Encephalomyocarditis virus disrupts stress granules, the critical platform for triggering antiviral innate immune responses.
In response to stress, cells induce ribonucleoprotein aggregates, termed stress granules (SGs). SGs are transient loci containing translation-stalled mRNA, which is eventually degraded or recycled for translation. Infection of some viruses, including influenza A virus with a deletion of nonstructural protein 1 (IAVΔNS1), induces SG-like protein aggregates. Previously, we showed that IAVΔNS1-induced SGs are required for efficient induction of type I interferon (IFN). Here, we investigated SG formation by different viruses using green fluorescent protein (GFP)-tagged Ras-Gap SH3 domain binding protein 1 (GFP-G3BP1) as an SG probe. HeLa cells stably expressing GFP-G3BP1 were infected with different viruses, and GFP fluorescence was monitored live with time-lapse microscopy. SG formations by different viruses was classified into 4 different patterns: no SG formation, stable SG formation, transient SG formation, and alternate SG formation. We focused on encephalomyocarditis virus (EMCV) infection, which exhibited transient SG formation. We found that EMCV disrupts SGs by cleavage of G3BP1 at late stages of infection (>8 h) through a mechanism similar to that used by poliovirus. Expression of a G3BP1 mutant that is resistant to the cleavage conferred persistent formation of SGs as well as an enhanced induction of IFN and other cytokines at late stages of infection. Additionally, knockdown of endogenous G3BP1 blocked SG formation with an attenuated induction of IFN and potentiated viral replication. Taken together, our findings suggest a critical role of SGs as an antiviral platform and shed light on one of the mechanisms by which a virus interferes with host stress and subsequent antiviral responses.


Effect of the application of acid treated biosolids on marigold (Tagetes erecta) development.
The use of biosolids for land restoration and crop production is a potential solution to improve food production worldwide. However, the microbial content usually restricts its application in crops that are consumed uncooked. An alternative practice is their use in floriculture. In this study, the effects of acid treated sludge on the development of marigold (Tagetes erecta) plants were evaluated under green house conditions. Biosolids were applied at the agronomic rate (AR) based on nitrogen requirements of the marigold. In addition, higher rates (10 and 20xAR) were applied to study their effect on the plants. Biosolids were mixed with tepetate (hard volcanic indurate layers). Due to its origin, tepetate lacks nutrients and organic matter to adequately support plant development. The best treatment for marigold development was 10xAR, as plants reached an average height of 107 cm, with a growing speed of 1.01 cm/d, which is 20 times more than the control. Plants that received no biosolids produced 0.25 buds and 0.5 flowers per plant. In contrast, AR and 10xAR showed a production that ranged from 2 to 29 buds/plant and 4 to 15 flowers/plant, respectively. These results indicate the viability of reusing acid treated biosolids to improve marigold development.


AR HMD Guidance for Controlled Hand-Held 3D Acquisition.
Photogrammetry is a popular method of 3D reconstruction that uses conventional photos as input. This method can achieve high quality reconstructions so long as the scene is densely acquired from multiple views with sufficient overlap between nearby images. However, it is challenging for a human operator to know during acquisition if sufficient coverage has been achieved. Insufficient coverage of the scene can result in holes, missing regions, or even a complete failure of reconstruction. These errors require manually repairing the model or returning to the scene to acquire additional views, which is time-consuming and often infeasible. We present a novel approach to photogrammetric acquisition that uses an AR HMD to predict a set of covering views and to interactively guide an operator to capture imagery from each view. The operator wears an AR HMD and uses a handheld camera rig that is tracked relative to the AR HMD with a fiducial marker. The AR HMD tracks its pose relative to the environment and automatically generates a coarse geometric model of the scene, which our approach analyzes at runtime to generate a set of human-reachable acquisition views covering the scene with consistent camera-to-scene distance and image overlap. The generated view locations are rendered to the operator on the AR HMD. Interactive visual feedback informs the operator how to align the camera to assume each suggested pose. When the camera is in range, an image is automatically captured. In this way, a set of images suitable for 3D reconstruction can be captured in a matter of minutes. In a user study, participants who were novices at photogrammetry were tasked with acquiring a challenging and complex scene either without guidance or with our AR HMD based guidance. Participants using our guidance achieved improved reconstructions without cases of reconstruction failure as in the control condition. Our AR HMD based approach is self-contained, portable, and provides specific acquisition guidance tailored to the geometry of the scene being captured.


