transposons related to Tn1545 were studied by hybridization in 47 clinical isolates of Streptococcus pneumoniae resistant to tetracycline. Resistance to tetracycline was always associated with resistance to minocycline and was due to the presence of the tet(M) gene. Association of tet(M) with int-Tn, the gene encoding the protein required for the movements of Tn1545-like transposons, was found in all but one strain of S. pneumoniae. In contrast, int-Tn was detected in only 2 of 37 strains of Staphylococcus spp. harboring tet(M).


Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study.
Patients with osteoarthritis (OA) take a variety of health supplements in an attempt to reduce pain and improve function. The aim of this study was to determine the efficacy of methylsulfonylmethane (MSM) in treating patients with knee OA. This study was a prospective, randomized, double-blind, controlled clinical trial. Forty nine men and women 45-90 (mean 68 ± SD 7.3) years of age with knee OA according to the American College of Rheumatology clinical criteria for OA of the knee and with radiographic confirmed knee OA were enrolled in the study and randomly assigned into 2 groups: One received MSM in doses of 1.125 grams 3 times daily for 12 weeks and the other received a placebo in the same dosing frequency. The primary outcomes were the WOMAC Osteoarthritis Index for pain, stiffness and physical function, the Aggregated Locomotor Function (ALF) test that evaluates each patient's physical function, the SF-36 quality of life health survey and the visual-analogue-scale (VAS) for pain. The secondary outcomes were Knee Society Clinical Rating System for Knee Score (KSKS) and Function Score (KSFS). Patients were assessed at baseline, 6 weeks and 12 weeks. All continuous variables were tested by the Kolmogorov-Smirnov test for Normal distribution. Changes within the groups and differences between the groups were calculated by repeated measures of analysis (ANOVA) with one nested variable. There were significant differences between treatment groups over time in WOMAC physical function (14.6 mm [CI: 4.3, 25.0]; p = 0.04) and in WOMAC total score (15.0 mm [CI: 5.1, 24.9]; p = 0.03). Treatment groups did not differ significantly in WOMAC pain (12.4 mm [CI: 0.0, 24.8]); p = 0.08) or WOMAC stiffness (27.2 mm [CI: 8.2, 46.2]; p = 0.08). There was a non-significant difference in SF-36 total score between treatment groups (11.6 [CI: 1.0, 22.1]; p = 0.54). A significant difference was found between groups in VAS for pain (0.7 s [CI: -0.9, 2.4]; p = 0.05). Secondary outcomes showed non-significant differences between the two groups. Patients with OA of the knee taking MSM for 12 weeks showed an improvement in pain and physical function. These improvements, however, are small and it is yet to be determined if they are of clinical significance. ClinicalTrials.gov: NCT01188213.


Mini-open lateral retro-pleural thoracic corpectomy for osteomyelitis.
Thoracic vertebral body corpectomy with associated deformity and neural element compression can be challenging. Multiple approaches have been proposed including trans-pedicular, costotransversectomy and trans-thoracic. Approach related pitfalls, nuances, morbidity and complication profile differ with each technique. A mini-open retro-pleural approach provides great access to bony pathology and neural elements without the need to violate the thoracic cavity or chest-tube placement postoperatively. Here we present a 56-year-old male with progressive back pain and suspected osteomyelitis/discitis at T-9 & T-10 who presented with progressive deformity and failure of empiric antibiotic treatment. He underwent a two-level lateral corpectomy. The technique and operative nuances to a lateral retro-pleural approach to thoracic corpectomy are presented. Important surgical concepts such as patient positioning, appropriate use of intraoperative fluoroscopy, regional anatomy, postoperative care and pitfalls are outlined. Emphasis is made on a true lateral approach, posterior rib resection, wide retro-pleural dissection and preservation of the parietal pleura as you descent on to the vertebral body. Identifying the correct plane of dissection, timely corpectomy, placement of expandable cage and correction of deformity are discussed. Water-tight closure with removal of retro-pleural air utilizing an intra-operative water-seal technique using a red-rubber catheter is shown. Nuvasive owns the copyright for figures included within the video and has given JNSPG permission to use them. The video can be found here: http://youtu.be/17Xo_u3WHNg.


The aspirin story - from willow to wonder drug.
The story of the discovery of aspirin stretches back more than 3500 years to when bark from the willow tree was used as a pain reliever and antipyretic. It involves an Oxfordshire clergyman, scientists at a German dye manufacturer, a Nobel Prize-winning discovery and a series of pivotal clinical trials. Aspirin is now the most commonly used drug in the world. Its role in preventing cardiovascular and cerebrovascular disease has been revolutionary and one of the biggest pharmaceutical success stories of the last century.


Stereoscopic mechanisms: binocular responses of the striate cells of cats to moving light and dark bars.
New knowledge concerning the internal structure and response properties of the receptive fields of striate cells calls for a fresh appraisal of their binocular interactions in the interest of a better understanding of the neural mechanisms underlying binocular depth discrimination. Binocular position-disparity response profiles were recorded from 71 simple and B-cells in response to moving light and dark bars. Predominantly excitatory (PE) cells (N = 48) had disparity response profiles that were spatially closely similar to their respective monocular responses. In addition, the centrally located excitatory subregions were flanked on one or both sides by non-specific inhibitory regions. PE cells with a preferred stimulus orientation within 30 degrees of the vertical (N = 17) showed binocular facilitations with maximal values that were always more than twice (mean 3.3) the sum of the two monocular responses to the same stimuli and generally greater than the facilitations shown by cells with orientations more than 30 degrees from the vertical (N = 29; mean 2.2 times the sum of the respective monocular responses). The strength of the binocular facilitation depended on the stimulus contrast, the facilitation decreasing with increasing contrast. The receptive-field disparity distribution of the 31 PE cells capable of making significant horizontal disparity discriminations has standard deviations of 0.37 degrees and 0.40 degrees, respectively. Predominantly inhibitory cells (PI) (N = 23) showed two basic types of disparity response profile: symmetric (N = 17) and asymmetric (N = 6). Uncertainty regarding the precise location of the binocular fixation point in the anaesthetized and paralysed preparation made it difficult to categorize PI cells adequately.


Locally transmitted malaria in Tawau, Sabah, Malaysia.
Tawau was the epicentre of malaria infections in the 1970-1990's, when industrialisation swept across the state of Sabah, Malaysia. Since then, effective public health intervention, mainly the Malaria Elimination Programme, introduced in 1998, has seen the disease shrivel down into its final elimination phase. Here we retrospectively analyse the case of a 63 year old male with multiple comorbidities who had no exposure to localities with high risk of infection- thus raising the question regarding the means of transmission. Multiple interviews and an entomological survey were conducted to elucidate the possible mechanism of infection in this patient. Findings point to locally-transmitted malaria, likely introduced by a patient from an endemic region in Tawau. Transmission via this route is rare, and has never before been reported in our setting. This rare case highlights the need for constant vigilance in malaria control and elimination, especially when the target of country-wide elimination is close.


Respiratory virus infections and aeroallergens in acute bronchial asthma.
Two hundred and fifty six attacks of acute bronchial asthma occurring in 169 children aged over 2 years were studied during a two year period. More attacks occurred during spring and autumn than at other times of the year. In 73 patients (29%) a respiratory virus infection was diagnosed, with the same seasonal variation as the asthmatic attacks. Most of the virus infections were caused by rhinovirus (45%) and respiratory syncytial virus (19%). There was no significant correlation between asthmatic attacks in patients with birch pollen, grass pollen, or Cladosporium herbarum allergy and counts of the respective pollen or spores in the air. More seasonal attacks occurred in patients with cladosporium allergy than in patients without cladosporium allergy but there was no seasonal variation among birch or grass pollen allergic patients. Information about exposure to animals was obtained in only 12% of attacks occurring in 121 patients with allergy to animal dander. The single precipitating factor most frequently associated with acute asthma was respiratory virus infection.


Human bone marrow lymphocytes. I. Distribution of lymphocyte subpopulations in the bone marrow of normal individuals.
This study was undertaken to determine the proportions and in vitro immune capacities of lymphocyte populations in the bone marrows of normal humans. Relatively pure mononuclear cell suspensions were obtained from bone marrow aspirates by linear sucrose gradient centrifugations. Simultaneous peripheral blood and bone marrow specimens from each individual were assayed for lymphocyte surface markers and mitogen responsiveness. Maximal possible contamination of bone marrow aspirates by peripheral blood was determined by performing aspirates on individuals who had received 51chromium-labeled autologous erythrocytes. Rhymus-derived (T) lymphocytes, as determined by the sheep red blood cell (E) rosette assay, comprised 8.6-(plus or minus 1.6)% of the total bone marrow lymphocyte pool. Bone marrow-derived (B) lymphocytes, as determined by the presence of a complement receptor, made up 15.4-(plus or minus 1.9)% of the lymphocyte pool whereas 74.6 (plus or minus 2.4)% of mononuclear cells lacked easily detectable surface markers. These findings could not be explained by contamination with peripheral blood lymphocytes since contamination was corrected for in the calculations. Lymphocyte-enriched suspensions of bone marrow cells responded to stimulation with phytohemagglutinin, concanalin A, and particularly pokeweed mitogen. In vitro incubations of bone marrow and peripheral blood lymphocytes with tritiated thymidine followed by determinations of E and erythrocyte antibody complement (EAC) rosettes were performed. Simultaneous rosetteradioautographs demonstrated that the proliferative potential of bone marrow B lymphocytes was greater than peripheral blood B lymphocytes (P less than 0.01). On the other hand, the proliferative potential of bone marrow T lymphocytes was the same as that of peripheral blood T lymphocytes. These findings demonstrate that in addition to containing B lymphocytes the normal bone marrow contains a small fraction of T lymphocytes similar to the mature T lymphocyte pool found in the peripheral blood. These T cells most probably enter the bone marrow parenchyma as part of the normal recirculating lymphocyte pool.


