PLASMA BIOCHEMISTRY AND HEMATOLOGY REFERENCE VALUES OF CAPTIVE PANTHER CHAMELEONS (FURCIFER PARDALIS) WITH SPECIAL EMPHASIS ON SEASONALITY AND GENDER DIFFERENCES.
Blood samples of 86 captive panther chameleons (Furcifer pardalis) were collected in January and August from the ventral coccygeal vein in order to establish reference intervals of clinical healthy individuals under similar husbandry conditions for plasma biochemistry and hematology for this species. Significant differences were found in phosphorus, glucose, total protein, albumin, and white blood cell count between males and females in both seasons. Calcium, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase varied in only one season between genders. Significant differences between summer and winter values were present in both genders for uric acid, calcium, phosphorus, glucose, total protein, creatine kinase, and albumin. Additionally, females showed seasonal variations for alanine aminotransferase and aspartate aminotransferase whereas packed cell volume varied in males. Gravid females had significantly higher body weights and increased values for uric acid, calcium, phosphorus, alanine aminotransferase, total protein, and albumin. Cytomorphologic characteristics of blood cells in stained blood films were evaluated to serve as additional parameters for hematology.


Hyaluronan fragments improve wound healing on in vitro cutaneous model through P2X7 purinoreceptor basal activation: role of molecular weight.
hyaluronan biopolymer is used in dermatology but the underlying mechanism and the impact of its molecular weight have not yet been investigated in skin wound healing. The aim of our work was to study the role of HA molecular weight in the proliferative phase of wound healing and to understand how this physiological biopolymer acts to promote wound healing on a human keratinocyte in vitro model. wound healing closure was evaluated using scratch test assay, cell proliferation by counting cell with haemocytometer, expression of CD44 and ZO-1 (protein present in tight junctions specific of epithelia) using flow cytometry, and P2X7 receptor activation on living using a cytoflurometric method. Our study showed that medium hyaluronan fragment (MMW-HA, between 100 and 300 kDa) induced a significant increase in wound closure, increased ZO-1 protein expression and induced a slight activation of P2X7 receptor, contrary to high (between 1000 and 1400 kDa) and low (between 5 and 20 kDa) molecular hyaluronan fragments that had no healing effects. Basal activation of P2X7 receptor is already known to stimulate cell proliferation and this activation in our model plays a pivotal role in MMW-HA-induced wound healing. Indeed, we showed that use of BBG, a specific inhibitor of P2X7 receptor, blocked completely the beneficial effects of MMW-HA on wound healing. taken together, our results showed for the first time the relationship between P2X7 receptor and hyaluronan in wound healing, and that topical use of MMW-HA (fragment between 100 and 300 kDa) could represent a new therapeutic strategy to promote healing.


Walk-in clinics in Ontario. An atmosphere of tension.
To explore family practice (FP), emergency department (ED), and walk-in clinic (WIC) physicians' perceptions and experiences regarding the effect of walk-in clinics on Ontario's health care system. Qualitative method of focus groups. Hamilton, London, and Toronto, Ont. Sixty-three physicians participated in nine focus groups, each with four to nine participants. Family physicians, ED physicians, and WIC physicians attended separate focus groups. Nine focus groups were conducted in three cities in Ontario. Physicians' opinions, perceptions, and experiences regarding the role and effect of WICs on Ontario's health care system were explored. Focus groups were audiotaped and comments transcribed verbatim. The qualitative data analysis program NUD*IST was used to organize the data during sequential thematic analysis. Participants identified two key factors contributing to the evolution of WICs: patients' expectations for convenient health care and the perceived limited availability of family physicians. Participants thought these two related factors resulted in a gap in primary care services that WICs had filled. Throughout discussions, an atmosphere of tension permeated the focus groups. Tension seemed to arise from issues of duplication, competition, standards of practice and quality of care in WICs, the effect of environmental and personal factors on physicians' practice, and the practice philosophy adopted by WIC physicians. Both FP and ED participants acknowledged their contribution to the gap in primary care services. They appeared to attribute current problems in health care delivery to the perceived deficiencies of WICs. The outcome was a marked tension among participants.


The human cytomegalovirus UL55 (gB) and UL75 (gH) glycoprotein ligands initiate the rapid activation of Sp1 and NF-kappaB during infection.
The cellular transcription factors Sp1 and NF-kappaB were upregulated shortly after the binding of purified live or UV-inactivated human cytomegalovirus (HCMV) to the cell surface. The rapid time frame of transcription factor induction is similar to that seen in other systems in which cellular factors are induced following receptor-ligand engagement. This similarity suggested that a cellular receptor-viral ligand interaction might be involved in Sp1 and NF-kappaB activation during the earliest stages of HCMV infection. To focus on the possible role viral ligands play in initiating cellular events following infection, we first used purified viral membrane extracts to demonstrate that constituents on the membrane are responsible for cellular activation. Additionally, these studies showed, through the use of neutralizing antibodies, that the viral membrane mediators of this activation are the major envelope glycoproteins gB (UL55) and gH (UL75). To confirm these results, neutralizing anti-gB and -gH antibodies were used to block the interactions of these glycoproteins on whole purified virus with their cell surface receptors. In so doing, we found that Sp1 and NF-kappaB induction was inhibited. Lastly, through the use of purified viral gB protein and an anti-idiotypic antibody that mimics the image of the viral gH protein, it was found that the engagement of individual viral ligands with their appropriate cell surface receptors was sufficient to activate cellular Sp1 and NF-kappaB. These results support our hypothesis that HCMV glycoproteins mediate an initial signal transduction pathway which leads to the upregulation of host cell transcription factors and suggests a model wherein the orderly sequence of virus-mediated changes in cellular activation initiates with viral binding via envelope glycoproteins to the cognate cellular receptor(s).


Home visits during pregnancy enhance male partner HIV counselling and testing in Kenya: a randomized clinical trial.
HIV testing male partners of pregnant women may decrease HIV transmission to women and promote uptake of prevention of mother-to-child HIV transmission (PMTCT) interventions. However, it has been difficult to access male partners in antenatal care (ANC) clinics. We hypothesized that home visits to offer HIV testing to partners of women attending ANC would increase partner HIV testing. Women attending their first ANC were enrolled, interviewed using smartphone audio-computer-assisted self-interviews and randomized to home visits or written invitations for male partners to come to clinic, if they were married or cohabiting, unaccompanied by partners and had no prior couple HIV counselling and testing (CHCT). Enrolled men were offered CHCT (HIV testing and mutual disclosure). Prevalence of CHCT, male HIV seropositivity, couple serodiscordance and intimate partner violence, reported as physical threat from partner, were compared at 6 weeks. Among 495 women screened, 312 were eligible, and 300 randomized to clinic-based or home-based CHCT. Median age was 22 years (interquartile range 20-26 years), and 87% were monogamous. CHCT was significantly higher in home-visit than in clinic-invitation arm (n = 128, 85% vs. n = 54, 36%; P < 0.001). Home-arm identified more HIV-seropositive men (12.0 vs. 8.0%; P = 0.248) and more HIV-discordant couples (14.7 vs. 4.7%; P = 0.003). There was no difference in intimate partner violence. Home visits of pregnant women were safe and resulted in more male partner testing and mutual disclosure of HIV status. This strategy could facilitate prevention of maternal HIV acquisition, improve PMTCT uptake and increase male HIV diagnosis.


Blockade of the renin-angiotensin system.
The renin-angiotensin-aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin-converting enzyme inhibitors inhibit angiotensin-converting enzyme and have been shown to be effective in many cardiovascular diseases. They should be considered for the treatment of hypertension in patients with heart failure, previous myocardial infarction, diabetes, or proteinuria. There are a number of side-effects associated with angiotensin-converting enzyme inhibitors, especially persistent dry cough. Angiotensin II receptor antagonists (sartans) provide a more specific blockade of the renin-angiotensin-aldosterone system and are associated with fewer side-effects, including cough. Their long-term efficacy and tolerability in the treatment of patients with hypertension has, however, yet to be established. Periodic monitoring of renal function and electrolytes is required in patients treated with an angiotensin-converting enzyme inhibitor or a sartan.


Pathogenecity of Yersinia enterocolitica for mice.
A laboratory infection of Yersinia enterocolitica in mice which closely resembles the naturally acquired human infection is described Intravenous inoculation of mice with small numbers of Y. enterocolitica gives rise to a systemic, pyogenic infection involving primarily the spleen, liver, and lungs. Massive neutrophil infiltration of these organs occurs early in the infection, eventually leading to large abscesses and pulmonary consolidation. Mice infected intragastrically show neutophil infiltration in the Peyer's patches of the distal ileum less than 24h postinfection. The Peyer's patches are unable to contain the infection which spreads to the mesenteric lymph node, causing large abscesses in the medullary regions. Soon after, the infection becomes systemic with abscesses forming in the liver, spleen, and lungs, and the total peripheral leukocyte count rises dramatically to over 30,000/mm2. A serological response, in the form of agglutinating antibody, begins to appear 2 weeks after infection. Possible causes of death and the usefulness of this infectious disease model are discussed.