An amino acid-electrolyte beverage may increase cellular rehydration relative to carbohydrate-electrolyte and flavored water beverages.
In cases of dehydration exceeding a 2% loss of body weight, athletic performance can be significantly compromised. Carbohydrate and/or electrolyte containing beverages have been effective for rehydration and recovery of performance, yet amino acid containing beverages remain unexamined. Therefore, the purpose of this study is to compare the rehydration capabilities of an electrolyte-carbohydrate (EC), electrolyte-branched chain amino acid (EA), and flavored water (FW) beverages. Twenty men (n = 10; 26.7 ± 4.8 years; 174.3 ± 6.4 cm; 74.2 ± 10.9 kg) and women (n = 10; 27.1 ± 4.7 years; 175.3 ± 7.9 cm; 71.0 ± 6.5 kg) participated in this crossover study. For each trial, subjects were dehydrated, provided one of three random beverages, and monitored for the following three hours. Measurements were collected prior to and immediately after dehydration and 4 hours after dehydration (3 hours after rehydration) (AE = -2.5 ± 0.55%; CE = -2.2 ± 0.43%; FW = -2.5 ± 0.62%). Measurements collected at each time point were urine volume, urine specific gravity, drink volume, and fluid retention. No significant differences (p > 0.05) existed between beverages for urine volume, drink volume, or fluid retention for any time-point. Treatment x time interactions existed for urine specific gravity (USG) (p < 0.05). Post hoc analysis revealed differences occurred between the FW and EA beverages (p = 0.003) and between the EC and EA beverages (p = 0.007) at 4 hours after rehydration. Wherein, EA USG returned to baseline at 4 hours post-dehydration (mean difference from pre to 4 hours post-dehydration = -0.0002; p > 0.05) while both EC (-0.0067) and FW (-0.0051) continued to produce dilute urine and failed to return to baseline at the same time-point (p < 0.05). Because no differences existed for fluid retention, urine or drink volume at any time point, yet USG returned to baseline during the EA trial, an EA supplement may enhance cellular rehydration rate compared to an EC or FW beverage in healthy men and women after acute dehydration of around 2% body mass loss.


Patient engagement in the design of an intervention to prevent muscle loss in individuals with knee osteoarthritis and a body mass index (BMI) ≥ 35.
Interventions for knee osteoarthritis (OA) in adults with a large body size (defined as a body mass index [BMI] ≥ 35 kg/m2 ) often prioritise weight-loss, which may overshadow specific benefits for physical function, metabolic health, and body composition. As part of the development of a future clinical study, we gathered perspectives from individuals living with knee OA and a large body size to inform the proposed intervention design and delivery. Purposive and voluntary sampling was used to engage individuals ≥40 years of age with self-reported knee OA and a BMI ≥ 35 kg/m2 . An anonymous electronic survey was distributed on social media between April 2020 and June 2020. Open-ended questions addressed a proposed 12-week multimodal intervention (involving targeted nutrition, resistance exercises, and self-management support). An optional semi-structured interview was offered upon completion, with interviews recorded and transcribed verbatim. Reflexive thematic analysis and interpretation guided by an acceptability framework was used to identify recommendations for the intervention design and delivery. Twenty individuals living across Canada completed the survey (100% female; 18 aged <65 years and 2 ≥ 65 years). Ten individuals completed the interview. From aggregate survey and interview data, three recommendations were generated: (1) the effectiveness of the intervention for health improvement (specifically mobility and pain) must be emphasised to avoid perceived weight-loss expectations; (2) extend support beyond 12-weeks and consider terminology free from weight-bias to enhance acceptance; (3) include optional customisation of intervention delivery to reduce acceptability-related burden. These female patient-derived recommendations may improve perceived intervention acceptability, and thereby may enhance participant enrolment and retention in clinical trials.