What is cumulative cultural evolution?
In recent years, the phenomenon of cumulative cultural evolution (CCE) has become the focus of major research interest in biology, psychology and anthropology. Some researchers argue that CCE is unique to humans and underlies our extraordinary evolutionary success as a species. Others claim to have found CCE in non-human species. Yet others remain sceptical that CCE is even important for explaining human behavioural diversity and complexity. These debates are hampered by multiple and often ambiguous definitions of CCE. Here, we review how researchers define, use and test CCE. We identify a core set of criteria for CCE which are both necessary and sufficient, and may be found in non-human species. We also identify a set of extended criteria that are observed in human CCE but not, to date, in other species. Different socio-cognitive mechanisms may underlie these different criteria. We reinterpret previous theoretical models and observational and experimental studies of both human and non-human species in light of these more fine-grained criteria. Finally, we discuss key issues surrounding information, fitness and cognition. We recommend that researchers are more explicit about what components of CCE they are testing and claiming to demonstrate.


Mortality and exposure response among 14,458 electrical capacitor manufacturing workers exposed to polychlorinated biphenyls (PCBs).
We expanded an existing cohort of workers (n = 2,588) considered highly exposed to polychlorinated biphenyls (PCBs) at two capacitor manufacturing plants to include all workers with at least 90 days of potential PCB exposure during 1939-1977 (n = 14,458). Causes of death of a priori interest included liver and rectal cancers, previously reported for the original cohort, and non-Hodgkin lymphoma (NHL), melanoma, and breast, brain, intestine, stomach, and prostate cancers, based on other studies. We ascertained vital status of the workers through 1998, and cumulative PCB exposure was estimated using a new job exposure matrix. Analyses employed standardized mortality ratios (SMRs; U.S., state, and county referents) and Poisson regression modeling. Mortality from NHL, melanoma, and rectal, breast, and brain cancers were neither in excess nor associated with cumulative exposure. Mortality was not elevated for liver cancer [21 deaths; SMR 0.89; 95% confidence interval (CI), 0.55-1.36], but increased with cumulative exposure (trend p-value = 0.071). Among men, stomach cancer mortality was elevated (24 deaths; SMR 1.53; 95% CI, 0.98-2.28) and increased with cumulative exposure (trend p-value = 0.039). Among women, intestinal cancer mortality was elevated (67 deaths; SMR 1.31; 95% CI, 1.02-1.66), especially in higher cumulative exposure categories, but without a clear trend. Prostate cancer mortality, which was not elevated (34 deaths; SMR 1.04; 95% CI, 0.72-1.45), increased with cumulative exposure (trend p-value = 0.0001). This study corroborates previous studies showing increased liver cancer mortality, but we cannot clearly associate rectal, stomach, and intestinal cancers with PCB exposure. This is the first PCB cohort showing a strong exposure-response relationship for prostate cancer mortality.


Phencyclidine-induced immunodepression.
Phencyclidine ("PCP" or "angel dust") and some of its derivatives are psychotomimetic drugs that have been used in general anesthesia for some time. This drug blocks potassium ion channels in brain tissue, and there is a specific PCP binding to lymphocytes. In a study of the effects of this drug on immunocyte function, it was found that humoral and cellular immune responses in vitro were depressed when immunocytes were treated with PCP before biological assay. This finding has implications for PCP abuse and also for the use of its derivative in general anesthesia, where it may contribute to postoperative infection.


Decreased metalloprotease 9 induction, cardiac fibrosis, and higher autophagy after pressure overload in mice lacking the transcriptional regulator p8.
Left ventricular remodeling, including the deposition of excess extracellular matrix, is key to the pathogenesis of heart failure. The stress-inducible transcriptional regulator p8 is increased in failing human hearts and is required both for agonist-stimulated cardiomyocyte hypertrophy and for cardiac fibroblasts matrix metalloprotease-9 (MMP9) induction. In the heart, upregulation of autophagy is an adaptive response to stress and plays a causative role in cardiomyopathies. We have recently shown that p8 ablation in cardiac cells upregulates autophagy and that, in vivo, loss of p8 results in a decrease of cardiac function. Here we investigated the effects of p8 genetic deletion in mediating adverse myocardial remodeling. Unstressed p8-/- mouse hearts manifested complex alterations in the expression of fibrosis markers. In addition, these mice displayed elevated autophagy and apoptosis compared with p8+/+ mice. Transverse aortic constriction (TAC) induced left ventricular p8 expression in p8+/+ mice. Pressure overload caused left ventricular remodeling in both genotypes, however, p8-/- mice showed less cardiac fibrosis induction. Consistent with this, although MMP9 induction was attenuated in the p8-/- mice, induction of MMP2 and MMP3 were strikingly upregulated while TIMP2 was downregulated. Left ventricular autophagy increased after TAC and was significantly higher in the p8-/- mice. Thus p8-deletion results in reduced collagen fibrosis after TAC, but in turn, is associated with a detrimental higher increase in autophagy. These findings suggest a role for p8 in regulating in vivo key signaling pathways involved in the pathogenesis of heart failure.


Taxing sugar-sweetened beverages: impact on overweight and obesity in Germany.
Consumption of sugar-sweetened beverages (SSBs) increases the risk of overweight and obesity. Taxing SSBs could decrease daily energy consumption and body weight. This model-based study evaluated the impact of a 20% SSB-sales tax on overweight and obesity in the context of Germany. The population aged 15-79 years was modelled. Taxation was assumed to affect energy consumption via demand elasticities, which affected weight and BMI. Model-based analysis was performed to estimate the tax impact on BMI in different age, gender and income groups. Implementing a 20% SSB tax reduced energy consumption mainly in younger age groups, males, and those with low income. Taxation decreased the mean BMI in younger groups, with the largest decrease in those aged 20-29 years, while effects in groups 60 years or above were minimal. In absolute terms, taxation was estimated to avoid 1,028,000 (-3% relative reduction) overweight individuals and 479,000 obese individuals (-4%). Overweight decreased the most in males aged 20-29 years (408,000 fewer cases /-22%), the same applied for obesity (204,000/-22%). An SSB tax could have significant impact on overweight and obesity, which could translate into substantial reductions of morbidity and mortality.


Electro-optically generating and controlling right- and left-handed circularly polarized multiring modes of light beams.
We propose a simple method for generating and controlling right- and left-handed circularly polarized (RHP and LHP) multiring modes of light beams by means of Pockels effect in a single strontium barium niobate (SBN) crystal. The numerical results show that an LHP Laguerre-Gaussian LG(0l) beam, propagating along the optical axis of the crystal, will partly turn into an RHP vortex light field of order l+2. Moreover, a pair of the LHP and RHP components of the output light field is LG-like modes sharing an identically radial index, which is electro-optically controllable. The power ratio between these two components depends on the applied electric field and the mode of input beam.


Forecasting COVID-19 daily cases using phone call data.
The need to forecast COVID-19 related variables continues to be pressing as the epidemic unfolds. Different efforts have been made, with compartmental models in epidemiology and statistical models such as AutoRegressive Integrated Moving Average (ARIMA), Exponential Smoothing (ETS) or computing intelligence models. These efforts have proved useful in some instances by allowing decision makers to distinguish different scenarios during the emergency, but their accuracy has been disappointing, forecasts ignore uncertainties and less attention is given to local areas. In this study, we propose a simple Multiple Linear Regression model, optimised to use phone call data to forecast the number of daily confirmed cases. Moreover, we produce a probabilistic forecast that allows decision makers to better deal with risk. Our proposed approach outperforms ARIMA, ETS, Seasonal Naive, Prophet and a regression model without call data, evaluated by three point forecast error metrics, one prediction interval and two probabilistic forecast accuracy measures. The simplicity, interpretability and reliability of the model, obtained in a careful forecasting exercise, is a meaningful contribution to decision makers at local level who acutely need to organise resources in already strained health services. We hope that this model would serve as a building block of other forecasting efforts that on the one hand would help front-line personal and decision makers at local level, and on the other would facilitate the communication with other modelling efforts being made at the national level to improve the way we tackle this pandemic and other similar future challenges.