Osseointegration of biochemically modified implants in an osteoporosis rodent model.
The present study examined the impact of implant surface modifications on osseointegration in an osteoporotic rodent model. Sandblasted, acid-etched titanium implants were either used directly (control) or were further modified by surface conditioning with NaOH or by coating with one of the following active agents: collagen/chondroitin sulphate, simvastatin, or zoledronic acid. Control and modified implants were inserted into the proximal tibia of aged ovariectomised (OVX) osteoporotic rats (n = 32/group). In addition, aged oestrogen competent animals received either control or NaOH conditioned implants. Animals were sacrificed 2 and 4 weeks post-implantation. The excised tibiae were utilised for biomechanical and morphometric readouts (n = 8/group/readout). Biomechanical testing revealed at both time points dramatically reduced osseointegration in the tibia of oestrogen deprived osteoporotic animals compared to intact controls irrespective of NaOH exposure. Consistently, histomorphometric and microCT analyses demonstrated diminished bone-implant contact (BIC), peri-implant bone area (BA), bone volume/tissue volume (BV/TV) and bone-mineral density (BMD) in OVX animals. Surface coating with collagen/chondroitin sulphate had no detectable impact on osseointegration. Interestingly, statin coating resulted in a transient increase in BIC 2 weeks post-implantation; which, however, did not correspond to improvement of biomechanical readouts. Local exposure to zoledronic acid increased BIC, BA, BV/TV and BMD at 4 weeks. Yet this translated only into a non-significant improvement of biomechanical properties. In conclusion, this study presents a rodent model mimicking severely osteoporotic bone. Contrary to the other bioactive agents, locally released zoledronic acid had a positive impact on osseointegration albeit to a lesser extent than reported in less challenging models.


Adaptive deep brain stimulation in advanced Parkinson disease.
Brain-computer interfaces (BCIs) could potentially be used to interact with pathological brain signals to intervene and ameliorate their effects in disease states. Here, we provide proof-of-principle of this approach by using a BCI to interpret pathological brain activity in patients with advanced Parkinson disease (PD) and to use this feedback to control when therapeutic deep brain stimulation (DBS) is delivered. Our goal was to demonstrate that by personalizing and optimizing stimulation in real time, we could improve on both the efficacy and efficiency of conventional continuous DBS. We tested BCI-controlled adaptive DBS (aDBS) of the subthalamic nucleus in 8 PD patients. Feedback was provided by processing of the local field potentials recorded directly from the stimulation electrodes. The results were compared to no stimulation, conventional continuous stimulation (cDBS), and random intermittent stimulation. Both unblinded and blinded clinical assessments of motor effect were performed using the Unified Parkinson's Disease Rating Scale. Motor scores improved by 66% (unblinded) and 50% (blinded) during aDBS, which were 29% (p = 0.03) and 27% (p = 0.005) better than cDBS, respectively. These improvements were achieved with a 56% reduction in stimulation time compared to cDBS, and a corresponding reduction in energy requirements (p < 0.001). aDBS was also more effective than no stimulation and random intermittent stimulation. BCI-controlled DBS is tractable and can be more efficient and efficacious than conventional continuous neuromodulation for PD.


Polar vortices on Earth and Mars: A comparative study of the climatology and variability from reanalyses.
Polar vortices on Mars provide case-studies to aid understanding of geophysical vortex dynamics and may help to resolve long-standing issues regarding polar vortices on Earth. Due to the recent development of the first publicly available Martian reanalysis dataset (MACDA), for the first time we are able to characterise thoroughly the structure and evolution of the Martian polar vortices, and hence perform a systematic comparison with the polar vortices on Earth. The winter atmospheric circulations of the two planets are compared, with a specific focus on the structure and evolution of the polar vortices. The Martian residual meridional overturning circulation is found to be very similar to the stratospheric residual circulation on Earth during winter. While on Earth this residual circulation is very different from the Eulerian circulation, on Mars it is found to be very similar. Unlike on Earth, it is found that the Martian polar vortices are annular, and that the Northern Hemisphere vortex is far stronger than its southern counterpart. While winter hemisphere differences in vortex strength are also reported on Earth, the contrast is not as large. Distinctions between the two planets are also apparent in terms of the climatological vertical structure of the vortices, in that the Martian polar vortices are observed to decrease in size at higher altitudes, whereas on Earth the opposite is observed. Finally, it is found that the Martian vortices are less variable through the winter than on Earth, especially in terms of the vortex geometry. During one particular major regional dust storm on Mars (Martian year 26), an equatorward displacement of the vortex is observed, sharing some qualitative characteristics of sudden stratospheric warmings on Earth.


Crystal structure of glutamate-1-semialdehyde-2,1-aminomutase from Arabidopsis thaliana.
Glutamate-1-semialdehyde-2,1-aminomutase (GSAM) catalyzes the isomerization of glutamate-1-semialdehyde (GSA) to 5-aminolevulinate (ALA) and is distributed in archaea, most bacteria and plants. Although structures of GSAM from archaea and bacteria have been resolved, a GSAM structure from a higher plant is not available, preventing further structure-function analysis. Here, the structure of GSAM from Arabidopsis thaliana (AtGSA1) obtained by X-ray crystallography is reported at 1.25 Å resolution. AtGSA1 forms an asymmetric dimer and displays asymmetry in cofactor binding as well as in the gating-loop orientation, which is consistent with previously reported Synechococcus GSAM structures. While one monomer binds PMP with the gating loop fixed in the open state, the other monomer binds either PMP or PLP and the gating loop is ready to close. The data also reveal the mobility of residues Gly163, Ser164 and Gly165, which are important for reorientation of the gating loop. Furthermore, the asymmetry of the AtGSA1 structure supports the previously proposed negative cooperativity between monomers of GSAM.


The function-led design of Z-scheme photocatalytic systems based on hollow carbon nitride semiconductors.
A ternary photocatalyst has been successfully constructed through the integration of Au, CdS and hollow carbon nitride nanospheres (HCNS), where Au nanoparticles were designed to shuttle interparticle transfer of charge carriers between CdS and HCNS photosensitizers to establish two-photon (Z-scheme) photocatalytic tandem systems for solar fuel production. The solid-state CdS-Au-HCNS Z-scheme nanocomposites were efficient for H2 evolution (with a quantum yield of 8.7% at 420 nm) and CO2 reduction catalysis with visible light irradiation. This work further proves the feasibility of employing hollow conjugated polymer photocatalysts in the function-led design of artificial Z-type photosynthetic machinery on soft material interfaces.


Evaluation of the effect of respiratory and anatomical variables on a Fourier technique for markerless, self-sorted 4D-CBCT.
A novel technique based on Fourier transform theory has been developed that directly extracts respiratory information from projections without the use of external surrogates. While the feasibility has been demonstrated with three patients, a more extensive validation is necessary. Therefore, the purpose of this work is to investigate the effects of a variety of respiratory and anatomical scenarios on the performance of the technique with the 4D digital extended cardiac torso phantom. FT-phase and FT-magnitude methods were each applied to identify peak-inspiration projections and quantitatively compared to the gold standard of visual identification. Both methods proved to be robust across the studied scenarios with average differences in respiratory phase <10% and percentage of projections assigned within 10% of the gold standard >90%, when incorporating minor modifications to region-of-interest (ROI) selection and/or low-frequency location for select cases of DA and lung percentage in the field of view of the projection. Nevertheless, in the instance where one method initially faltered, the other method prevailed and successfully identified peak-inspiration projections. This is promising because it suggests that the two methods provide complementary information to each other. To ensure appropriate clinical adaptation of markerless, self-sorted four-dimensional cone-beam CT (4D-CBCT), perhaps an optimal integration of the two methods can be developed.


Polycyclic aromatic hydrocarbon exposure in oesophageal tissue and risk of oesophageal squamous cell carcinoma in north-eastern Iran.
To evaluate the association between polycyclic aromatic hydrocarbon (PAH) exposure in oesophageal epithelial tissue and oesophageal squamous cell carcinoma (ESCC) case status in an ESCC case-control study in a high-risk population in north-eastern Iran. Tissue microarrays (TMAs) of non-tumoral oesophageal biopsies from patients with biopsy-proven ESCC and gastrointestinal clinic patients with no endoscopic or biopsy evidence of ESCC (control subjects) in a rural region in north-eastern Iran were immunohistochemically stained. Immunohistochemistry was performed using monoclonal antibodies 8E11 and 5D11 raised against benzo[a]pyrene (B[a]P) diol epoxide (BPDE)-I-modified guanosine and BPDE-I-modified DNA, respectively. Staining intensity was quantified by image analysis and the average staining in three replicates was calculated. The main outcome measure was adjusted ORs with 95% CIs for the association between antibody staining intensity and ESCC case status. Cultured ESCC cells exposed to B[a]P in vitro showed dose-dependent staining with 8E11 but not with 5D11. With 8E11, sufficient epithelial tissue was available in the TMA cores to analyse 91 cases and 103 controls. Compared with the lowest quintile of 8E11 staining in the controls, adjusted ORs for the 2nd to 5th quintiles were 2.42, 5.77, 11.3 and 26.6 (95% CI 5.21 to 135), respectively (p for trend <0.001). With 5D11, 89 cases and 101 controls were analysed. No association between staining and case status was observed (ORs for the 2nd to 5th quintiles were 1.26, 0.88, 1.06 and 1.63 (95% CI 0.63 to 4.21), p for trend=0.40). Dramatically higher levels of 8E11 staining were observed in non-tumoral oesophageal epithelium from patients with ESCC than from control subjects. This finding strengthens the evidence for a causal role for PAHs in oesophageal carcinogenesis in north-eastern Iran.