The effect of entrainment on the timing of periodic eye movements.
We performed an experiment in which eight healthy individuals made periodic eye movements at five pacing interval conditions (500 ms, 750 ms, 1000 ms, 1250 ms, and 1500 ms). Three methods of entrainment were used in the synchronization phase: saccade, continuous pursuit and discontinuous pursuit. The stimulus train was extinguished and in the continuation phase, subjects made saccadic eye movements at the entrained movement frequencies between two static targets. Using the Wing-Kristofferson model, clock and motor variance were extracted from the time series of continuation trials for all three entrainment conditions. Our results revealed a main effect of time interval on total variance clock variance (as predicted by Weber's law) and on motor variance. We also report that the pursuit entrainment conditions resulted in and mean duration and variance to the saccade entrainment. These results suggest that the neural networks recruited to support a periodic motor timing task depend on the method used to establish the temporal reference.


Role of Toll-like receptors in systemic Candida albicans infections.
Toll-like receptors (TLRs) constitute a family of pattern-recognition receptors (PRRs) that recognize molecular signatures of microbial pathogens and function as sensors for infection. Recognition of Candida albicans by TLRs on mature immune cells, such as phagocytic cells, activates intracellular signalling pathways that trigger production of proinflammatory cytokines which are critical for innate host defence and orchestrate the adaptive response. TLR2, and TLR4 in a minor extent, recognize cell wall-associated ligands; endosomal TLR9 and TLR7 recognize DNA and RNA respectively. Interaction of C. albicans with TLRs is a complex process, as TLRs may collaborate with other PRRs and expression of surface-associated fungal ligands depends on the strain and the morphotype (yeasts or hyphae), thus defining the final induced adaptive response (Th1/Th2/Th17). TLRs are also expressed on hematopoietic stem and progenitor cells (HSPCs) where they may play a role in modulating hematopoiesis; engagement of TLR2 induces, upon recognition of C. albicans, the differentiation of HSPCs towards specific subsets of mature myeloid cells. This has opened a new perspective for anti-Candida immunointervention.


Liver function tests: Association with cardiovascular outcomes.
An association between nonalcoholic fatty liver disease and cardiovascular disease has been repeatedly reported. Several studies have focused on levels of gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT) in relation to cardiovascular outcomes. Evidence indicates that GGT may have a potential role for cardiovascular risk stratification while the role of ALT for cardiac prognosis remains controversial. A conceptual framework that includes not only GGT and ALT but also markers of hepatocyte apoptosis such as cytokeratin-18 fragments should be developed.


Gene-gene interactions among CX3CL1, LEPR and IL-6 related to coronary artery disease in Chinese Han population.
The purpose of this study was to investigate the impact of the interactions among CX3CL1 (rs170364 and rs614230), LEPR (rs6700896), and IL-6 (rs2066992) polymorphisms on the risk of coronary artery disease (CAD) in Chinese Han population. 120 CAD patients and 109 healthy controls were enrolled in the study. Polymerase chain reaction (PCR) and direct sequencing methods were used to analyze the genotypes of CX3CL1, LEPR, and IL-6 polymorphisms. Multifactor dimensionality reduction (MDR) software was utilized to analyze gene-gene interactions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used for evaluating the association between gene polymorphisms or gene-gene interactions and CAD risk. In the study, TT genotype of rs170364 in CX3CL1 might decrease the CAD risk (OR=0.39, 95% CI=0.16-0.98). No significant correlation was found between T allele of rs170364 and CAD risk (P>0.05). CC genotype and C allele in rs614230 (CX3CL1) were significantly related with decreased risk of CAD (OR=0.38, 95% CI=0.17-0.86; OR=0.66, 95% CI=0.45-0.97). For IL-6 rs2066992 polymorphism. GG genotype could increase the risk of CAD (OR=2.32, 95% CI=1.04-5.17). Whereas, no significant correlation was observed between LEPR rs6700896 and CAD susceptibility. MDR analysis showed that CX3CL1, LEPR and IL-6 genes might jointly promote the occurrence of CAD. The interactions of CX3CL1, LEPR and IL-6 genes might increase the risk of CAD.