Delayed onset of a daytime nap facilitates retention of declarative memory.
Learning followed by a period of sleep, even as little as a nap, promotes memory consolidation. It is now generally recognized that sleep facilitates the stabilization of information acquired prior to sleep. However, the temporal nature of the effect of sleep on retention of declarative memory is yet to be understood. We examined the impact of a delayed nap onset on the recognition of neutral pictorial stimuli with an added spatial component. Participants completed an initial study session involving 150 neutral pictures of people, places, and objects. Immediately following the picture presentation, participants were asked to make recognition judgments on a subset of "old", previously seen, pictures versus intermixed "new" pictures. Participants were then divided into one of four groups who either took a 90-minute nap immediately, 2 hours, or 4 hours after learning, or remained awake for the duration of the experiment. 6 hours after initial learning, participants were again tested on the remaining "old" pictures, with "new" pictures intermixed. Interestingly, we found a stabilizing benefit of sleep on the memory trace reflected as a significant negative correlation between the average time elapsed before napping and decline in performance from test to retest (p = .001). We found a significant interaction between the groups and their performance from test to retest (p = .010), with the 4-hour delay group performing significantly better than both those who slept immediately and those who remained awake (p = .044, p = .010, respectively). Analysis of sleep data revealed a significant positive correlation between amount of slow wave sleep (SWS) achieved and length of the delay before sleep onset (p = .048). The findings add to the understanding of memory processing in humans, suggesting that factors such as waking processing and homeostatic increases in need for sleep over time modulate the importance of sleep to consolidation of neutral declarative memories.


Comparative immunohistochemical distribution of three small-conductance Ca2+-activated potassium channel subunits, SK1, SK2, and SK3 in mouse brain.
To investigate the distribution of all three SK channel subunits in the mouse central nervous system, we performed immunohistochemistry using sequence-specific antibodies directed against SK1, SK2, and SK3 proteins. Expression of SK1 and SK2 proteins revealed a partly overlapping distribution pattern restricted to a limited number of brain areas (e.g., neocortex, hippocampal formation). In contrast, SK3 immunoreactivity was rather complementary and predominantly detected in phylogenetically older brain regions like basal ganglia, thalamus, and various brain stem nuclei (e.g., locus coeruleus, tegmental nuclei). At the cellular level, SK1- and SK2-like immunoreactivity was primarily localized to somatic and dendritic structures, whereas the majority of SK3-like immunoreactivity was associated with varicose fibers.


Reliability and validity of the symptoms of major depressive illness.
In two consecutive studies, we examined the interrater reliability and then the concurrent validity of interview ratings for individual symptoms of major depressive illness. The concurrent validity of symptoms was determined by assessing the degree to which symptoms observed or reported during an interview were observed in daily behavior. Results indicated that most signs and symptoms of major depression and melancholia can be reliably rated by clinicians during a semistructured interview. Ratings of observable symptoms (signs) assessed during the interview were valid indicators of dysfunction observed in daily behavior. Several but not all ratings based on patient report of symptoms were at variance with observation. These discordant patient-reported symptoms may have value as subjective reports but were not accurate descriptions of observed dysfunction.


[Feeding behavior, rumination, reticulo-ruminal fermentation and plasma volatile fatty acids, compared in goats and sheep; influence of the diet].
Two-year old Alpine she-goats (n = 3) and Texel ewes (n = 3) were compared as to eating behaviour, rumination and volatile fatty acids (VFA) in rumen and blood. The animals were fed once daily with two different proportions (20 and 80%) of barley and hay. Dry matter intake was fixed at 48 g D.M/kg P0.75 per day. In similar feeding and environmental conditions, eating behaviour and rumination of goats and sheep did not differ much: the goats tended to eat faster and there were more rumination periods in the sheep. Latency time, mean duration of rumination periods, daily rumination time and circadian pattern of rumination did not differ significantly between the two species (fig. 1). With both diets we observed a higher VFA concentration and a lower acetate/propionate ratio in the rumen of the ewes; however, rumen pH was lower only in those eating the 80% barley ration (fig. 2). Blood VFA in the jugular vein did not differ between sheep and goats (fig. 3). The proportion of cereals and hay in the diets affected rumen fermentation and rumination pattern in both species. With a higher concentrate/roughage ratio, rumen and plasma VFA increased, while the pH and acetate/propionate ratio in the lumen juice, the number of rumination periods and daily rumination time decreased. When the animals were fed the 80% barley ration, there was practically no rumination in the first 9 h after the single meal. During this time, rumen pH was minimal and VFA levels in the rumen and blood were maximal.


Antibiotic resistance profile and co-production of extended spectrum beta lactamases and AmpC in Acinetobacter spp. in a level 1 trauma center from India.
Acinetobacter baumannii has now emerged as a significant nosocomial pathogen in health-care setting ESP in intensive care units. Rapidly growing resistance among clinical isolates suggests a need to detect resistance mechanisms in this organism. The present study was designed to compare the various phenotypic tests available with the gold standard of genotype. The present study was conducted to include all isolates of Acinetobacter spp. isolated over 3 years. Their resistance to various antibiotics was determined and extended spectrum beta-lactamases (ESBL) and AmpC production in the isolates showing resistance to ceftazidime/ceftriaxone/cefotaxime (CAZ/CTR/CTX) was determined. ESBL and AmpC production was confirmed using polymerase chain reaction (PCR). A total of 154 strains were isolated, and all the strains were tested for ESBL and AmpC detection. Of the strains tested, 15 (9.7%), 17 (11%), 24 (15.6%), 27 (17.5%), 54 (35%), 67 (43.5%), and 72 (46.7%) strains showed ESBL production using CTX/CTX-clavulanate double-disc synergy test (DDST), CTX/CTX-clavulanate E-test, CAZ/CAZ-clavulanate DDST, CAZ/CAZ-clavulanate E-test, Piperacillin/Piperacillin-tazobactam (TZ) DDST, CTR/CTR-Sulbactum DDST, and Piperacillin/Piperacillin-TZ E-test, respectively. 20 (12.9%) and 19 (12.3%) of strains were positive for AmpC production using AmpC disc test and Boronic acid inhibition test, respectively. Genotype analysis using PCR for TEM, SHV, CTXM, PER, and VEB genes was done and 69 (51.5%) strains were positive for TEM gene. ESBL detection in Acinetobacter spp. is difficult as standard guidelines for the same are not available unlike in enterobacteriaceae, and there are no zone diameter breakpoints for aztreonam and cefpodoxime. In comparison, piperacillin/piperacillin-TZ E-test had the best sensitivity and specificity for ESBL detection. Standard guidelines for ESBL detection in nil fermeners like Acinetobacter spp. must be laid down for ease of detection. Use of piperacillin/piperacillin-tazobactam E-test could be used as one of the standard methods.


Fatal crash involvement and laws against alcohol-impaired driving.
It is estimated that in 1985 about 1,560 fewer drivers were involved in fatal crashes because of three types of drinking-driving laws. The laws studied were per se laws that define driving under the influence using blood alcohol concentration (BAC) thresholds; laws that provide for administrative license suspension or revocation prior to conviction for driving under the influence (often referred to as "administrative per se" laws); and laws that mandate jail or community service for first convictions of driving under the influence. It is estimated that if all 48 of the contiguous states adopted laws similar to those studied here, and if these new laws had effects comparable to those reported here, another 2,600 fatal driver involvements could be prevented each year. During hours when typically at least half of all fatally injured drivers have a BAC over 0.10 percent, administrative suspension/revocation is estimated to reduce the involvement of drivers in fatal crashes by about 9 percent; during the same hours, first offense mandatory jail/community service laws are estimated to have reduced driver involvement by about 6 percent. The effect of per se laws was estimated to be a 6 percent reduction during hours when fatal crashes typically are less likely to involve alcohol. These results are based on analyses of drivers involved in fatal crashes in the 48 contiguous states of the United States during the years 1978 to 1985.


Manipulating the emission intensity and lifetime of NaYF4:Yb3+,Er3+ simultaneously by embedding it into CdS photonic crystals.
Photonic crystals (PCs) have long been considered effective for tuning upconversion luminescence due to their photonic band gap (PBG) and the redistribution of density of optical states (DOS). Although the emission intensity can be changed obviously by the PC effect, rarely an obvious lifetime change consistent with theory is observed due to the low refractive index of PS or SiO2 spheres in the commonly used PCs. Herein, CdS/NaYF4:Yb3+,Er3+ composite PCs with a high refractive index contrast are fabricated in one step with upconversion nanoparticles filled inside CdS PCs. When the upconversion emission peak lies at the edge of the PBGs of the composite PCs, a dramatic decrease in lifetime by 28% and 41% is observed for the green and red emissions, respectively. At the same time, obvious emission intensity enhancements are also observed. In contrast, PS PCs with a low refractive index contrast show a slight effect on the lifetime of upconversion luminescence with their emission peak at the edge of the PBGs. Our results agree well with theory and prove that a sufficiently large refractive index contrast is necessary for PCs to dramatically tune the luminescence lifetime and intensity simultaneously.