Efficiency and outcome of non-invasive versus invasive positive pressure ventilation therapy in respiratory failure due to chronic obstructive pulmonary disease.
Application noninvasive ventilation in the patients with exacerbation of chronic obstructive pulmonary disease (COPD) reduced mortality. This case-control study was designed to compare efficiency and outcome of non-invasive (NIV) versus invasive positive pressure ventilation (IPPV) in respiratory failure due to COPD. The patients were assigned to NIV or IPPV intermittantly.The clinical parameters, including RR (respiratory rate), BP (blood pressure), HR (heart rate) and PH, PaCO2, PaO2 before and 1, 4 and 24 h after treatment were measured. Demographic information such as age, sex, severity of disease based on APACHE score, length of stay and outcome were recorded. Fifty patients were enrolled in the NIV group and 50 patients in IPPV. The mean age was 70.5 in NIV and 63.9 in invasive ventilation group (p>0.05). In IPPV group, the average values of PH: PCO2: and PO2, were 7.22±0.11, 69.64 + 24.25: and 68.86±24.41 .In NIV, the respective values were 7.30±0.07, 83.94±18.95, and 60.60±19.88. In NIV group, after 1, 4 and 24 h treatment, the clinical and ventilation parameters were stable. The mean APACHE score in was IPPV, 26.46±5.45 and in NIV was 12.26±5.54 (p<0.05). The average length of hospital stay in IPPV was 15.90±10 and in NIV 8.12±6.49 days (p<0.05). The total mortality in the NIV was 4 (8%) and in IPPV, 27 patients (54%) (p<0.05). This study indicates that using NIPPV is a useful therapeutic mode of treatment for respiratory failure with acceptable success rate and lower mortality. The application of NIPPV reduces hospital stay, intubation and its consequent complications.


Proximal shift in the distribution of adenomatous polyps in Korea over the past ten years.
Several reports have suggested a trend of right-side shift of colorectal cancer; however, there were only a few studies on the chronologic changes in the distribution of adenomatous polyps. We aimed to study the changes in the distribution of colorectal adenomatous polyps over the past ten years. We reviewed medical records of patients who underwent a colonoscopy at Yonsei University Severance Hospital, Seoul, Korea between January 1996 and December 2005. Patients who had an adenomatous polyp with a diameter of at least 5mm were included. Of these, patients with a history of colon resection, colorectal cancer, colorectal polyp, inflammatory bowel disease, HNPCC, or familial adenomatous polyposis were excluded. A total of 2,498 patients and 4,591 adenomatous polyps were included in this study. Analysis with respect to number of patients showed significant increases in the proportion of patients with adenomatous polyp on the proximal colon, from 48.5% to 66.3% (p<0.001). Analysis with respect to number of polyps revealed that the proportion of adenomatous polyps on the proximal colon significantly increased from 48.9% to 62.3% (p<0.001). The proportion of adenomatous polyp on the proximal colon significantly increased over the past 10 years.


Analysis of the microbial functional diversity within water-stressed soil communities by flow cytometric analysis and CTC+ cell sorting.
Total and active cell counts within soil samples were determined by culture-independent methods using flow cytometry and preparative Nycodenz gradient centrifugation. Whole cells were purified from soil cores and total extractable cell counts assessed by SYBR Green II fluorescence, while active cell counts were determined by 5-cyano-2,3-ditolyl tetrazolium chloride reduction (CTC+ cells). Parallel microcosms, maintained at either field water capacity or subjected to drying, indicated that the total extractable cell count remained between 10(8) and 10(9) g(-1) (dry weight). In contrast, the CTC+ active count fell threefold in dried microcosms (6% of total cell count) when compared to wetted microcosms (18% of total cell count). Specifically, these data highlighted an overall deactivation of microbial biomass during water stress, with 16S rDNA analyses of flow-sorted CTC+ cells demonstrating shifts within the active diversity. Flow cytometry coupled with cell purification techniques represents a significant tool for operationally defining an active and redundant microbial component within soil communities and is demonstrated during water stress.


Kidney replacement therapy in pediatric patients on mechanical circulatory support: challenges for the pediatric nephrologist.
The use of mechanical circulatory support (MCS) therapies in children with medically refractory cardiac failure has increased over the past two decades. With the growing experience and expertise, MCS is currently offered as a bridge to recovery or heart transplantation and in some cases even as destination therapy. Acute kidney injury (AKI) is common in patients with end-stage heart failure (ESHF). When severe AKI develops requiring kidney replacement therapy (KRT), these patients present unique challenges for the pediatric nephrology team. The use of KRT has not been adequately described in children with ESHF on the newer MCS. We also present original case series data from our center experience. The purpose of this review is to familiarize the reader with the current MCS technologies, approach to their selection, how they interact when combined with current KRT circuits, and distinguish similarities and differences. We will attempt to highlight the distinctive features of each technology, specifically focusing on growing trends in use of continuous-flow ventricular assist devices (CF-VAD) as it poses additional challenges to the pediatric nephrologist.


Conjugation of a self-antigen to papillomavirus-like particles allows for efficient induction of protective autoantibodies.
High avidity and long-lasting autoantibodies to a self-polypeptide (TNF-alpha) were generated after parenteral vaccination of mice with low doses of virus-like particle-based (VLP-based) vaccines that were constructed by linking mouse TNF-alpha peptides to the surface of papillomavirus VLPs. High-titer autoantibodies were induced with or without coadministration of potent conventional adjuvants, but were enhanced by coadministration of CFA. Compared with immunization with the fusion protein alone, attachment to VLPs increased autoantibody titers 1,000-fold. A comparison of Ab responses against the self (TNF-alpha) and foreign components of the fusion protein showed that VLP conjugation abrogated the ability of the humoral immune system to distinguish between self and foreign. Similar levels of IgM were detected to self and foreign epitopes regardless of the assembly state of the antigen, suggesting that conjugation of self-peptides to VLPs promotes survival or expansion of mature autoreactive B cells. In a mouse model, vaccination with conjugated particles inhibited development of type II collagen-induced arthritis. Together, these results suggest a potentially flexible method to efficiently generate autoantibodies against specific self-proteins that mediate arthritis and other diseases.


The Use of Tranexamic Acid for Upper Gastrointestinal Bleeding by Medical and Surgical Intensivists: A Single Center Experience.
Tranexamic acid (TXA) may be beneficial in the management of upper gastrointestinal bleeding (UGIB). We sought to investigate how frequently intensivists at our academic institution use TXA for patients with UGIB, and to investigate whether the utilization rate of TXA differs between surgical and medical intensivists, and provide an updated literature review on the subject. We performed a retrospective cohort study of patients admitted for UGIB to the surgical intensive care unit (SICU) and the medical intensive care unit (MICU) at our academic healthcare facility (University of Florida Health - Shands Hospital) from January 1, 2013 to December 31, 2016. The patients were categorized as receiving or not receiving TXA. The overall utilization rate of TXA was calculated, and the utilization rates for the MICU and SICU were compared using a two-sample test for equality of two proportions with continuity correction. The study cohort included a total of 1,829 patients with a diagnosis of UGIB. Of those, 988 were treated in the MICU and 841 were treated in the SICU. Of the 988 patients in the MICU, six received TXA (0.61%), while 10 (1.19%) of the 841 patients in the SICU received TXA. The overall utilization rate of TXA was 0.87%. The odds of receiving TXA in the SICU were 1.97 times greater than in the MICU (odds ratio (OR): 1.97, 95% confidence interval (CI): 0.74 - 5.2, P = 1.83). Our study suggests that TXA may be underused in the management of UGIB, and that the utilization rate does not differ significantly between surgical and medical intensivists.


The effect of work-related sustained trapezius muscle activity on the development of neck and shoulder pain among young adults.
This study aimed to evaluate if sustained trapezius muscle activity predicts neck and shoulder pain over a 2.5-year period. Forty young adults (15 hairdressers, 14 electricians, 5 students and 6 with various work) were followed during their first years of working life. Self-reported neck and shoulder pain during the last four weeks was assessed seven times over the observational period. Upper-trapezius muscle activity was measured during a full working day by bilateral surface electromyography (EMG) at baseline (winter 2006/7). Sustained trapezius muscle activity was defined as continuous muscle activity with amplitude >0.5% EMGmax lasting >4 minutes. The relative time of sustained muscle activity during the working day was calculated and further classified into low (0-29%), moderate (30-49%) and high (50-100%) level groups. Generalized estimating equations (GEE), adjusted for time, gender, mechanical workload, control-over-work intensity, physical activity, tobacco use, and prior neck and shoulder pain, showed that participants with a high level of sustained muscle activity had a rate of neck and shoulder pain three times higher than the low level group during a 2.5-year period. The association was strongest at the same time and shortly after the EMG measurement, indicating a time-lag of ≤6 months. The results support the hypothesis that sustained trapezius muscle activity is associated with neck and shoulder pain. This association was strongest analyzing cross-sectional and short-term effects.


Major cellular and physiological impacts of ocean acidification on a reef building coral.
As atmospheric levels of CO(2) increase, reef-building corals are under greater stress from both increased sea surface temperatures and declining sea water pH. To date, most studies have focused on either coral bleaching due to warming oceans or declining calcification due to decreasing oceanic carbonate ion concentrations. Here, through the use of physiology measurements and cDNA microarrays, we show that changes in pH and ocean chemistry consistent with two scenarios put forward by the Intergovernmental Panel on Climate Change (IPCC) drive major changes in gene expression, respiration, photosynthesis and symbiosis of the coral, Acropora millepora, before affects on biomineralisation are apparent at the phenotype level. Under high CO(2) conditions corals at the phenotype level lost over half their Symbiodinium populations, and had a decrease in both photosynthesis and respiration. Changes in gene expression were consistent with metabolic suppression, an increase in oxidative stress, apoptosis and symbiont loss. Other expression patterns demonstrate upregulation of membrane transporters, as well as the regulation of genes involved in membrane cytoskeletal interactions and cytoskeletal remodeling. These widespread changes in gene expression emphasize the need to expand future studies of ocean acidification to include a wider spectrum of cellular processes, many of which may occur before impacts on calcification.