Comparative Efficacy of Neuromodulation Technologies for Overactive Bladder in Adults: A Network Meta-Analysis of Randomized Controlled Trials.
The aim of this study was to investigate the comparative efficacy of neuromodulation technologies for overactive bladder (OAB) syndrome in adults. A computerized search was conducted of Cochrane Library, EMBASE, MEDLINE (via PubMed), Web of Science, CNKI, Wan Fang Data, and ClinicalTrials.gov up to April 21, 2022. The search selected clinical trials with random allocation to percutaneous tibial nerve stimulation (PTNS), transcutaneous tibial nerve stimulation (TTNS), vaginal electrical stimulation (VES), sacral neuromodulation (SNM), parasacral stimulation (PS), pudendal neuromodulation, or placebo. The main outcomes were the voiding diary, OAB-related quality of life, and positive response rate. The Cochrane Risk of Bias tool (RoB 2.0) was used to assess the risk of bias of each included study, and the Grading of Recommendations Assessment, Development, and Evaluation tool was used to evaluate the overall evidence quality of key outcomes. The study included 21 randomized controlled trials involving 1433 participants, and all trials were used for the meta-analysis. In the network meta-analyses, five of six neuromodulation technologies, including PTNS, TTNS, VES, SNM, and PS, were related to higher efficacy than the placebo. Ranking probability showed that SNM was the most efficacious therapy for improving OAB-related quality of life, urinary episodes, and urinary frequency. For urgency incontinence episodes and the number of pads, PTNS and TTNS were the most efficacious modalities, respectively. Neuromodulation technologies, including PTNS, TTNS, VES, SNM, and PS, may be effective and safe solutions for OAB syndrome in adults. Moreover, SNM is the most efficacious regimen for OAB-related quality of life, urinary episodes, and urinary frequency. PTNS and TTNS are the most efficacious modalities for reducing urgency incontinence episodes and the number of pads, respectively. Future studies should pay more attention to the quality of study design and report, patients who may benefit the most from neuromodulation, and the long-term effect, cost-effectiveness, and satisfaction of neuromodulation.


Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry.
Neuropsychiatric symptoms (NPS) are common manifestations of neurodegenerative disorders and are often early signs of those diseases. Among those neurodegenerative diseases, TDP-43 proteinopathies are an increasingly recognized cause of early neuropsychiatric manifestations. TDP-43-related diseases include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE). The majority of TDP-43-related diseases are sporadic, but a significant proportion is hereditary, with progranulin (GRN) mutations and C9orf72 repeat expansions as the most common genetic etiologies. Studies reveal that NPS can be the initial manifestation of those diseases or can complicate disease course, but there is a lack of awareness among clinicians about TDP-43-related diseases, which leads to common diagnostic mistakes or delays. There is also emerging evidence that TDP-43 accumulations could play a role in late-onset primary psychiatric disorders. In the absence of robust biomarkers for TDP-43, the diagnosis remains primarily based on clinical assessment and neuroimaging. Given the association with psychiatric symptoms, clinical psychiatrists have a key role in the early identification of patients with TDP-43-related diseases. This narrative review provides a comprehensive overview of the pathobiology of TDP-43, resulting clinical presentations, and associated neuropsychiatric manifestations to help guide clinical practice.


Fast dissolving drug-drug eutectics with improved compressibility and synergistic effects.
Combinational therapy has become increasingly popular in recent times due to various advantages like greater therapeutic effect, reduced number of prescriptions, lower administrative costs, and an increase in patient compliance. Drug-drug multicomponent adducts could help in combination of drugs at supramolecular level. Two drug-drug eutectics of etodolac with paracetamol (EP) and etodolac with propranolol hydrochloride (EPHC) were successfully designed and synthesized for the first time. These eutectics significantly improved dissolution and material properties. A 6 to 9 fold enhancement in % dissolution efficiency was found at 1min suggesting the fast dissolving capabilities of the eutectic mixtures when compared to plain drug. In addition, eutectic mixtures have shown improved hardness compared to plain drugs. EP and EPHC have shown around 5 fold and 3 fold improvements in hardness respectively at 10MPa when compared to plain etodolac. Cell culture studies have shown improved effects of EP. Western blotting analysis revealed that the said combination successfully reduced various inflammatory mediators like TNF-α, COX-2 and IL-6. Whereas, the eutectic combination EPHC has shown enhanced cytotoxic effects with synergistic combination index and favorable dose reduction index. The generated multi-component systems EP and EPHC with fast dissolving capabilities, improved hardness at lower pressures and synergistic effects represent prospective combinations for effective treatment of osteoarthritis and cancer chemotherapy respectively.