Proteome from patients with metabolic syndrome is regulated by quantity and quality of dietary lipids.
Metabolic syndrome is a multi-component disorder associated to a high risk of cardiovascular disease. Its etiology is the result of a complex interaction between genetic and environmental factors, including dietary habits. We aimed to identify the target proteins modulated by the long-term consumption of four diets differing in the quality and quantity of lipids in the whole proteome of peripheral blood mononuclear cells (PBMC). A randomized, controlled trial conducted within the LIPGENE study assigned 24 MetS patients for 12 weeks each to 1 of 4 diets: a) high-saturated fatty acid (HSFA), b) high-monounsaturated fatty acid (HMUFA), c) low-fat, high-complex carbohydrate diets supplemented with placebo (LFHCC) and d) low-fat, high-complex carbohydrate diets supplemented with long chain (LC) n-3 polyunsaturated fatty acids (PUFA) (LFHCC n-3). We analyzed the changes induced in the proteome of both nuclear and cytoplasmic fractions of PBMC using 2-D proteomic analysis. Sixty-seven proteins were differentially expressed after the long-term consumption of the four diets. The HSFA diet induced the expression of proteins responding to oxidative stress, degradation of ubiquitinated proteins and DNA repair. However, HMUFA, LFHCC and LFHCC n-3 diets down-regulated pro-inflammatory and oxidative stress-related proteins and DNA repairing proteins. The long-term consumption of HSFA, compared to HMUFA, LFHCC and LFHCC n-3, seems to increase the cardiovascular disease (CVD) risk factors associated with metabolic syndrome, such as inflammation and oxidative stress, and seem lead to DNA damage as a consequence of high oxidative stress.


Pattern and degree of left ventricular remodeling following a tailored surgical approach for hypertrophic obstructive cardiomyopathy.
Background The role of a tailored surgical approach for hypertrophic cardiomyopathy (HCM) on regional ventricular remodelling remains unknown. The aims of this study were to evaluate the pattern, extent and functional impact of regional ventricular remodelling after a tailored surgical approach. Methods From 2005 to 2008, 44 patients with obstructive HCM underwent tailored surgical intervention. Of those, 14 were ineligible for cardiac magnetic resonance (CMR) studies. From the remainder, 14 unselected patients (42±12 years) underwent pre- and post-operative CMR studies at a median 12 months post-operatively (range 4-37 months). Regional changes in left ventricular (LV) thickness as well as global LV function following surgery were assessed using CMR Tools (London, UK). Results Pre-operative mean echocardiographic septal thickness was 21±4 mm and mean LV outflow gradient was 69±32 mmHg. Following surgery, there was a significant degree of regional regression of LV thickness in all segments of the LV, ranging from 16% in the antero-lateral midventricular segment to 41% in the anterior basal segment. Wall thickening was significantly increased in basal segments but showed no significant change in the midventricular or apical segments. Globally, mean indexed LV mass decreased significantly after surgery (120±29g/m2 versus 154±36g/m2; p<0.001). There was a trend for increased indexed LV end-diastolic volume (70±13 mL versus 65±11 mL; p=0.16) with a normalization of LV ejection fraction (68±7% versus 75±9%; p<0.01). Conclusion Following a tailored surgical relief of outflow obstruction for HCM, there is a marked regional reverse LV remodelling. These changes could have a significant impact on overall ventricular dynamics and function.


Rare and intractable fibrodysplasia ossificans progressiva shows different PBMC phenotype possibly modulated by ascorbic acid and propranolol treatment.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare congenital intractable disease associated with a mutation in ACVR1 gene, characterized by skeleton malformations. Ascorbic acid (AA) and propranolol (PP) in combination is reported to minimize flare-ups in patients. FOP leukocyte phenotype may possibly be modulated by AA and PP treatment. In this study, expression of 22 potential target genes was analyzed by RT-PCR in peripheral blood mononuclear cells culture (PBMC) from FOP patients and controls to determine effectiveness of the combination therapy. PBMC were treated with AA, PP and AA+PP combination. Basal expression of 12 of the 22 genes in FOP PBMC was statistically different from controls. ACVR1, ADCY2, ADCY9 and COL3 were downregulated while COL1 was upregulated. ADRB1, ADRB2, RUNX2, TNF-α and ACTB, were all overexpressed in FOP PBMC. In control, AA upregulated COL1, SVCT1, ACTB, AGTR2 and downregulated ADCY2. In FOP cells, AA upregulated ACVR1, BMP4, COL1, COL3, TNF-α, ADCY2, ADCY9, AGTR2 and MAS, while downregulated ADBR2, RUNX2, ADCY1, SVCT1 and ACTB. PP increased ADBR1 and decreased RUNX2, TNF-α, AGTR1, ACTB and CHRNA7 genes in treated control PBMC compared to untreated. PP upregulated ADBR1, ADBR2 and MAS, and downregulated TNF-α and ACTB in treated FOP PBMC versus untreated. AA+PP augmented ADRB1 and ADRB2 expressions in control PBMC. In FOP PBMC, AA+PP augmented ACVR1, COL1, COL3, ADBR1, AGTR2 and MAS expression and downregulated ADBR2, RUNX2, ACTB and MRGD. These data show distinct gene expression modulation in leukocytes from FOP patients when treated with AA and or PP.


Phosphomimics destabilize Hsp27 oligomeric assemblies and enhance chaperone activity.
Serine phosphorylation of the mammalian small heat-shock protein Hsp27 at residues 15, 78, and 82 is thought to regulate its structure and chaperone function; however, the site-specific impact has not been established. We used mass spectrometry to assess the combinatorial effect of mutations that mimic phosphorylation upon the oligomeric state of Hsp27. Comprehensive dimerization yielded a relatively uncrowded spectrum, composed solely of even-sized oligomers. Modification at one or two serines decreased the average oligomeric size, while the triple mutant was predominantly a dimer. These changes were reflected in a greater propensity for oligomers to dissociate upon increased modification. The ability of Hsp27 to prevent amorphous or fibrillar aggregation of target proteins was enhanced and correlated with the amount of dissociated species present. We propose that, in vivo, phosphorylation promotes oligomer dissociation, thereby enhancing chaperone activity. Our data support a model in which dimers are the chaperone-active component of Hsp27.


Enhancing plasticity in central networks improves motor and sensory recovery after nerve damage.
Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.


"My body breaks. I take solution." Inhalant use in Delhi as pleasure seeking at a cost.
Inhalant use has existed in India since the 1970s and has increased significantly over the last decades, especially among street-oriented young people. The latter constitute a heterogeneous category: children from street families, children 'of' the street, rag pickers, and part-time street children. There are also inhalant-using schoolchildren and young people in slums. Fieldwork was conducted for 1 year. Team ethnography, multi-sited and comparative research, flexibility of methods and writing field notes were explicit parts of the research design. Most research was undertaken with six groups in four areas of Delhi, exemplifying six generic categories of inhalant-using street-oriented young people. Inhalants in India are branded: Eraz-Ex diluter and whitener, manufactured by Kores, are used throughout Delhi; Omni glue in one specific area. There is a general lack of awareness and societal indifference towards inhalant use, with the exception of the inhalant users themselves, who possess practical knowledge. They conceive of inhalants as nasha, encapsulating the materiality of the substances and the experiential aspects of intoxication and addiction. Fragments of group interviews narrate the sensory appeal of inhalants, and an ethnographic vignette the dynamics of a sniffing session. These inhalant-using street children seek intoxication in a pursuit of pleasure, despite the harm that befalls them as a result. Some find nasha beautiful, notwithstanding the stigmatization, violence and bodily deterioration; others experience it as an overpowering force. A source of attraction and pleasure, inhalants ravage street children's lives. In this mysterious space of lived experience, their self-organization evolves. Distinguishing between hedonic and side effects, addiction helps to understand inhalant use as at once neurobiological, cultural, and involving agency. The implications are that India needs to develop a policy of treatment and employment to deal with the addiction.


Impact of plant species evenness, dominant species identity and spatial arrangement on the structure and functioning of soil microbial communities in a model grassland.
Plant communities, through species richness and composition, strongly influence soil microorganisms and the ecosystem processes they drive. To test the effects of other plant community attributes, such as the identity of dominant plant species, evenness, and spatial arrangement, we set up a model mesocosm experiment that manipulated these three attributes in a full factorial design, using three grassland plant species (Anthoxanthum odoratum, Plantago lanceolata, and Lotus corniculatus). The impact of the three community attributes on the soil microbial community structure and functioning was evaluated after two growing seasons by ester-linked phospholipid fatty-acids analysis, substrate-induced respiration, basal respiration, and nitrogen mineralization and nitrification rates. Our results suggested that the dominant species identity had the most prevalent influence of the three community attributes, with significant effects on most of the measured aspects of microbial biomass, composition and functioning. Evenness had no effects on microbial community structure, but independently influenced basal respiration. Its effects on nitrogen cycling depended on the identity of the dominant plant species, indicating that interactions among species and their effects on functioning can vary with their relative abundance. Systems with an aggregated spatial arrangement had a different microbial community composition and a higher microbial biomass compared to those with a random spatial arrangement, but rarely differed in their functioning. Overall, it appears that dominant species identity was the main driver of soil microorganisms and functioning in these model grassland communities, but that other plant community attributes such as evenness and spatial arrangement can also be important.