Empirical evidence for differential organ reductions during trans-oceanic bird flight.
Since the early 1960s it has been held that migrating birds deposit and use only fat as fuel during migratory flight, with the non-fat portion of the body remaining homeostatic. Recent evidence from field studies has shown large changes in organ sizes in fuelling birds, and theory on fuel use suggests protein may be a necessary fuel during flight. However, an absence of information on the body condition of migrants before and after a long flight has hampered understanding of the dynamics of organs during sustained flight. We studied body condition in a medium-sized shorebird, the great knot (Calidris tenuirostris), before and after a flight of 5400 km from Australia to China during northward migration. Not only did these birds show the expected large reduction in fat content after migration, there was also a decrease in lean tissue mass, with significant decreases in seven organs. The reduction in functional components is reflected in a lowering of the basal metabolic rate by 42% [corrected]. Recent flight models have tried to separate the 'flexible' part of the body from the constant portion. Our results suggest that apart from brains and lungs no organs are homeostatic during long-distance flight. Such organ reductions may be a crucial adaptation for long-distance flight in birds.


Biomechanical and clinical factors related to stage I posterior tibial tendon dysfunction.
Case control. To investigate differences in arch height, ankle muscle strength, and biomechanical factors in individuals with stage I posterior tibial tendon dysfunction (PTTD) in comparison to healthy individuals. PTTD is a progressive condition, so early recognition and treatment are essential to help delay or reverse the progression. However, no previous studies have investigated stage I PTTD, and no single study has measured static anatomical structure, muscle strength, and gait mechanics in this population. Twelve individuals with stage I PTTD and 12 healthy, age- and gender-matched control subjects, who were engaged in running-related activities, participated in this study. Measurements of arch height index, maximum voluntary ankle invertor muscle strength, and 3-dimensional rearfoot and medial longitudinal arch kinematics during walking were obtained. The runners with PTTD demonstrated significantly lower seated arch height index (P = .02) and greater (P = .03) and prolonged (P = .05) peak rearfoot eversion angle during gait, compared to the healthy runners. No differences were found in standing arch height index values (P = .28), arch rigidity index (P = .06), ankle invertor strength (P = .49), or peak medial longitudinal arch values (P = .49) between groups. The increased foot pronation is hypothesized to place greater strain on the posterior tibialis muscle, which may partially explain the progressive nature of this condition.


Mapping strengths into virtues: the relation of the 24 VIA-strengths to six ubiquitous virtues.
The Values-in-Action-classification distinguishes six core virtues and 24 strengths. As the assignment of the strengths to the virtues was done on theoretical grounds it still needs empirical verification. As an alternative to factor analytic investigations the present study utilizes expert judgments. In a pilot study the conceptual overlap among five sources of knowledge (strength's name including synonyms, short definitions, brief descriptions, longer theoretical elaborations, and item content) about a particular strength was examined. The results show that the five sources converged quite well, with the short definitions and the items being slightly different from the other. All strengths exceeded a cut-off value but the convergence was much better for some strengths (e.g., zest) than for others (e.g., perspective). In the main study 70 experts (from psychology, philosophy, theology, etc.) and 41 laypersons rated how prototypical the strengths are for each of the six virtues. The results showed that 10 were very good markers for their virtues, nine were good markers, four were acceptable markers, and only one strength failed to reach the cut-off score for its assigned virtue. However, strengths were often markers for two or even three virtues, and occasionally they marked the other virtue more strongly than the one they were assigned to. The virtue prototypicality ratings were slightly positively correlated with higher coefficients being found for justice and humanity. A factor analysis of the 24 strengths across the ratings yielded the six factors with an only slightly different composition of strengths and double loadings. It is proposed to adjust either the classification (by reassigning strengths and by allowing strengths to be subsumed under more than one virtue) or to change the definition of certain strengths so that they only exemplify one virtue. The results are discussed in the context of factor analytic attempts to verify the structural model.


Digital technologies in the public-health response to COVID-19.
Digital technologies are being harnessed to support the public-health response to COVID-19 worldwide, including population surveillance, case identification, contact tracing and evaluation of interventions on the basis of mobility data and communication with the public. These rapid responses leverage billions of mobile phones, large online datasets, connected devices, relatively low-cost computing resources and advances in machine learning and natural language processing. This Review aims to capture the breadth of digital innovations for the public-health response to COVID-19 worldwide and their limitations, and barriers to their implementation, including legal, ethical and privacy barriers, as well as organizational and workforce barriers. The future of public health is likely to become increasingly digital, and we review the need for the alignment of international strategies for the regulation, evaluation and use of digital technologies to strengthen pandemic management, and future preparedness for COVID-19 and other infectious diseases.


Single dose artemisinin-mefloquine treatment for acute uncomplicated falciparum malaria.
For the treatment of patients with acute falciparum malaria, the combination of artemisinin as a single dose with a single dose of mefloquine was studied in 4 separate prospective trials, comprising 405 adults and 139 children with uncomplicated falciparum malaria in 2 in-patient and 2 rural out-patient studies in Viet Nam. Adults received oral artemisinin and children artemisinin suppositories. Randomized comparative treatment schedules were: artemisinin alone for 5 d, mefloquine-sulfadoxine-pyrimethamine (MSP), or quinine plus sulfadoxine-pyrimethamine (SP). Parasite clearance times (PCT) were rapid for artemisinin treated inpatients (90%: 14.8-20.4 h) but also for patients receiving MSP (PCT 90%: 18.0 h) and quinine (PCT 90%: 22.5 h). The recrudescence rate (RI) during a 28 d follow-up period among the patients given artemisinin plus mefloquine was 15% in the adult in-patients and zero in the adult and children out-patients. RI in the artemisinin 5 d treatment group was 33.3%; among those given artemisinin plus SP it was 47.3% in in-patients and in out-patients 46.1%. In the MSP treated out-patients RI was 1.5% in adults and zero in children. Artemisinin as a single dose (oral in adults and as a suppository in children) in combination with mefloquine was effective in rapidly lowering parasitaemia and in preventing recrudescence in hospital in-patients and in out-patients attending a rural health clinic. MSP alone as a single dose also rapidly reduced parasitaemia (but not as quickly as the artemisinin-mefloquine combination in out-patient children) and prevented recrudescence.


The short-term synthesis and infant-regulated removal of milk in lactating women.
We studied how short-term milk synthesis responds to milk removal by observing breast volume before and after each breastfeed over 24 h periods within the homes of seven lactating mothers, using the Computerized Breast Measurement system. Short-term rates of milk synthesis varied markedly between the breasts of individual mothers, varied markedly between interfeed intervals for individual breasts and, for six of the thirteen breasts studied, were positively related to the degree to which the breast was emptied (r2 ranging from 0.32 to 0.95). In addition, the infants rarely emptied the breasts of available milk (mean +/- S.D. of degree of emptying postfeed = 76 +/- 20%, n = 147) and, within women, storage capacity of a breast was related to the demand for milk from that breast (r2 = 0.91, P < 0.0001). It was concluded that the infants were self-regulating their milk intake. Furthermore, the storage capacity of the breast, variations in the short-term rates of milk synthesis and responsiveness of milk synthesis to the degree of breast emptying provided mechanisms whereby maternal milk supply could be directly linked to infant demand. Our findings are discussed with reference to the autocrine control of milk synthesis.


Doubt in the Insula: Risk Processing in Obsessive-Compulsive Disorder.
Extensive cleaning or checking of patients with obsessive-compulsive disorder (OCD) are often interpreted as strategies to avoid harm and as an expression of the widespread belief that OCD patients are more risk-averse. However, despite its clinical significance, the neural basis of risk attitude in OCD is unknown. Here, we investigated neural activity during risk processing using functional magnetic resonance imaging and simultaneously assessed risk attitude using a separate behavioral paradigm in OCD patients with different symptoms versus healthy controls (HCs). We found opposite insula responses to high versus low risk in OCD patients compared to HCs: a positive correlation between insula activity and risk-aversion in patients versus a negative correlation in controls. Although OCD patients overall were not more risk-averse than controls, there were differences between subgroups of OCD patients: patients with doubt/checking symptoms were more risk-averse than other patients. Taken together, OCD patients show a reversed pattern of risk processing by the insula compared to HCs. Moreover, the data suggest that increased activation of the insula signals an abnormal urge to avoid risks in the subpopulation of OCD patients with doubt and checking symptoms. These results indicate a role for the insula in excessive risk-avoidance relevant to OCD.


Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study.
To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure. In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25-1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01-1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion. An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.


Scar formation and lack of regeneration in adult and neonatal liver after stromal injury.
Known as a uniquely regenerative tissue, the liver shows a remarkable capacity to heal without scarring after many types of acute injury. In contrast, during chronic liver disease, the liver responds with fibrosis, which can progress to cirrhosis and ultimately liver failure. The cause of this shift from a nonfibrotic to a fibrotic response is unknown. We hypothesized that stromal injury is a key event that prevents restoration of normal liver architecture. To test this, we developed a model of stromal injury using a surgical incision through the normal liver in adult and neonatal mice. This injury produces minimal cell death but locally complete stromal (extracellular matrix) disruption. The adult liver responds with inflammation and stellate cell activation, culminating in fibrosis characterized by collagen deposition. This sequence of events is remarkably similar to the fibrotic response leading to cirrhosis. Studies in neonates reveal a similar fibrotic response to a stromal injury. These findings suggest that extracellular matrix disruption leads not to regeneration but rather to scar, similar to other mammalian organs. These findings may shed light on the pathogenesis of chronic liver disease, and suggest therapeutic strategies.


Extended cognition in science communication.
The aim of this article is to propose a methodological externalism that takes knowledge about science to be partly constituted by the environment. My starting point is the debate about extended cognition in contemporary philosophy and cognitive science. Externalists claim that human cognition extends beyond the brain and can be partly constituted by external devices. First, I show that most studies of public knowledge about science are based on an internalist framework that excludes the environment we usually utilize to make sense of science and does not allow the possibility of extended knowledge. In a second step, I argue that science communication studies should adopt a methodological externalism and accept that knowledge about science can be partly realized by external information resources such as Wikipedia.