Warming-induced global soil carbon loss attenuated by downward carbon movement.
The fate of soil organic carbon (SOC) under warming is poorly understood, particularly across large extents and in the whole-soil profile. Using a data-model integration approach applied across the globe, we find that downward movement of SOC along the soil profile reduces SOC loss under warming. We predict that global SOC stocks (down to 2 m) will decline by 4% (~80 Pg) on average when SOC reaches the steady state under 2°C warming, assuming no changes in net primary productivity (NPP). To compensate such decline (i.e. maintain current SOC stocks), a 3% increase of NPP is required. Without the downward SOC movement, global SOC declines by 15%, while a 20% increase in NPP is needed to compensate that loss. This vital role of downward SOC movement in controlling whole-soil profile SOC dynamics in response to warming is due to the protection afforded to downward-moving SOC by depth, indicated by much longer residence times of SOC in deeper layers. Additionally, we find that this protection could not be counteracted by promoted decomposition due to the priming of downward-moving new SOC from upper layers on native old SOC in deeper layers. This study provides the first estimation of whole-soil SOC changes under warming and additional NPP required to compensate such changes across the globe, and reveals the vital role of downward movement of SOC in reducing SOC loss under global warming.


An Isoform of the Oncogenic Splice Variant AIMP2-DX2 Detected by a Novel Monoclonal Antibody.
AIMP2-DX2, an exon 2-deleted splice variant of AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2), is highly expressed in lung cancer and involved in tumor progression in vivo. Oncogenic function of AIMP2-DX2 and its correlation with poor prognosis of cancer patients have been well established; however, the application of this potentially important biomarker to cancer research and diagnosis has been hampered by a lack of antibodies specific for the splice variant, possibly due to the poor immunogenicity and/or stability of AIMP2-DX2. In this study a monoclonal antibody, H5, that specifically recognizes AIMP2-DX2 and its isoforms was generated via rabbit immunization and phage display techniques, using a short peptide corresponding to the exon 1/3 junction sequence as an antigen. Furthermore, based on mutagenesis, limited cleavage, and mass spectrometry studies, it is also suggested that the endogenous isoform of AIMP2-DX2 recognized by H5 is produced by proteolytic cleavage of 33 amino acids from N-terminus and is capable of inducing cell proliferation similarly to the uncleaved protein. H5 monoclonal antibody is applicable to enzyme-linked immunosorbent assay, immunoblot, immunofluorescence, and immunohistochemistry, and expected to be a valuable tool for detecting AIMP2-DX2 with high sensitivity and specificity for research and diagnostic purposes.


Comparative molecular modeling of Anopheles gambiae CYP6Z1, a mosquito P450 capable of metabolizing DDT.
One of the challenges faced in malarial control is the acquisition of insecticide resistance that has developed in mosquitoes that are vectors for this disease. Anopheles gambiae, which has been the major mosquito vector of the malaria parasite Plasmodium falciparum in Africa, has over the years developed resistance to insecticides including dieldrin, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), and pyrethroids. Previous microarray studies using fragments of 230 An. gambiae genes identified five P450 loci, including CYP4C27, CYP4H15, CYP6Z1, CYP6Z2, and CYP12F1, that showed significantly higher expression in the DDT-resistant ZAN/U strain compared with the DDT-susceptible Kisumu strain. To predict whether either of the CYP6Z1 and CYP6Z2 proteins might potentially metabolize DDT, we generated and compared molecular models of these two proteins with and without DDT docked in their catalytic sites. This comparison indicated that, although these two CYP6Z proteins share high sequence identity, their metabolic profiles were likely to differ dramatically from the larger catalytic site of CYP6Z1, potentially involved in DDT metabolism, and the more constrained catalytic site of CYP6Z2, not likely to metabolize DDT. Heterologous expressions of these proteins have corroborated these predictions: only CYP6Z1 is capable of metabolizing DDT. Overlays of these models indicate that slight differences in the backbone of SRS1 and variations of side chains in SRS2 and SRS4 account for the significant differences in their catalytic site volumes and DDT-metabolic capacities. These data identify CYP6Z1 as one important target for inhibitor design aimed at inactivating insecticide-metabolizing P450s in natural populations of this malarial mosquito.