A pilot study to identify areas for further improvements in patient and public involvement in health technology assessments for medicines.
Patient and public participation in health technology assessment (HTA) of medicines has been cited as an important component of the decision-making structure; however, how to actually achieve meaningful involvement is less understood. Our objectives were to conduct a pilot study to form the basis of future research and to gain insight into how to practically and meaningfully advance patient and public input in HTAs for medicines. Semi-structured interviews (n = 13) with informants in Australia (n = 7), Canada (n = 3), and the UK (n = 3) were conducted across agencies and experts (n = 9), as well as patient and advocacy groups (n = 4). This pilot study identified through structured interviews three areas for further consideration. Advancement area 1 indicates that industry could help bring the patient perspective into the HTA process through incorporating patient experiences early in the drug development process and by including qualitative research on patient experiences in HTA dossiers. Advancement area 2 involves recognizing and supporting the role of patient advocacy groups, and making use of their access to the genuine patient perspective and experience of living with the condition in question. Finally, advancement area 3 is the continuous development of HTA systems and processes to better facilitate involvement, increasing transparency and feedback, exploring new options for reaching patients, and focusing on creating an active and informed health consumer. The HTA process is becoming increasingly transparent to patients and the public; however, more effort is required to fully engage patients in the decision-making processes for medicine HTAs. This pilot study identified three key areas for further advancement in this field, and recognized a need for further research in the areas of measuring the impact of patient engagement on decision making in medicine HTAs, as well as the best methods to better prepare patient advocacy groups through HTA education and training. These research recommendations will form the basis of a future study with a larger, more comprehensive sample.


Extended-Family Talk about Sex and Teen Sexual Behavior.
Research shows that family communication about sexuality can protect against teens' risky sexual behavior. However, few studies assess talk with extended family about sex or how this communication relates to teens' sexual behavior. The current study includes cross-sectional survey data from 952 adolescents. Structural equation modeling (SEM) was used to assess associations between teens' sexual risk behaviors and communication with extended family about protection methods, risks of sex and relational approaches to sex, defined as talk about sex within a close relationship. For sexually active teens, talk about protection methods was associated with fewer sexual partners and talk about risks of sex was associated with more sexual partners regardless of teen gender and the generation of extended family with whom teens talk. Results suggest that extended-family talk about sex may influence teens' sexual behavior independent of effects of teen⁻parent communication. However, the direction of the effect depends on the content of the conversations. These findings suggest the need to explore whether and how extended family could be included in health prevention and intervention programs, because programs which include family largely focus on parents.


Substance Use Related Stigma: What we Know and the Way Forward.
To conduct a systematic review of the literature investigating the relationship between stigma experienced by individuals who use drugs. We conducted an online literature search and identified articles related to stigma among individuals who use drugs. Studies evaluating associations between stigma and socio-demographic variables and if applicable clinical and substance use variables are presented. In addition, recommendations for future research are provided. We identified 26 articles describing 28 studies evaluating stigma. The majorities of studies were published in the last 11 years and conducted in the U.S. Samples were relatively diverse: 41.7% of all participants who provided data identified as racial/ethnic minorities. The vast majority of the relationships between stigma and socio-demographic characteristics were included in only one or very few studies, which limits conclusions. The relationship between stigma and psychological well-being is the only consistent finding reported in the literature. Specifically, results suggest that stigma has a detrimental effect on psychological well-being among individuals who use drugs. While this literature is expanding at a rapid pace, this review indicates several areas for future research and needed improvements in research methodology in this area. Specifically, lack of comprehensive description of sample characteristics, lack of construct identification and proper definition, a dearth of longitudinal studies and limited research describing relationships between stigma and substance use behavior are a few areas identified for further research.


A new and sensitive Co-operational polymerase chain reaction for rapid detection of Ralstonia solanacearum in water.
Three primers from 16S rRNA were successfully assayed simultaneously in one reaction for sensitive detection of Ralstonia solanacearum in watercourses. The protocol is a modification of the Co-operational polymerase chain reaction (Co-PCR), which allows the simultaneous and co-operational action of the primers. It specifically amplified R. solanacearum strains belonging to biovars 1, 2 and 4. No products were obtained from any of the 162 unidentified isolates from river water. The sensitivity of the assay was <1 cfu/ml as determined by analysis of heat-treated water samples spiked with R. solanacearum, also containing indigenous microbiota up to 10(5) cfu/ml. The developed Co-PCR assay was more sensitive than other standard PCR assays in the analysis of 51 Spanish environmental water samples. Namely 31.3% of the samples were positive using the newly developed assay, whereas 13.7% or less positive samples were found with the other protocols. The Co-PCR improves the detection sensitivity of R. solanacearum and provides an important tool for its routine detection from environmental water samples and for epidemiological studies.


Hospital variation in mortality after emergent bowel resections: The role of failure-to-rescue.
Hospital variation in failure-to-rescue (FTR) rates has partially explained nationwide differences in mortality after elective surgeries. To examine the role of FTR among emergency general surgery, we compared nationwide risk-adjusted mortality, complications, and FTR rates after emergent bowel resections. We identified patients who underwent emergent small or large bowel resections in the 2010 to 2011 Nationwide Inpatient Sample using the American Association for the Surgery of Trauma criteria. We then calculated risk-adjusted mortality rates for each hospital using multivariable logistic regressions and postestimation, which adjusted for patient age, sex, race and ethnicity, payer status, comorbidities, and hospital clustering. After excluding hospitals with fewer than 10 resections per year, we ranked the remaining hospitals by their risk-adjusted mortality rates and divided them into five quintiles. We compared both risk-adjusted complication rates and FTR rates between the top (lowest mortality) and bottom (highest mortality) quintiles. We identified 21,564 emergent bowel resections, weighted to 105,925 procedures nationwide. The bottom quintile of hospitals had an overall risk-adjusted mortality rate that was 10.9 times higher than that of the top quintile of hospitals (15.3% vs. 1.4%). While risk-adjusted complication rates were similarly high for both the bottom and the top quintiles of hospitals (22.5% vs. 15.7%), the risk-adjusted FTR rates were 10.8 times higher in the bottom quintile of hospitals relative to the top quintile of hospitals (33.4% vs. 3.1%). Using larger hospital volume thresholds yielded similar findings. Furthermore, large variations existed in complication-specific FTR rates (surgical site infection [6.6%] to myocardial infarction [29.4%]). Nationwide hospital variation in risk-adjusted mortality rates exist after emergent bowel resections. As complication rates were similar across hospitals, the significantly higher FTR rates at higher-mortality hospitals may drive this variation in mortality. System-level initiatives addressing the management of postoperative complications may improve patient care and reduce variation in outcomes. Prognostic and epidemiological study, level IV.


Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression.
This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult outpatients stabilized on a regimen of lithium. In a double-blind, placebo-controlled study, 117 outpatients with DSM-III-R bipolar disorder, depressive phase, were randomly assigned to treatment with paroxetine (N=35), imipramine (N=39), or placebo (N=43) for 10 weeks. In addition to lithium monotherapy, patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms. Patients were stratified on the basis of trough serum lithium levels determined at the screening visit (high: >0.8 meq/liter; low: </=0.8 meq/liter). Primary efficacy was assessed by change from baseline in scores on the Hamilton Rating Scale for Depression and the Clinical Global Impression illness severity scale. Differences in overall efficacy among the three groups were not statistically significant. For patients with high serum lithium levels, antidepressant response at endpoint also did not significantly differ from placebo. However, both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels. Compared to imipramine, paroxetine resulted in a lower incidence of adverse events, most notably emergence of manic symptoms. Antidepressants may not be useful adjunctive therapy for bipolar depressed patients with high serum lithium levels. However, antidepressant therapy may be beneficial for patients who cannot tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium.


ICTV Virus Taxonomy Profile: Flaviviridae.
The Flaviviridae is a family of small enveloped viruses with RNA genomes of 9000-13 000 bases. Most infect mammals and birds. Many flaviviruses are host-specific and pathogenic, such as hepatitis C virus in the genus Hepacivirus. The majority of known members in the genus Flavivirus are arthropod borne, and many are important human and veterinary pathogens (e.g. yellow fever virus, dengue virus). This is a summary of the current International Committee on Taxonomy of Viruses (ICTV) report on the taxonomy of the Flaviviridae, which is available at www.ictv.global/report/flaviviridae.