Multiple site electromyograph amplitude estimation.
Temporal whitening of individual surface electromyograph (EMG) waveforms and spatial combination of multiple recording sites have separately been demonstrated to improve the performance of EMG amplitude estimation. This investigation combined these two techniques by first whitening, then combining the data from multiple EMG recording sites to form an EMG amplitude estimate. A phenomenological mathematical model of multiple sites of the surface EMG waveform, with analytic solution for an optimal amplitude estimate, is presented. Experimental surface EMG waveforms were then sampled from multiple sites during nonfatiguing, constant-force, isometric contractions of the biceps or triceps muscles, over the range of 10-75% maximum voluntary contraction. A signal-to-noise ratio (SNR) was computed from each amplitude estimate (deviations about the mean value of the estimate were considered as noise). Results showed that SNR performance: 1) increased with the number of EMG sites, 2) was a function of the sampling frequency, 3) was predominantly invariant to various methods of determining spatial uncorrelation filters, 4) was not sensitive to the intersite correlations of the electrode configuration investigated, and 5) was best at lower levels of contraction. A moving average root mean square estimator (245-ms window) provided an average +/- standard deviation (A +/- SD) SNR of 10.7 +/- 3.3 for single site unwhitened recordings. Temporal whitening and four combined sites improved the A +/- SD SNR to 24.6 +/- 10.4. On one subject, eight whitened combined sites were achieved, providing an A +/- SD SNR or 35.0 +/- 13.4.


Comparative structural and functional analysis of orthomyxovirus polymerase cap-snatching domains.
Orthomyxovirus Influenza A virus (IAV) heterotrimeric polymerase performs transcription of viral mRNAs by cap-snatching, which involves generation of capped primers by host pre-mRNA binding via the PB2 subunit cap-binding site and cleavage 10-13 nucleotides from the 5' cap by the PA subunit endonuclease. Thogotoviruses, tick-borne orthomyxoviruses that includes Thogoto (THOV), Dhori (DHOV) and Jos (JOSV) viruses, are thought to perform cap-snatching by cleaving directly after the cap and thus have no heterogeneous, host-derived sequences at the 5' extremity of their mRNAs. Based on recent work identifying the cap-binding and endonuclease domains in IAV polymerase, we determined the crystal structures of two THOV PB2 domains, the putative cap-binding and the so-called '627-domain', and the structures of the putative endonuclease domains (PA-Nter) of THOV and DHOV. Despite low sequence similarity, corresponding domains have the same fold confirming the overall architectural similarity of orthomyxovirus polymerases. However the putative Thogotovirus cap-snatching domains in PA and PB2 have non-conservative substitutions of key active site residues. Biochemical analysis confirms that, unlike the IAV domains, the THOV and DHOV PA-Nter domains do not bind divalent cations and have no endonuclease activity and the THOV central PB2 domain does not bind cap analogues. On the other hand, sequence analysis suggests that other, non-influenza, orthomyxoviruses, such as salmon anemia virus (isavirus) and Quaranfil virus likely conserve active cap-snatching domains correlating with the reported occurrence of heterogeneous, host-derived sequences at the 5' end of the mRNAs of these viruses. These results highlight the unusual nature of transcription initiation by Thogotoviruses.


Tea drinking habits and osteoporotic hip/femur fractures: A case-control study.
To explore the relationship between tea drinking habits and osteoporotic hip/femur fractures. Paired case-control method was used for face-to-face interviews from January 2010 to June 2014. Patients (n=435) with newly osteoporotic hip/femur fracture and 435 controls with the same gender and age (±3) were given questionnaire survey. The survey content included general situation, detailed tea drinking and other diet condition, health-related behavior and family history of fractures, etc. Single factor logistic analysis showed that the habit of drinking tea can significantly reduce the risk of hip/femur fracture. Cumulative year of tea drinking, the cumulative amount of tea and tea concentration (low dose group) have the maximum protection for fracture, while the high dose group is weaker in protection (trend test, P<0.05). After adjustment for age, energy, BMI, education degree, parents' history of fracture, second hand smoke exposure, calcium supplements, and equivalent energy consumption of physical activity, etc, the above association still showed significant linear trend, but the associated strength was slightly reduced. But stratified analysis found that the effect of tea drinking was only statistically significant in men. And there were no statistically significant differences of people with different education degree. Regular tea drinking can reduce the risk of osteoporotic hip/femur fractures in middle-aged and elderly men.


The importance of lag time extension in determining bacterial resistance to antibiotics.
It is widely appreciated that widespread antibiotic resistance has significantly reduced the utility of today's antibiotics. Many antibiotics now fail to cure infectious diseases, although they are classified as effective bactericidal agents based on antibiotic susceptibility tests. Here, via kinetic growth assays, we evaluated the effects of 12 commonly used antibiotics on the lag phase of a range of pure environmental isolates and of sludge bacterial communities with a high diversity. We show that an extended lag phase offers bacteria survival advantages and promotes regrowth upon the removal of antibiotics. By utilizing both lag phase extension and IC50, the killing efficiency of an antibiotic on a strain or a community can be easily revealed. Interestingly, for several strains of relevance to endemic nosocomial infections (e.g. Acinetobacter sp. and Pseudomonas aeruginosa) and the diverse sludge communities, tetracycline and quinolone antibiotics are most likely to be resisted via extended lag phase. This discovery is significant from a clinical point view since underestimation of bacteria resistance can lead to the recurrence of diseases.


Psychiatric service staff perceptions of implementing a shared decision-making tool: a process evaluation study.
Shared decision making, SDM, in psychiatric services, supports users to experience a greater sense of involvement in treatment, self-efficacy, autonomy and reduced coercion. Decision tools adapted to the needs of users have the potential to support SDM and restructure how users and staff work together to arrive at shared decisions. The aim of this study was to describe and analyse the implementation process of an SDM intervention for users of psychiatric services in Sweden. The implementation was studied through a process evaluation utilizing both quantitative and qualitative methods. In designing the process evaluation for the intervention, three evaluation components were emphasized: contextual factors, implementation issues and mechanisms of impact. The study addresses critical implementation issues related to decision-making authority, the perceived decision-making ability of users and the readiness of the service to increase influence and participation. It also emphasizes the importance of facilitation, as well as suggesting contextual adaptations that may be relevant for the local organizations. The results indicate that staff perceived the decision support tool as user-friendly and useful in supporting participation in decision-making, and suggest that such concrete supports to participation can be a factor in implementation if adequate attention is paid to organizational contexts and structures.


The foot of Homo naledi.
Modern humans are characterized by a highly specialized foot that reflects our obligate bipedalism. Our understanding of hominin foot evolution is, although, hindered by a paucity of well-associated remains. Here we describe the foot of Homo naledi from Dinaledi Chamber, South Africa, using 107 pedal elements, including one nearly-complete adult foot. The H. naledi foot is predominantly modern human-like in morphology and inferred function, with an adducted hallux, an elongated tarsus, and derived ankle and calcaneocuboid joints. In combination, these features indicate a foot well adapted for striding bipedalism. However, the H. naledi foot differs from modern humans in having more curved proximal pedal phalanges, and features suggestive of a reduced medial longitudinal arch. Within the context of primitive features found elsewhere in the skeleton, these findings suggest a unique locomotor repertoire for H. naledi, thus providing further evidence of locomotor diversity within both the hominin clade and the genus Homo.


Inference and Analysis of Population Structure Using Genetic Data and Network Theory.
Clustering individuals to subpopulations based on genetic data has become commonplace in many genetic studies. Inference about population structure is most often done by applying model-based approaches, aided by visualization using distance-based approaches such as multidimensional scaling. While existing distance-based approaches suffer from a lack of statistical rigor, model-based approaches entail assumptions of prior conditions such as that the subpopulations are at Hardy-Weinberg equilibria. Here we present a distance-based approach for inference about population structure using genetic data by defining population structure using network theory terminology and methods. A network is constructed from a pairwise genetic-similarity matrix of all sampled individuals. The community partition, a partition of a network to dense subgraphs, is equated with population structure, a partition of the population to genetically related groups. Community-detection algorithms are used to partition the network into communities, interpreted as a partition of the population to subpopulations. The statistical significance of the structure can be estimated by using permutation tests to evaluate the significance of the partition's modularity, a network theory measure indicating the quality of community partitions. To further characterize population structure, a new measure of the strength of association (SA) for an individual to its assigned community is presented. The strength of association distribution (SAD) of the communities is analyzed to provide additional population structure characteristics, such as the relative amount of gene flow experienced by the different subpopulations and identification of hybrid individuals. Human genetic data and simulations are used to demonstrate the applicability of the analyses. The approach presented here provides a novel, computationally efficient model-free method for inference about population structure that does not entail assumption of prior conditions. The method is implemented in the software NetStruct (available at https://giligreenbaum.wordpress.com/software/).


Global threats to human water security and river biodiversity.
Protecting the world's freshwater resources requires diagnosing threats over a broad range of scales, from global to local. Here we present the first worldwide synthesis to jointly consider human and biodiversity perspectives on water security using a spatial framework that quantifies multiple stressors and accounts for downstream impacts. We find that nearly 80% of the world's population is exposed to high levels of threat to water security. Massive investment in water technology enables rich nations to offset high stressor levels without remedying their underlying causes, whereas less wealthy nations remain vulnerable. A similar lack of precautionary investment jeopardizes biodiversity, with habitats associated with 65% of continental discharge classified as moderately to highly threatened. The cumulative threat framework offers a tool for prioritizing policy and management responses to this crisis, and underscores the necessity of limiting threats at their source instead of through costly remediation of symptoms in order to assure global water security for both humans and freshwater biodiversity.