Validity and reliability of the Caregiver Reaction Assessment scale among primary informal caregivers for older persons in Singapore.
Previous studies evaluating the validity and reliability of the Caregiver Reaction Assessment (CRA) scale (24 items; five subscales: schedule, health, finances, family support, and esteem) in different countries are not fully congruent. This article assesses the validity and reliability of the CRA among informal caregivers of older persons in Singapore. Data from a national survey of 1190 primary informal caregivers of Singaporeans aged ≥75 years with ≥1 activity of daily living limitation was analyzed. Fit of the five-factor model was tested in half of the sample using confirmatory factor analysis (CFA) and the other half subjected to exploratory factor analysis (EFA). The CRA was modified accordingly and again subjected to CFA. The CRA's measurement equivalence/invariance (ME/I) across language of administration (Chinese/English/Malay) was assessed. CFA showed a poor fit for the five-factor model. EFA suggested the presence of four factors, three items to have neither sufficient nor unique factor loadings and items on two of the subscales to load on a single factor. CFA of the 'modified' CRA (21 items; four subscales: schedule and health, finances, family support, and esteem) suggested a better fit for the four-factor model than for the five-factor model. ME/I analysis supported partial invariance of the CRA across language of administration. The CRA scale should be assessed for relevance in Asian settings. With the suggested modifications, it is suitable for assessing negative and positive effects of caregiving among informal caregivers of older persons with activity limitations in Singapore.


The impact of item order on ratings of cancer risk perception.
Although perceived risk is central to most theories of health behavior, there is little consensus on its measurement with regard to item wording, response set, or the number of items to include. In a methodological assessment of perceived risk, we assessed the impact of changing the order of three commonly used perceived risk items: quantitative personal risk, quantitative population risk, and comparative risk. Participants were 432 men and women enrolled in an ancillary study of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Three groups of consecutively enrolled participants responded to the three items in one of three question orders. Results indicated that item order was related to the perceived risk ratings of both ovarian (P < 0.05) and colorectal (P < 0.05) cancers. Perceptions of risk were significantly lower when the comparative rating was made first. The findings suggest that compelling participants to consider their own risk relative to the risk of others results in lower ratings of perceived risk. Although the use of multiple items may provide more information than when only a single method is used, different conclusions may be reached depending on the context in which an item is assessed.


Factors Associated with Readiness to VCT Service Utilization among Pregnant Women Attending Antenatal Clinics in Northwestern Ethiopia: A Health Belief Model Approach.
One of the consequences of Human Immunodeficiency Virus infection in women is the transmission of the virus to their children. Voluntary counseling and testing is an entry point for prevention of mother to child transmission). This study therefore, investigated readiness to Voluntary counseling and testing service utilization and associated factors among pregnant women attending antenatal care clinics using a health belief model. Health institution based cross-sectional study supplemented with qualitative method was conducted at Debremarkos town from February 15 to March 25, 2008. A total of 418 Antenatal care clients were interviewed. In addition four focus group discussion and five in-depth interviews were performed. Out of 418 pregnant women 254(60.8%) had heard of, Voluntary counseling and testing of these 141 (55.5%) were not ready to use. R Voluntary counseling and testing eadiness of women to utilize Voluntary counseling and testing was significantly associated with knowledge on mother to child transmission, gravidity, gestational age, occupation and educational status. Most women 161 (63.4%) had low perceived susceptibility to HIV and 199(78.3%) had high perceived barrier to Voluntary counseling and testing. The qualitative result showed spouse's disapproval, fear of blood drawing and knowing HIV status, stigma and discrimination were mentioned as barriers. Among the HBM constructs, perceived susceptibility, benefit, barrier and self efficacy were important predictors of women's readiness to. Voluntary counseling and testing This study showed pregnant women's readiness to utilize is l Voluntary counseling and testing ow. It is useful hence, to implement Information Education Communication/Behavioral Change Communication strategies to increase readiness. The use of behavioral model will likely assist the intervention.