BKV agnoprotein interacts with α-soluble N-ethylmaleimide-sensitive fusion attachment protein, and negatively influences transport of VSVG-EGFP.
The human polyomavirus BK (BKV) infects humans worldwide and establishes a persistent infection in the kidney. The BK virus genome encodes three regulatory proteins, large and small tumor-antigen and the agnoprotein, as well as the capsid proteins VP1 to VP3. Agnoprotein is conserved among BKV, JC virus (JCV) and SV40, and agnoprotein-deficient mutants reveal reduced viral propagation. Studies with JCV and SV40 indicate that their agnoproteins may be involved in transcription, replication and/or nuclear and cellular release of the virus. However, the exact function(s) of agnoprotein of BK virus remains elusive. As a strategy of exploring the functions of BKV agnoprotein, we decided to look for cellular interaction partners for the viral protein. Several partners were identified by yeast two-hybrid assay, among them α-SNAP which is involved in disassembly of vesicles during secretion. BKV agnoprotein and α-SNAP were found to partially co-localize in cells, and a complex consisting of agnoprotein and α-SNAP could be co-immunoprecipitated from cells ectopically expressing the proteins as well as from BKV-transfected cells. The N-terminal part of the agnoprotein was sufficient for the interaction with α-SNAP. Finally, we could show that BKV agnoprotein negatively interferes with secretion of VSVG-EGFP reporter suggesting that agnoprotein may modulate exocytosis. We have identified the first cellular interaction partner for BKV agnoprotein. The most N-terminal part of BKV agnoprotein is involved in the interaction with α-SNAP. Presence of BKV agnoprotein negatively interferes with secretion of VSVG-EGFP reporter.


Expanding the Cultural Adaptation Framework for Population-Level Impact.
Attention to cultural diversity and cultural adaptation of evidence-based interventions (EBIs) has been a longstanding priority in prevention science. However, EBIs for diverse populations present several challenges for broad dissemination and population impact. The five papers in this special issue underscore some of these challenges and offer new ways of thinking and recommendations for the next generation of type 2 translation research. This commentary underscores three broad recommendations, including the need for a more expanded conceptualization and empirical understanding of the core tension between fidelity and adaptation; greater focus on the systems of care that deliver EBIs to culturally diverse populations, including increased attention to such issues as access and engagement; and greater flexibility in strategies to adapt and evaluate interventions within and across communities and settings that serve diverse populations. By offering exemplars and suggestions to address these challenges, these papers collectively help to realign research on cultural adaptation with its ultimate goal of reducing health disparities by ensuring greater access, impact, and equity of prevention services in a dynamic, multicultural society. However, other fundamental challenges remain unaddressed, including the need to reduce inequalities that exist in the health, education, social service, and justice systems that will ultimately support broad diffusion of EBIs for diverse populations.


A new targeted capture method using bacterial artificial chromosome (BAC) libraries as baits for sequencing relatively large genes.
To analyze a specific genome region using next-generation sequencing technologies, the enrichment of DNA libraries with targeted capture methods has been standardized. For enrichment of mitochondrial genome, a previous study developed an original targeted capture method that use baits constructed from long-range polymerase chain reaction (PCR) amplicons, common laboratory reagents, and equipment. In this study, a new targeted capture method is presented, that of bacterial artificial chromosome (BAC) double capture (BDC), modifying the previous method, but using BAC libraries as baits for sequencing a relatively large gene. We applied the BDC approach for the 214 kb autosomal region, ring finger protein 213, which is the susceptibility gene of moyamoya disease (MMD). To evaluate the reliability of BDC, cost and data quality were compared with those of a commercial kit. While the ratio of duplicate reads was higher, the cost was less than that of the commercial kit. The data quality was sufficiently the same as that of the kit. Thus, BDC can be an easy, low-cost, and useful method for analyzing individual genome regions with substantial length.


Involvement of the Rab27 binding protein Slac2c/MyRIP in insulin exocytosis.
Rab27a is a GTPase associated with insulin-containing secretory granules of pancreatic beta-cells. Selective reduction of Rab27a expression by RNA interference did not alter granule distribution and basal secretion but impaired exocytosis triggered by insulin secretagogues. Screening for potential effectors of the GTPase revealed that the Rab27a-binding protein Slac2c/MyRIP is associated with secretory granules of beta-cells. Attenuation of Slac2c/MyRIP expression by RNA interference did not modify basal secretion but severely impaired hormone release in response to secretagogues. Although beta-cells express Myosin-Va, a potential partner of Slac2c/MyRIP, no functional link between the two proteins could be demonstrated. In fact, overexpression of the Myosin-Va binding domain of Slac2c/MyRIP did not affect granule localization and hormone exocytosis. In contrast, overexpression of the actin-binding domain of Slac2c/MyRIP led to a potent inhibition of exocytosis without detectable alteration in granule distribution. This effect was prevented by point mutations that abolish actin binding. Taken together our data suggest that Rab27a and Slac2c/MyRIP are part of a complex mediating the interaction of secretory granules with cortical actin cytoskeleton and participate to the regulation of the final steps of insulin exocytosis.


Characterization of transcription factor AP-2 β mutations involved in familial isolated patent ductus arteriosus suggests haploinsufficiency.
Patent ductus arteriosus (PDA) is one of the most common congenital heart defects. Transcription factor AP-2 beta (TFAP2B) mutations are associated with the Char syndrome, a disorder associated with PDA, and with facial and fingers abnormalities. Recently, we identified two TFAP2B mutations in two families without Char syndrome phenotype, c.601+5G>A and c.435_438delCCGG, and these TFAP2B mutations were associated with familial isolated PDA. The aim of this study was to identify the effects of these mutations on TFAP2B function. Plasmids containing the wild-type or mutated TFAP2B were constructed and transfected in cells. Plasmids containing the TFAP2B coactivator, Cpb/p300-interacting transactivator 2 (CITED2), was also transfected. TFAP2B expression was detected by luciferase expression and by Western blot analysis. These mutations resulted in loss of transactivation function, which could not be improved by Cpb/p300-interacting transactivator 2. The c.601+5G>A mutated gene did not express any protein, whereas the c.435_438delCCGG mutation did not impact the transactivation function activated by the wild-type TFAP2B. These results suggest that a haploinsufficiency effect of TFAP2B could be involved in familial isolated PDA.


Nationwide Access to Endovascular Treatment for Acute Ischemic Stroke in Portugal.
Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. Overall endovascular treatment rates and procedural times in Portugal are comparable to other international registries. We found geographic heterogeneity, with lower endovascular treatment rates and longer onset-to-puncture time in southern and inner regions. The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.


Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens.
A diagnosis of low-grade fibromyxoid sarcoma (LGFMS) remains problematic because of its bland-looking histologic features that can be potentially confused with other benign or low-grade fibromyxoid lesions. Recent cytogenetic and molecular analyses have shown that most LGFMSs have a characteristic chromosomal abnormality, t(7;16)(q33;p11), resulting in the FUS-CREB3L2 fusion gene. However, such assays have only rarely been used to analyze formalin-fixed, paraffin-embedded tumor samples. In the present study, we conducted a reverse transcription-polymerase chain reaction assay to detect the FUS-CREB3L2 fusion transcripts using formalin-fixed, paraffin-embedded tumor tissue specimens from 16 LGFMSs including 3 cases with giant collagen rosettes. The primers were newly designed to specifically amplify most of the junctional regions of the FUS-CREB3L2 fusion gene transcripts previously reported. The FUS-CREB3L2 fusion gene transcripts were detected in 14/16 (88%) cases of LGFMS. A nucleotide sequence analysis of the PCR products revealed that different portions of the FUS exon 6 or 7 were fused with various sites of the CREB3L2 exon 5, resulting in 12 different nucleotide sequences. We also tested a primer set to detect the FUS-CREB3L1 fusion transcript, which is a rare variant of the gene fusion in LGFMS, although no PCR products were identified in any case. The FUS-CREB3L2 fusion transcripts were not detected in any of the 123 other soft-tissue tumors, including desmoid-type fibromatoses, myxofibrosarcomas, soft-tissue perineuriomas, and congenital or adult fibrosarcomas. These data suggest that our reverse transcription-polymerase chain reaction assay is a reliable method to detect FUS-CREB3L2, which can thus help in accurately diagnosing LGFMS.


Systemic administration of a centrally acting acetylcholinesterase inhibitor improves outcome from hemorrhagic shock during acute alcohol intoxication.
Previously, we have demonstrated that acute alcohol intoxication impairs hemodynamic counter-regulation to hemorrhage in unanesthetized rats, and that this phenomenon is associated with an impaired neuroendocrine response to blood loss. Moreover, we demonstrated that central acetylcholinesterase inhibition restores the hemodynamic and neuroendocrine responses to hemorrhage in alcohol-intoxicated rats. We hypothesized that similar responses could be elicited by systemic administration of physostigmine, an acetylcholinesterase inhibitor that penetrates the blood brain barrier. The relevance of this approach was to establish effectiveness of a more clinically applicable route of drug administration than that used previously. Chronically catheterized adult male Sprague-Dawley rats (250-275 g) were administered a bolus of physostigmine (i.v., 100 microg/kg) at rest, and in a separate study, simultaneously with Ringer's lactate solution after an overnight intragastric infusion of 30% alcohol (approximately 7 g/kg for 15 h) or 52% isocaloric dextrose and fixed-pressure hemorrhage. I.v. physostigmine administration immediately increased sympathetic outflow via activation of central nicotinic receptors and improved the pressor response to fluid resuscitation in both dextrose controls and alcohol-intoxicated animals. The improved hemodynamic recovery achieved with physostigmine was also associated with attenuation of the rises in the markers of liver and renal damage alanine aminotransferase and blood urea nitrogen in alcohol-intoxicated animals. Additional studies are warranted to determine the effect of central acetylcholinesterase inhibition on tissue injury and survival after severe blood loss, as well as its effects on long-term metabolic and inflammatory responses.