Leptin: Is It Thermogenic?
Animals that lack the hormone leptin become grossly obese, purportedly for 2 reasons: increased food intake and decreased energy expenditure (thermogenesis). This review examines the experimental evidence for the thermogenesis component. Analysis of the data available led us to conclude that the reports indicating hypometabolism in the leptin-deficient ob/ob mice (as well as in the leptin-receptor-deficient db/db mice and fa/fa rats) derive from a misleading calculation artefact resulting from expression of energy expenditure per gram of body weight and not per intact organism. Correspondingly, the body weight-reducing effects of leptin are not augmented by enhanced thermogenesis. Congruent with this, there is no evidence that the ob/ob mouse demonstrates atrophied brown adipose tissue or diminished levels of total UCP1 mRNA or protein when the ob mutation is studied on the inbred C57BL/6 mouse background, but a reduced sympathetic nerve activity is observed. On the outbred "Aston" mouse background, brown adipose tissue atrophy is seen, but whether this is of quantitative significance for the development of obesity has not been demonstrated. We conclude that leptin is not a thermogenic hormone. Rather, leptin has effects on body temperature regulation, by opposing torpor bouts and by shifting thermoregulatory thresholds. The central pathways behind these effects are largely unexplored.


Are You What You Read? Predicting Implicit Attitudes to Immigration Based on Linguistic Distributional Cues From Newspaper Readership; A Pre-registered Study.
The implicit association test (IAT) measures bias towards often controversial topics (e.g., race, religion), while newspapers typically take strong positive/negative stances on such issues. In a pre-registered study, we developed and administered an immigration IAT to readers of the Daily Mail (a typically anti-immigration publication) and the Guardian (a typically pro-immigration publication) newspapers. IAT materials were constructed based on co-occurrence frequencies from each newspapers' website for immigration-related terms (migrant/immigrant) and positive/negative attributes (skilled/unskilled). Target stimuli showed stronger negative associations with immigration concepts in the Daily Mail compared to the Guardian, and stronger positive associations in the Guardian corpus compared to the Daily Mail corpus. Consistent with these linguistic distributional differences, Daily Mail readers exhibited a larger IAT bias, revealing stronger negative associations to immigration concepts compared to Guardian readers. This difference in overall bias was not fully explained by other variables, and raises the possibility that exposure to biased language contributes to biased implicit attitudes.


Determining phosphorus and sediment release rates from five Irish tillage soils.
The aim of this study was to compare the nutrient and sediment releases from five Irish tillage soils, inclined at 10- and 15-degree slopes, under a simulated rainfall intensity of 30 mm h(-1) in a controlled laboratory study. Using the relationship between soil test phosphorus (STP) in the five soils and the dissolved reactive phosphorus (DRP) released in surface runoff, a runoff dissolved phosphorus risk indicator (RDPRI) was developed to identify the STP level for Irish tillage soils above which there may be a potential threat to surface water quality. The results of this study indicated that tillage soils may produce surface runoff P concentrations in excess of 30 microg L(-1) (the value above which eutrophication of rivers is likely to occur and the maximum allowable concentration of DRP in rivers under the EU Water Framework Directive, WFD) if their Morgan's phosphorus (P(m)), Mehlich 3 phosphorus (M3-P), and water extractable phosphorus (WEP) concentrations exceed 9.5 mg L(-1), 67.2 mg kg(-1), and 4.4 mg kg(-1), respectively. This work reinforces the statutory agronomic based requirements of the European Communities (Good Agricultural Practice for Protection of Waters) Regulations 2009 (S.I. no. 101 of 2009). A statistical analysis showed that WEP gave the best prediction for runoff DRP.


Primary Diffuse large B-Cell lymphoma of testis: A single centre experience and review of literature.
Primary testicular lymphoma constitutes 1-2% of Non-Hodgkin's lymphomas affecting elderly men >60 years of age. Most often it is a Diffuse large B cell lymphoma (DLBCL) and treatment involves multimodality approach involving surgery, chemotherapy and radiotherapy. Outcome remains poor in spite of aggressive therapy. We retrospectively reviewed 286 registered cases of DLBCL (aged >14 years) from 2007 to 2011 and found nine primary testicular involvement patients. These cases were analyzed for baseline clinical features, investigations, staging, treatment and outcome. Median age was 58 (46-76) years. All patients presented with testicular swelling, two had the presence of B symptoms, and three with abdominal lymphadenopathy. Six had stage IE disease and three patients had stage IIE. All patients underwent orchiectomy. Eight patients received combination chemotherapy and six completed three or more cycles. Four achieved complete response, among these three relapsed after 32, 42, 70 months and one was lost to follow up. Two had a progressive disease, among these one died of disease and one alive with disease. Complete follow up was available from five patients and median survival was 36 months (11-78 months). Primary testicular DLBCL is uncommon, needs multimodality treatment and central nervous system prophylaxis to improve the survival. The outcome needs to be further investigated using biological approaches (Rituximab based) and/or more aggressive management.


Naphthalene-fused BODIPY near-infrared dye as a stable contrast agent for in vivo photoacoustic imaging.
Photoacoustic imaging (PAI) has emerged as an advantageous modality with high resolution and deep tissue penetration. However, its application is limited by the lack of available contrast agents. In this work, we report the synthesis of a naphthalene fused BODIPY dimer Na-BD, and the impact of the electronic structure on the oxidative cyclo-dehydrogenation process was systematically studied. Na-BD exhibited intense NIR absorption, much better photo-stability and higher PA activity compared to commercial ICG dye, which makes it an excellent contrast agent for PAI. Moreover, the in vivo PAI studies based on Na-BD loaded BSA nanoparticles were carried out and they demonstrated a significant passive targeting capacity by exploiting the enhanced permeability and retention effect in the tumor region.


Developing competencies for multidisciplinary hospice and palliative care professionals in Korea.
Competency-based assessment helps to improve performance and to standardize education programs for hospice and palliative care professionals. This paper aims to report the process and results of developing the hospice and palliative care competencies by multidisciplinary experts in Korea. The competency development task force team of Korean hospice and palliative care professionals was comprised of seven physicians, four nurses, two social workers, and two clergy. To build consensus regarding competencies, the team performed a two-round Delphi survey. The importance of competency domains was assessed by using a 5-point Likert scale. After the completion of the Delphi survey, final competency domains were decided in a consensus meeting. The competencies were composed of knowledge, skills, and attitudes. The competency domains were identified as the following: 11 domains and 16 subdomains for physicians, 11 domains for nurses, 5 domains and 15 subdomains for social workers, as well as 3 domains and 5 subdomains for spiritual care providers. The high importance domains were different by specialties. Physical care and treatment for physicians, symptom management for nurses, bereavement care for social workers, and communication for spiritual care providers were ranked as highly important. For nurses and spiritual care providers, attitude-related domains were ranked the highest in importance. The competencies developed by multidisciplinary professionals are useful to identify the appropriate roles of each hospice and palliative care specialist involved in a team approach to patient care.


Incidence and Outcome of Acute Cardiorenal Syndrome in Hospitalized Children.
To determine the incidence, etiology and outcome of Cardiorenal syndrome (CRS) in hospitalized children. A prospective cohort study was carried out in 242 children between 6 mo to 18 y of age hospitalized with primary cardiac, renal or any systemic disorder at a tertiary care center in India. The primary outcome was the development of CRS. Univariate and multivariate logistic regression analysis were performed to determine the risk of mortality secondary to CRS. Among 242 children, 67 (27.7%) children developed CRS and the rest 175 (72.3%) did not. Among those with CRS, 40.3%, 20.9%, and 38.8% had CRS-1, 3 and 5, respectively. Cardiac diseases leading to CRS were myocarditis (40.7%) followed by congenital heart disease (25.9%), rheumatic heart disease (18.5%), and dilated cardiomyopathy (7.4%); renal disease associated with CRS was acute glomerulonephritis (100%) and major systemic disorders leading to CRS were septicemia (53.8%), malaria (23.1%), scrub typhus (7.7%), and acute gastroenteritis (3.8%). The occurrence of CRS was associated with an increased risk of mortality (OR 6.3, 95% CI: 2.8, 14.1; p 0.000). A subgroup analysis revealed that children with CRS having acute kidney injury stage 2 and 3 also had a higher risk of mortality (p 0.001). The incidence of CRS is quite high in children with cardiac, renal or systemic diseases and is associated with a significant risk of mortality. Children presenting with these illnesses should be monitored for the occurrence of CRS so that early intervention may reduce mortality.


Soil Suppressiveness to Fusarium Disease Following Organic Amendments and Solarization.
Soil suppressiveness to soilborne pathogens can evolve following the incorporation of plant residues in the soil and solarization. We studied its occurrence by assessing disease incidence and severity in sandy soil which was infested after the disinfestation treatment. Disease incidence and severity of crown and root rot in cucumber plants inoculated with Fusarium oxysporum f. sp. radicis-cucumerinum macroconidia were reduced by 20 to 80% when seedlings were planted in the tested soils 2 to 34 months after soil amendment. Residues of Diplotaxis tenuifolia (wild rocket [WR]), Artemisia dracunculus (tarragon), Salvia officinalis (sage), and Brassica oleracea var. italica (broccoli) were most effective for inducing soil suppressiveness. Effective soil suppressiveness continued to be evident after repeated inoculations and plantings in the same soil without additional treatment between inoculations. Moreover, residues of WR induced soil suppressiveness in two additional tested soils differing in their physical and chemical properties. Residues of Rosmarinus officinalis (rosemary), Coriandrum sativum (coriander), Mentha piperita (peppermint), and B. oleraceae var. botrytis (cauliflower) induced disease suppression at the first inoculated planting but not upon repeated inoculation and planting. The contribution of soil solarization to the evolution of soil suppressiveness, albeit evident, was inconsistent. Soil suppressiveness to Fusarium crown and root rot was also observed when cucumber seed were sown in soils which were initially amended with WR residues and later infested with F. oxysporum f. sp. radicis-cucumerinum chlamydospores. There is a potential for the use of plant residues for inducing soil suppressiveness and further contributing to the control of diseases caused by soilborne pathogens.