Overweight, obesity and breast cancer prognosis: optimal body size indicator cut-points.
Evidence from the data provided in numerous published articles indicates that obesity and overweight can have a negative prognosis role in breast cancer. However, different Body Size Indicators (BSI) and cut-points have been employed and may partly explain discrepancies between the findings of various studies. 14,709 women were recruited, treated and followed for a first unilateral breast cancer. After randomly splitting the patients' data into two groups, a maximum statistical outcome approach was used to select optimal BSI cut-points from a "training sample", when prognosis events were investigated. External validation was then carried out using a "validation sample", and agreement between the selected optimal BSI cut-points was assessed. Body Mass Index (BMI), weight (W), Ideal Weight Ratio (IWR) and Body Surface Area (BSA) were used, and were assessed at the time of diagnosis. The selected optimal BSI cut-points were reliable when overall survival, metastasis recurrence and disease free interval events were investigated. The chosen BMI cut-point values matched the overweight cut-point value given by the World Health Organization. Agreement between defined binary BSI was acceptable; however, it varied from "fair" to "very good". Analysis of second primary cancer occurrence and contralateral recurrence events was not conclusive. When local and node recurrence events were taken into account, the results were inconsistent and were linked to an unconfirmed relationship between stoutness and these prognosis events. Efficient, optimal BSI cut-points indicate a poorer prognosis, illustrated by a shortened overall survival and an increase of metastasis recurrences, from a BMI value of 25 kg/m(2), a W value of 60 kg, an IWR value of 20% and a BSA value of 1.7 m(2). Further BSI cut-point investigations are needed, taking into account contralateral recurrence and second primary cancer events.


Foot posture in people with medial compartment knee osteoarthritis.
Foot posture has long been considered to contribute to the development of lower limb musculoskeletal conditions as it may alter the mechanical alignment and dynamic function of the lower limb. This study compared foot posture in people with and without medial compartment knee osteoarthritis (OA) using a range of clinical foot measures. The reliability of the foot measures was also assessed. The foot posture of 32 patients with clinically and radiographically-confirmed OA predominantly in the medial compartment of the knee and 28 asymptomatic age-matched healthy controls was investigated using the foot posture index (FPI), vertical navicular height and drop, and the arch index. Independent t tests and effect size (Cohen's d) were used to investigate the differences between the groups in the foot posture measurements. Significant differences were found between the control and the knee OA groups in relation to the FPI (1.35 ± 1.43 vs. 2.46 ± 2.18, p = 0.02; d = 0.61, medium effect size), navicular drop (0.02 ± 0.01 vs. 0.03 ± 0.01, p = 0.01; d = 1.02, large effect size) and the arch index (0.22 ± 0.04 vs. 0.26 ± 0.04, p = 0.04; d = 1.02, large effect size). No significant difference was found for vertical navicular height (0.24 ± 0.03 vs. 0.23 ± 0.03, p = 0.54; d = 0.04, negligible effect size). People with medial compartment knee OA exhibit a more pronated foot type compared to controls. It is therefore recommended that the assessment of patients with knee OA in clinical practice should include simple foot measures, and that the potential influence of foot structure and function on the efficacy of foot orthoses in the management of medial compartment knee OA be further investigated.


Management of Morbidity and Mortality in a New Zealand White Rabbit Model of SteroidInduced Osteonecrosis of the Femoral Head.
Steroid-induced osteonecrosis of the femoral head (SONFH) is a condition documented in humans and animals exposed to chronic steroid administration. The rabbit has become a preferred animal model for investigating the pathogenesis and treatment of SONFH due to its shared femoral vascular anatomy with human patients, relative size of the femoral head, and general fecundity. However, morbidity and mortality are frequent during the steroid induction period, prior to surgical manipulation. These problems are poorly reported and inadequately described in the literature. In this study, we report the clinical, gross, and histopathologic findings of New Zealand white (NZW) rabbits undergoing the steroid induction phase of the SONFH model. Severe weight loss (>30%), lipemia, hypercholesterolemia, hyperglycemia, and elevations in ALT and AST were consistent findings across all rabbits, although these changes did not differentiate asymptomatic rabbits from those that became clinically symptomatic or died. Euthanized and spontaneously deceased rabbits exhibited hepatomegaly, hepatic lipidosis/glycogenosis, and hepatocellular necrosis, in addition to a lipid-rich and proteinaceous thoracic effusion. A subset of rabbits developed opportunistic pulmonary infections with Bordetella bronchiseptica and Escherichia coli and small intestine infections with Lawsonia intracellularis superimposed on hepatic and thoracic disease. Together, these findings allowed us to establish a clinical decision-making flowchart that reduced morbidities and mortalities in a subsequent cohort of SONFH rabbits. Recognition of these model-associated morbidities is critical for providing optimal clinical care during the disease induction phase of SONFH.