Dynamic characterization of viscoelastic porous foams used in vehicles based on an inverse finite element method.
Viscoelastic properties of porous materials, typical of those used in vehicles for noise insulation and absorption, are estimated from measurements and inverse finite element procedures. The measurements are taken in a near vacuum and cover a broad frequency range: 20 Hz to 1 kHz. The almost cubic test samples were made of 25 mm foam covered by a "heavy layer" of rubber. They were mounted in a vacuum chamber on an aluminum table, which was excited in the vertical and horizontal directions with a shaker. Three kinds of response are measured allowing complete estimates of the viscoelastic moduli for isotropic materials and also providing some information on the degree of material anisotropicity. First, frequency independent properties are estimated, where dissipation is described by constant loss factors. Then, fractional derivative models that capture the variation with frequency of the stiffness and damping are adapted. The measurement setup is essentially two-dimensional and calculations are three-dimensional and for a state of plane strain. The good agreement between measured and calculated response provides some confidence in the presented procedures. If, however, the material model cannot fit the measurements well, the inverse procedure yields a certain degree of arbitrariness to the parameter estimation.


Hydrostatic pressure-induced release of stored calcium in cultured rat optic nerve head astrocytes.
Elevated intraocular pressure is associated with glaucomatous optic nerve damage. Other investigators have shown functional changes in optic nerve head astrocytes subjected to elevated hydrostatic pressure (HP) for 1 to 5 days. Recently, the authors reported ERK1/2, p90(RSK) and NHE1 phosphorylation after 2 hours. Here they examine calcium responses at the onset of HP to determine what precedes ERK1/2 phosphorylation. Cytoplasmic calcium concentration ([Ca(2+)](i)) was measured in cultured rat optic nerve astrocytes loaded with fura-2. The cells were placed in a closed imaging chamber and subjected to an HP increase of 15 mm Hg. Protein phosphorylation was detected by Western blot analysis. The increase of HP caused an immediate slow increase in [Ca(2+)](i). The response persisted in calcium-free solution and when nickel chloride (4 mM) was added to suppress channel-mediated calcium entry. Previous depletion of the ER calcium stores by cyclopiazonic acid abolished the HP-induced calcium level increase. The HP-induced increase persisted in cells exposed to xestospongin C, an inhibitor of IP3R-mediated calcium release. In contrast, ryanodine receptor (RyR) antagonist ruthenium red (10 microM) or dantrolene (25 microM) inhibited the HP-induced calcium increase. The HP-induced calcium increase was abolished when ryanodine-sensitive calcium stores were pre-depleted with caffeine (3 mM). HP caused ERK1/2 phosphorylation. The magnitude of the ERK1/2 phosphorylation response was reduced by ruthenium red and dantrolene. Increasing HP causes calcium release from a ryanodine-sensitive cytoplasmic store and subsequent ERK1/2 activation. Calcium store release appears to be a required early step in the initial astrocyte response to an HP increase.


Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice.
Clinical trials have demonstrated that probiotics may be effective in the treatment and prevention of atopic disease in children but there have been few reports of therapeutic effects of oral probiotics outside the gastrointestinal tract. We investigated the effect of two probiotic organisms on the response to antigen challenge in a mouse model of allergic airway inflammation. We used an ovalbumin-sensitized asthma model in BALB/c and Toll-like receptor 9-deficient mice. Animals were treated with probiotic organisms via gavaging needle before antigen challenge. After antigen challenge, airway responsiveness to methacholine, influx of inflammatory cells to the lung, and cytokine levels in bronchoalveolar lavage fluid were assessed. Oral treatment with live Lactobacillus reuteri but not Lactobacillus salivarius significantly attenuated the influx of eosinophils to the airway lumen and parenchyma and reduced the levels of tumor necrosis factor, monocyte chemoattractant protein-1, IL-5, and IL-13 in bronchoalveolar lavage fluid of antigen-challenged animals, but there was no change in eotaxin or IL-10. L. reuteri but not L. salivarius also decreased allergen-induced airway hyperresponsiveness. These responses were dependent on Toll-like receptor 9 and were associated with increased activity of indoleamine 2,3-dioxygenase. Killed organisms did not mimic the ability of the live L. reuteri to attenuate inflammation or airway hyperresponsiveness. Oral treatment with live L. reuteri can attenuate major characteristics of an asthmatic response in a mouse model of allergic airway inflammation. These results suggest that oral treatment with specific live probiotic strains may have therapeutic potential in the treatment of allergic airway disease.


Assessment of oral mucosal lesions among eunuchs residing in Bhopal city, Madhya Pradesh, India: a cross-sectional study.
The present cross-sectional study following the STROBE guidelines was conducted to assess the prevalence of oral mucosal lesions among males, females, and eunuchs residing in Bhopal city, Madhya Pradesh India. Based on convenient non-probability snowball sampling technique, all the self-identified eunuchs residing in the city of Bhopal who were present at the time of examination and who fulfilled the selection criteria were examined. A cross section of the general population (males and females) residing in the same locality where these eunuchs live was also examined. The World Health Organization (WHO) oral health assessment proforma (1997) was used to collect the information on oral mucosal lesions. All the obtained data were analyzed by using a Statistical Package for Social Sciences version 20. Overall prevalence of oral mucosal lesions was 127 (19.9%) among the study subjects. Fifty-nine (28.5%) eunuchs, 56 (25.7%) males, and 12 (5.6%) females were observed to have some oral mucosal lesions. Oral submucous fibrosis (6.4%), leukoplakia (5.5%), and traumatic ulceration (4.2%) were the major oral mucosal conditions observed. The information presented in this study adds to our understanding of the common oral mucosal lesions occurring in the eunuch population. Efforts to increase patient awareness of the oral effects of tobacco use and to eliminate the habit are needed to improve the oral and general health of eunuchs.


CGAT: computational genomics analysis toolkit.
Computational genomics seeks to draw biological inferences from genomic datasets, often by integrating and contextualizing next-generation sequencing data. CGAT provides an extensive suite of tools designed to assist in the analysis of genome scale data from a range of standard file formats. The toolkit enables filtering, comparison, conversion, summarization and annotation of genomic intervals, gene sets and sequences. The tools can both be run from the Unix command line and installed into visual workflow builders, such as Galaxy.


Prominin-1 controls stem cell activation by orchestrating ciliary dynamics.
Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle-dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol-binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases.


Effect of soaking, sprouting, fermentation and cooking on nutrient composition and some anti-nutritional factors of sorghum (Guinesia) seeds.
This study was designed to determine the effect of soaking, sprouting, fermentation and cooking on nutrient composition and some antinutritional factors of sorghum seeds (guinesia). Standard assay procedures were adopted to resolve both the nutrients and the antinutritional factors content of the products. Combination of cooking and fermentation improved the nutrient quality and drastically reduced the antinutritional factors to safe levels much greater than any of the other processing methods tested.


Three-dimensional line edge roughness in pre- and post-dry etch line and space patterns of block copolymer lithography.
In this work, we employ large-scale coarse-grained molecular dynamics (CGMD) simulations to study the three-dimensional line edge roughness associated with line and space patterns of chemo-epitaxially directed symmetric block copolymers (BCPs) on a flat substrate. The di-block copolymer chain length and interaction parameters are validated with the experimental BCP period, L0 and corresponding molecular weight. Defect-free lamellae are formed, after which the system is quenched below the glass transition temperature before selectively dry-etching off one of the BCP phases. The effect of varying etch-selectivity on post-etch resist domain morphology was studied. The roughness of the polymer domain was evaluated over three process stages: annealing, pre-etching, and post-etching. Power spectral density plots were then generated to elucidate the contributions of low and high frequency roughness for the three process stages. The roughness results obtained from simulations are shown to be in close agreement with the roughness result obtained from analyzing experimental SEM images. Parameters like the Hurtz roughness exponent and correlation length inherent to the process and the BCP were also revealed from the experimental study.