Classification methods for ongoing EEG and MEG signals.
Classification algorithms help predict the qualitative properties of a subject's mental state by extracting useful information from the highly multivariate non-invasive recordings of his brain activity. In particular, applying them to Magneto-encephalography (MEG) and electro-encephalography (EEG) is a challenging and promising task with prominent practical applications to e.g. Brain Computer Interface (BCI). In this paper, we first review the principles of the major classification techniques and discuss their application to MEG and EEG data classification. Next, we investigate the behavior of classification methods using real data recorded during a MEG visuomotor experiment. In particular, we study the influence of the classification algorithm, of the quantitative functional variables used in this classifier, and of the validation method. In addition, our findings suggest that by investigating the distribution of classifier coefficients, it is possible to infer knowledge and construct functional interpretations of the underlying neural mechanisms of the performed tasks. Finally, the promising results reported here (up to 97% classification accuracy on 1-second time windows) reflect the considerable potential of MEG for the continuous classification of mental states.


The effects of lacosamide on cognition, quality-of-life measures, and quality of life in patients with refractory partial epilepsy.
The objective of this study was to examine cognitive and quality-of-life measures/quality of life outcomes with adjunctive lacosamide therapy in patients with treatment-resistant partial epilepsy. This was a prospective, open-label, nonblinded, adjunctive therapy test-retest (within subjects) study of patients with treatment-resistant partial epilepsy in which outcome (cognitive functioning and mood/quality of life) was measured in the same subject before and after adjunctive lacosamide administration for 24weeks. The cognitive assessment included the following: Controlled Oral Word Association Test, Buschke Selective Reminding Test, Brief Visuospatial Memory Test-Revised, Stroop Color Word Test, Symbol Digit Modalities Test, Digit Span, Digit Cancellation, and Trails A and B. The quality-of-life measures/quality-of-life assessment included the following: Beck Depression Inventory-II, Profile of Mood States, and Quality of Life Inventory-89. Lacosamide was started at 100mg (50mg twice daily) and could be titrated as needed up to 400mg/day (200mg twice daily). Baseline concomitant AEDs were kept constant. Composite scores were calculated for a pre-post difference score for the cognitive and mood/quality-of-life measures separately and used in regression analyses to correct for the effects of age, education, seizure frequency, seizure severity, dose of lacosamide, and number of AEDs at baseline. Thirty-four patients were enrolled (13 males, 21 females). Mean age was 38.8±2.43years. Mean seizure frequency decreased significantly from 2.0±2.55 seizures per week at baseline to 1.02±1.72 seizures per week at posttreatment (t=4.59, p<.0001) with a 50% responder rate seen in 18 patients (52.9%). No significant differences were found on the composite scores of the cognitive or the mood/quality-of-life measures after 6months of lacosamide. Lacosamide appeared to have low risks of significant changes in cognition or mood/quality of life. In addition, the present study supports prior studies that have proven lacosamide as an effective adjunctive therapy for the treatment of resistant partial epilepsy.


Identification and validation of oncologic miRNA biomarkers for luminal A-like breast cancer.
Breast cancer is a common disease with distinct tumor subtypes phenotypically characterized by ER and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression, and altered miRNA expression has been demonstrated in a variety of cancer states presenting the potential for exploitation as cancer biomarkers. Blood provides an excellent medium for biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A-like (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting. Blood samples were prospectively collected from patients with Luminal A-like breast cancer (n = 54) and controls (n = 56). RNA was extracted, reverse transcribed and subjected to microarray analysis (n = 10 Luminal A-like; n = 10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms. Expression of specific miRNAs was validated by RQ-PCR (n = 44 Luminal A; n = 46 Control) and potential relationships between circulating miRNA levels and clinicopathological features of breast cancer were investigated. Microarray analysis identified 76 differentially expressed miRNAs. ANN revealed 10 miRNAs for further analysis (miR-19b, miR-29a, miR-93, miR-181a, miR-182, miR-223, miR-301a, miR-423-5p, miR-486-5 and miR-652). The biomarker potential of 4 miRNAs (miR-29a, miR-181a, miR-223 and miR-652) was confirmed by RQ-PCR, with significantly reduced expression in blood of women with Luminal A-like breast tumors compared to healthy controls (p = 0.001, 0.004, 0.009 and 0.004 respectively). Binary logistic regression confirmed that combination of 3 of these miRNAs (miR-29a, miR-181a and miR-652) could reliably differentiate between cancers and controls with an AUC of 0.80. This study provides insight into the underlying molecular portrait of Luminal A-like breast cancer subtype. From an initial 76 miRNAs, 4 were validated with altered expression in the blood of women with Luminal A-like breast cancer. The expression profiles of these 3 miRNAs, in combination with mammography, has potential to facilitate accurate subtype-specific breast tumor detection.


EGCG protects against UVB-induced apoptosis via oxidative stress and the JNK1/c-Jun pathway in ARPE19 cells.
Ultraviolet B (UVB) radiation is part of the spectrum of light produced by the sun. This form of radiation has been implicated as one of the potential etiological factors causing age-related macular degeneration (AMD). Oxidative injury to the retinal pigment epithelium (RPE) has also been thought to play a key role in AMD. The aim of the present study was to determine the mechanism by which UVB causes damage to the RPE cells, whether it occurs through oxidative stress and the mitogen-activated protein kinase (MAPK) pathway and whether the green tea extract, (-)-epigallocatechin gallate (EGCG), has a protective role. Cell viability assays were used to determine the viability of the cells under different conditions. Cell death caused by apoptosis was determined using fluorescein isothiocyanate conjugated-annexin V/PI labeling, followed by flow cytometry. Intracellular reactive oxygen species (ROS) levels were measured by flow cytometry. Western blot analysis was used to detect UVB-induced MAPK signaling pathways. The findings showed that UVB induced apoptosis, which increased intracellular ROS in ARPE19 cells. Inhibition of c-Jun NH2-terminal kinase (JNK) with a specific inhibitor augmented this apoptosis, and anisomycin (an activator of JNK) attenuated this apoptosis. In addition, UVB decreased the phosphorylation of JNK1 and c-Jun. Finally, EGCG reduced the ROS generation and apoptosis, and also partially blocked the decreased phosphorylation of JNK1 and c-Jun by UVB irradiation. The findings show that UVB irradiation is able to induce apoptosis in ARPE19 cells through oxidative stress, but EGCG treatment attenuates this damage. In this situation, the JNK pathway plays an anti-apoptotic role. The use of selective activators or antioxidants may be useful in reducing the oxidative damage occurring in AMD.


Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development.
Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators with important functions in development and disease. Here, we sought to identify and functionally characterize novel lncRNAs critical for vertebrate development. By relying on human pluripotent stem cell differentiation models, we investigated lncRNAs differentially regulated at key steps during human cardiovascular development with a special focus on vascular endothelial cells. RNA sequencing led to the generation of large data sets that serve as a gene expression roadmap highlighting gene expression changes during human pluripotent cell differentiation. Stage-specific analyses led to the identification of 3 previously uncharacterized lncRNAs, TERMINATOR, ALIEN, and PUNISHER, specifically expressed in undifferentiated pluripotent stem cells, cardiovascular progenitors, and differentiated endothelial cells, respectively. Functional characterization, including localization studies, dynamic expression analyses, epigenetic modification monitoring, and knockdown experiments in lower vertebrates, as well as murine embryos and human cells, confirmed a critical role for each lncRNA specific for each analyzed developmental stage. We have identified and functionally characterized 3 novel lncRNAs involved in vertebrate and human cardiovascular development, and we provide a comprehensive transcriptomic roadmap that sheds new light on the molecular mechanisms underlying human embryonic development, mesodermal commitment, and cardiovascular specification.


Depression and cardiovascular disease: a clinical review.
Cardiovascular disease (CVD) and depression are common. Patients with CVD have more depression than the general population. Persons with depression are more likely to eventually develop CVD and also have a higher mortality rate than the general population. Patients with CVD, who are also depressed, have a worse outcome than those patients who are not depressed. There is a graded relationship: the more severe the depression, the higher the subsequent risk of mortality and other cardiovascular events. It is possible that depression is only a marker for more severe CVD which so far cannot be detected using our currently available investigations. However, given the increased prevalence of depression in patients with CVD, a causal relationship with either CVD causing more depression or depression causing more CVD and a worse prognosis for CVD is probable. There are many possible pathogenetic mechanisms that have been described, which are plausible and that might well be important. However, whether or not there is a causal relationship, depression is the main driver of quality of life and requires prevention, detection, and management in its own right. Depression after an acute cardiac event is commonly an adjustment disorder than can improve spontaneously with comprehensive cardiac management. Additional management strategies for depressed cardiac patients include cardiac rehabilitation and exercise programmes, general support, cognitive behavioural therapy, antidepressant medication, combined approaches, and probably disease management programmes.