Defining the structural basis of human plasminogen binding by streptococcal surface enolase.
The flesh-eating bacterium group A Streptococcus (GAS) binds and activates human plasminogen, promoting invasive disease. Streptococcal surface enolase (SEN), a glycolytic pathway enzyme, is an identified plasminogen receptor of GAS. Here we used mass spectrometry (MS) to confirm that GAS SEN is octameric, thereby validating in silico modeling based on the crystal structure of Streptococcus pneumoniae alpha-enolase. Site-directed mutagenesis of surface-located lysine residues (SEN(K252 + 255A), SEN(K304A), SEN(K334A), SEN(K344E), SEN(K435L), and SEN(Delta434-435)) was used to examine their roles in maintaining structural integrity, enzymatic function, and plasminogen binding. Structural integrity of the GAS SEN octamer was retained for all mutants except SEN(K344E), as determined by circular dichroism spectroscopy and MS. However, ion mobility MS revealed distinct differences in the stability of several mutant octamers in comparison with wild type. Enzymatic analysis indicated that SEN(K344E) had lost alpha-enolase activity, which was also reduced in SEN(K334A) and SEN(Delta434-435). Surface plasmon resonance demonstrated that the capacity to bind human plasminogen was abolished in SEN(K252 + 255A), SEN(K435L), and SEN(Delta434-435). The lysine residues at positions 252, 255, 434, and 435 therefore play a concerted role in plasminogen acquisition. This study demonstrates the ability of combining in silico structural modeling with ion mobility-MS validation for undertaking functional studies on complex protein structures.


Sentinels of inequity: examining policy requirements for equity-oriented primary healthcare.
Non-government, not-for-profit community health centres (CHCs) play a crucial role within healthcare systems in fostering equity, acting both as direct providers of services and as sentinels of health and social inequity. In a study of an intervention to promote equity-oriented health care, we enlisted four diverse primary healthcare clinics with mandates to serve highly marginalized populations. All of these CHCs operate as not-for-profit, non-government organizations (NGOs), and have a marginal relationship financially and socially to other parts of the system. The purpose of this paper is to provide an analysis of the factors that shape how CHCs are able to carry out an equity mandate and, from this, to identify what is required at the level of policy to enhance capacity to provide equity-oriented health care. We systematically examined the clinics' policy and funding contexts, and identified influences on the clinics' capacities to promote equity-oriented health care. We identified three key mechanisms of influence, each playing out against the backdrop of a contested and marginal position of CHCs within the health care system: a) accountability and performance frameworks; b) patterns of funding and allocation of resources, and c) pathways for emergent priorities. We examine these mechanisms, considering how each influenced the pursuit of equity, and propose policy directions to optimize the primary health care sectors' capacity to support equity-oriented health care. Although this analysis is based on a study within a high-income country, we argue that because the dynamics between community health centres and broader healthcare systems are similar across national boundaries, the implications have applicability to low and middle-income countries.


Malaria transmission-blocking antigen, Pfs230, mediates human red blood cell binding to exflagellating male parasites and oocyst production.
Malaria transmission requires that the parasites differentiate into gametocytes prior to ingestion by a mosquito during a blood meal. Once in the mosquito midgut the gametocytes emerge from red blood cells (RBCs), fertilize, develop into ookinetes and finally infectious sporozoites. Gamete surface antigen, Pfs230, is an important malaria transmission-blocking vaccine candidate, but its function has remained unclear. Two clones with distinct Pfs230 gene disruptions (Delta1.356 and Delta2.560) and a clone with a disruption of Pfs48/45 were used to evaluate the role of Pfs230 in the mosquito midgut. Pfs230 disruptants successfully emerge from RBCs and male gametes exflagellate producing microgametes. However, exflagellating Pfs230-minus males, in the presence or absence of Pfs48/45, are unable to interact with RBCs and form exflagellation centres. Oocyst production and mosquito infectivity is also significantly reduced, 96-92% and 76-71% respectively. In contrast, in the Pfs230 disruptants the expression and localization of other known sexual stage-specific antigens, including Pfs48/45, Pfs47, the Pfs230 paralogue (PfsMR5), Pfs16 or Pfs25, were not altered and the Pfs230-minus gametes retained resistance to the alternative pathway of human complement. These results suggest that Pfs230 is the surface molecule on males that mediates RBC binding and plays an important role in oocyst development, a critical step in malaria transmission.


Autogenous regulation of ethanolamine utilization by a transcriptional activator of the eut operon in Salmonella typhimurium.
The genes required for use of ethanolamine as a carbon and nitrogen source are encoded by a single operon (eut) whose expression is induced by the simultaneous presence of both ethanolamine and cobalamin (vitamin B12). The action of B12 as an inducer of this operon reflects the fact that this cofactor is required by the degradative enzyme ethanolamine lyase (eutBC). The eutR gene encodes a protein that activates transcription of the eut operon in response to the simultaneous presence of B12 and ethanolamine. The eutR gene is expressed by a weak constitutive promoter activity (PII) and by the main regulated promoter (PI). Because it is encoded within the operon that it activates, the EutR protein controls its own production. Initial induction of the eut operon by ethanolamine plus B12 causes an increase in expression of the eutR gene; this increase acts as part of a positive feedback loop that is required for maximal operon expression. Because of this mode of regulation, constitutive regulatory mutations, described here, include mutations that generate new internal promoters and thereby increase the basal level of eutR gene expression. In mutants with an increased level of activator protein, each inducer (B12 or ethanolamine), presented singly, is sufficient for partial operon induction.


Neuronal damage after ischemic injury in the middle cerebral arterial territory: deep watershed versus territorial infarction at MR perfusion and spectroscopic imaging.
To determine the temporal patterns of neuronal injury between infarction subtypes and their possible association with changes in cerebral blood volume (CBV). Twenty-five patients with ischemic injuries of middle cerebral arterial territories and receiving only conservative treatments were classified into territorial infarction (TI) (n = 16) and watershed infarction (WI) (n = 9) groups and were prospectively evaluated with longitudinal magnetic resonance (MR) examinations. Each patient underwent as many as five MR studies at various stroke stages following stroke symptom onset. Dynamic susceptibility-weighted contrast material-enhanced MR imaging was performed to yield the relative CBV (rCBV). Chemical shift imaging was used to measure the relative levels of N-acetylaspartate (NAA) and lactate of the ischemic brain tissue. Repeated-measures analysis of variance was used to examine the statistical significance in evolutional differences between TI and WI. For patients with TI, rCBV followed a progressively increasing pattern, from initial low values (0.46 +/- 0.28 [SD]) to peak high values (1.23 +/- 0.34) at early chronic stage. Relative NAA level decreased to 0.40 +/- 0.24 during acute stroke and was lost completely 4 days after ictus. Patients with WI showed consistently high rCBV throughout all stages, with residual relative NAA level (0.53 +/- 0.25) even at 1 month after symptom onset. Relative lactate level of patients with TI was significantly higher than that of patients with WI at the acute stage (P <.01). Differences in the temporal changes of both rCBV and brain metabolites between TI and WI were significant (P <.01). The different temporal patterns for stroke progression in TI and WI are associated with different evolutions of hemodynamics and neuronal injury.


Accurate route demonstration by experienced homing pigeons does not improve subsequent homing performance in naive conspecifics.
We describe an experiment that uses the grouping tendencies and navigational abilities of the homing pigeon (Columba livia) to investigate the possibility of socially mediated information transfer in a field setting. By varying the composition of paired-release types, we allowed some naive birds to receive an accurate demonstration of the home route whilst others were paired with similarly naive conspecifics. After this 'paired phase', we predicted that if any learning of spatial information occurred then naive members of the former pairs would outperform their untutored conspecifics when re-released individually during the subsequent 'single phase' of the experiment. This prediction was not confirmed. Neither homing speed nor initial orientation was superior in individually released tutored versus untutored birds, despite the fact that both performance measures were better in the earlier 'paired phase' with experienced demonstrators. Our results suggest that although naive homing pigeons clearly interact with their experienced partners, they are unable to transfer any individually useful spatial information to subsequent homing flights.


A nematode gene required for sperm vesicle fusion.
During maturation of spermatids to motile spermatozoa in Caenorhabditis elegans, large vesicles called membranous organelles (MOs) fuse with the spermatid plasma membrane. Mutations in the gene fer-1 cause abnormal spermatozoa in which the MOs do not fuse, although they abut the plasma membrane normally. Here we describe the fer-1 gene, which we found to be approximately 8.6 kb in length and to encode a 6.2 kb transcript whose expression is limited to the primary spermatocytes, the cells in which the MOs form. fer-1 is predicted to encode a 235 kDa protein which is highly charged except for a putative transmembrane domain near the C terminus. We identified the mutations associated with five fer-1 alleles, all of which are missense mutations causing single amino acid changes. FER-1 is not similar to any characterized proteins in sequence databases, nor does it contain known functional motifs other than the predicted transmembrane domain. The C-terminal transmembrane domain makes FER-1 resemble some viral fusion proteins, suggesting it may play a direct role in MO-plasma membrane fusion. FER-1 does show significant sequence similarity to several predicted human proteins of unknown function. Two of the identified fer-1 mutations are located in regions of similarity between FER-1 and two of these predicted proteins. This strengthens the biological significance of these similarities and suggests these regions of similarity represent functionally important domains of FER-1 and the human proteins.