Seropositivity of Lyme borreliosis and associated risk factors: a population-based study in Children and Adolescents in Germany (KiGGS).
Lyme borreliosis (LB) caused by spirochetes of the Borrelia burgdorferi sensu lato complex is the most common tick-borne disease in the northern hemisphere. Data on the distribution and on risk factors in Germany are sketchy. Blood samples of a nationwide population-based cross-sectional study from 2003-2006 in children and adolescents aged 1 to 17 years in Germany (KiGGS) were analysed (n = 12,614) to assess the seroprevalence of anti-Borrelia antibodies. Data from standardized interviews were used to assess potential risk factors. First, sera were screened for anti-Borrelia antibodies by ELISA. The overall prevalence was 4.8% (95% confidence interval (CI) 4.3-5.4%). Positive and borderline ELISA test results were confirmed by a line blot revealing a combined prevalence of 4.0% (95% CI 3.6-4.5%). Seroprevalence of ELISA was significantly higher in males (odds ratio (OR) = 1.37; CI 1.15-1.63) and in the southern part of Germany (OR = 1.41; CI 1.09-1.83), but significantly lower in children and adolescents with migration background (OR = 0.33; CI 0.24-0.44). Study participants from households with cats had a higher chance of seropositivity (OR = 6.7; CI 5.6-8.0). In a multivariable model the odds of seropositivity increases by 11% for every year of age for boys and 6% for girls. This survey is the first nationwide, representative seroprevalence survey of LB in children and young adolescents. The study shows that infections with Borrelia burgdorferi are endemic in all parts of Germany despite regional differences. Even at a young age children are exposed to tick bites including seropositivity. Encouraging a thorough check for ticks and promptly removal of ticks are the key public health strategies to reduce the risk of LB and other tick-borne diseases in children and adolescents. Further epidemiological studies are warranted to better understand the burden of disease related to LB.


Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.
Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to beta-cells suppressed [(14)C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.


Lithium prescribing during pregnancy: a UK primary care database study.
Women taking lithium must decide whether to continue the medication if they conceive or plan to conceive. Little is known about the extent of prescribing of lithium during pregnancy. To determine: 1) the prevalence of lithium prescribing during pregnancy and 2) to assess whether pregnancy is associated with discontinuation of lithium. First, we identified women receiving any lithium prescriptions before and during pregnancy using The Health Improvement Network (THIN) primary care database. Subsequently, we used a Kaplan-Meier plot to compare time to last prescription in women prescribed lithium continuously three months before pregnancy and a comparison group of non-pregnant women. Finally, we described the characteristics of the women prescribed lithium in pregnancy. Very few women were prescribed lithium during pregnancy; out of 458,761 pregnancies, we identified 47 (0.01%) in which lithium was prescribed after the 6th week of pregnancy (when the pregnancy was likely to be known). In our study of discontinuation, we found pregnant women were more likely to stop lithium than those who were not pregnant. Of the 52 women who were being continuously prescribed lithium three months before pregnancy, only 17 (33%) continued receiving prescriptions beyond the 6th week of pregnancy. However, most of these 17 women continued treatment throughout pregnancy. Pregnancy was strongly associated with discontinuation of lithium. Further evidence on the risks of lithium is needed so that women can weight these against the risk of a deterioration in maternal mental health.


Induction and characterization of minor histocompatibility antigens. Specific primary cytotoxic T lymphocyte responses in vitro.
A definite cytotoxic activity was developed in a BALB/c (H-2d) anti-DBA/2 primary mixed leukocyte culture (MLC), which received interleukin 2 (IL-2) on day 3 of culture. This cytotoxic activity was minor histocompatibility antigens (MIHA)-specific at the stimulator level, and was not developed in a syngeneic (BALB/c anti-BALB/c) MLC. The addition of IL-2 on day 3 of culture was crucial; no or very weak cytotoxic activity was developed in MLC receiving IL-2 on day 0 or on both day 0 and day 3. Only appropriate MIHA-allogeneic tumor cells were lysed as the target of the cytotoxic activity. The cytotoxic activity seemed MIHA-specific also at the target level; it lysed tumor cells of DBA/2 mouse origin but not those of BALB/c (syngeneic) origin. Phenotypes of the cytotoxic effector cell were Thy-1+ Lyt-2+. We concluded from these results that MIHA-specific cytotoxic T lymphocytes (CTL) were generated in the MIHA-allogeneic primary MLC. In this newly developed system, we studied genetic and antigenic requirements for primary anti-MIHA CTL responses in vitro. We demonstrated; among spleen cells (SC) of seven B10 H-2-congenic strains only SC of B10.D2 strain whose major histocompatibility complex (MHC) (H-2d) was compatible with the responder MHC effectively stimulated responder BALB/c (H-2d) SC for an anti-MIHA (DBA-C57BL-common) CTL response. Similarly, only SC of two out of seven C x B recombinant inbred strains (C x B.H and C x B.D), which were compatible at the MHC with responder SC, activated responder BALB/c SC for the response. The possibility that cells responding to H-2 alloantigens suppressed the anti-MIHA response was ruled out. Additional experiments showed that compatibility at the H-2K-end or the H-2D-end of the MHC was sufficient for a definite anti-MIHA response. These provided formal evidence that primary anti-MIHA CTL responses in vitro were MHC-restricted at the stimulator level. We then showed that sonication-disrupted SC or Sephadex G-10 column-passed nonadherent SC failed to stimulate responder SC for a primary anti-MIHA CTL response, whereas G-10-passed nonadherent SC responded well to adherent stimulator cells. Further study demonstrated that Ia+ adherent cells were the most active cell type as stimulator. Finally, we confirmed that the primary anti-MIHA CTL responses to adherent stimulator cells was MHC-restricted.


An integrated strategy for highly sensitive phosphoproteome analysis from low micrograms of protein samples.
Phosphoproteomics has become a popular proteomic technology for exploring cellular signaling networks. However, current approaches often require milligrams of protein samples which hamper their applications for translational studies with limited starting materials. In this study, we aimed to challenge the lowest starting material limit for phosphoproteome profiling. By carefully optimizing the well-established high-pH reversed-phase (RP) fractionation plus Ti4+-IMAC enrichment strategy, we achieved the identification of 15 260 and 8936 unique phosphopeptides from only 500 μg and 250 μg predigested peptides, respectively. To further improve the sensitivity of phosphoproteome analysis for low micrograms of protein samples, we developed an integrated strategy, termed Phospho-SISPROT. This technology integrates three tips in tandem for protein digestion by the simple and integrated spintip-based proteomics technology (SISPROT), phosphopeptide enrichment by the Ti4+-IMAC tip, and desalting by the StageTip, respectively, which could dramatically reduce the phosphoproteome analysis time from a couple of days to only 6 hours and improve the system sensitivity. The flow through of Phospho-SISPROT could be reused for the global protein identification, which is very helpful for accurate phosphoproteome analysis with limited starting materials. More than 5500 and 600 unique phosphopeptides were respectively identified from 20 μg and 1 μg pervanadate treated HEK 293T cell lysates processed by the Phospho-SISPROT. To the best of our knowledge, this performance is the highest reported to date by using the standard LC-MS/MS setup. We expect that the Phospho-SISPROT and the optimized high-pH RP fractionation plus Ti4+-IMAC enrichment strategy will be well suited for highly sensitive phosphoproteome analysis of rare biological samples.


Universality in the evolution of orientation columns in the visual cortex.
The brain's visual cortex processes information concerning form, pattern, and motion within functional maps that reflect the layout of neuronal circuits. We analyzed functional maps of orientation preference in the ferret, tree shrew, and galago--three species separated since the basal radiation of placental mammals more than 65 million years ago--and found a common organizing principle. A symmetry-based class of models for the self-organization of cortical networks predicts all essential features of the layout of these neuronal circuits, but only if suppressive long-range interactions dominate development. We show mathematically that orientation-selective long-range connectivity can mediate the required interactions. Our results suggest that self-organization has canalized the evolution of the neuronal circuitry underlying orientation preference maps into a single common design.


An age-size reaction norm yields insight into environmental interactions affecting life-history traits: a factorial study of larval development in the malaria mosquito Anopheles gambiae sensu stricto.
Environmental factors frequently act nonindependently to determine growth and development of insects. Because age and size at maturity strongly influence population dynamics, interaction effects among environmental variables complicate the task of predicting dynamics of insect populations under novel conditions. We reared larvae of the African malaria mosquito Anopheles gambiae sensu stricto (s.s.) under three factors relevant to changes in climate and land use: food level, water depth, and temperature. Each factor was held at two levels in a fully crossed design, for eight experimental treatments. Larval survival, larval development time, and adult size (wing length) were measured to indicate the importance of interaction effects upon population-level processes. For age and size at emergence, but not survival, significant interaction effects were detected for all three factors, in addition to sex. Some of these interaction effects can be understood as consequences of how the different factors influence energy usage in the context of a nonindependent relationship between age and size. Experimentally assessing interaction effects for all potential future sets of conditions is intractable. However, considering how different factors affect energy usage within the context of an insect's evolved developmental program can provide insight into the causes of complex environmental effects on populations.


Real-time feedback for spatiotemporal field stabilization in MR systems.
MR imaging and spectroscopy require a highly stable, uniform background field. The field stability is typically limited by hardware imperfections, external perturbations, or field fluctuations of physiological origin. The purpose of the present work is to address these issues by introducing spatiotemporal field stabilization based on real-time sensing and feedback control. An array of NMR field probes is used to sense the field evolution in a whole-body MR system concurrently with regular system operation. The field observations serve as inputs to a proportional-integral controller that governs correction currents in gradient and higher-order shim coils such as to keep the field stable in a volume of interest. The feedback system was successfully set up, currently reaching a minimum latency of 20 ms. Its utility is first demonstrated by countering thermal field drift during an EPI protocol. It is then used to address respiratory field fluctuations in a T2 *-weighted brain exam, resulting in substantially improved image quality. Feedback field control is an effective means of eliminating dynamic field distortions in MR systems. Third-order spatial control at an update time of 100 ms has proven sufficient to largely eliminate thermal and breathing effects in brain imaging at 7 Tesla.