Independent expression of the alpha and beta c-erbA genes in developing rat brain.
Thyroid hormone is important for normal brain development. Cellular responses to thyroid hormone are mediated by multiple nuclear receptors, classified into alpha- and beta-subtypes. In the rat, expression of both the alpha and beta genes results in several translation products. By using cRNA probes common to alpha transcripts or specific for alpha-1 and beta-1, we have studied the distribution of these transcripts in rat brain at different stages of development from embryonic day 14 to adult age by using in situ hybridization histochemistry. On embryonic day 14, the alpha-1 mRNA is already widely expressed at a low level in the developing brain. The alpha-1 mRNA is developmentally regulated and showed a peak in expression during the first 3 postnatal weeks in the cerebral cortex, amygdala, hippocampus, and cerebellum. The probe common to the alpha transcripts detected a widespread distribution and high levels of these forms in the same regions throughout postnatal development. The level of beta-1 mRNA before birth was low or undetectable. The beta-1 transcript showed developmental regulation as well, with a high level at birth in the mitral cell layer of the olfactory bulb, accumbens nucleus, caudate, and hippocampal field CA1 and increasing levels in other regions later during development. Complementary expression of the alpha and beta forms was seen in the cerebral cortex and hippocampus. The differential temporal and spatial distribution as well as coexpression at comparable levels in certain brain regions suggest different roles for the c-erbA proteins during brain development and in the mature animal.


Multi-Block Color-Binarized Statistical Images for Single-Sample Face Recognition.
Single-Sample Face Recognition (SSFR) is a computer vision challenge. In this scenario, there is only one example from each individual on which to train the system, making it difficult to identify persons in unconstrained environments, mainly when dealing with changes in facial expression, posture, lighting, and occlusion. This paper discusses the relevance of an original method for SSFR, called Multi-Block Color-Binarized Statistical Image Features (MB-C-BSIF), which exploits several kinds of features, namely, local, regional, global, and textured-color characteristics. First, the MB-C-BSIF method decomposes a facial image into three channels (e.g., red, green, and blue), then it divides each channel into equal non-overlapping blocks to select the local facial characteristics that are consequently employed in the classification phase. Finally, the identity is determined by calculating the similarities among the characteristic vectors adopting a distance measurement of the K-nearest neighbors (K-NN) classifier. Extensive experiments on several subsets of the unconstrained Alex and Robert (AR) and Labeled Faces in the Wild (LFW) databases show that the MB-C-BSIF achieves superior and competitive results in unconstrained situations when compared to current state-of-the-art methods, especially when dealing with changes in facial expression, lighting, and occlusion. The average classification accuracies are 96.17% and 99% for the AR database with two specific protocols (i.e., Protocols I and II, respectively), and 38.01% for the challenging LFW database. These performances are clearly superior to those obtained by state-of-the-art methods. Furthermore, the proposed method uses algorithms based only on simple and elementary image processing operations that do not imply higher computational costs as in holistic, sparse or deep learning methods, making it ideal for real-time identification.


Experimental Animal Models: Tools to Investigate Antidiabetic Activity.
About 2.8% of the global population are being suffered from Diabetes mellitus. Diabetes mellitus is a group of metabolic disorders that is characterized by an absolute lack of insulin and resulting in hyperglycemia. To overcome the challenges, many antidiabetic drugs are being used, and research is being carried out in search of more effective anti-diabetic drugs. To study the effectiveness of antidiabetic drugs, many diabetic models, chemicals, and diabetogenic hormones were used at the research level. In this review, we summarised various animal models used, chemicals that induce diabetes, their properties, and the mechanism of action of these models. Further, diabetes mellitus is generally induced in laboratory animals by several methods that include: chemical, surgical and genetic manipulations. To better understand both the pathogenesis and potential therapeutic agents, appropriate animal models of type 1 & type 2 diabetes mellitus are needed. However, for an animal model to have relevance to the study of diabetes, either the characteristics of the animal model should mirror the pathophysiology and natural history of diabetes or the model should develop complications of diabetes with an etiology similar to that of the human condition. There appears to be no single animal model that encompasses all of these characteristics, but there are many that provide very similar characteristics in one or more aspects of diabetes in humans. The use of the appropriate animal model based on these similarities can provide much-needed data on pathophysiological mechanisms operative in human diabetes.


Continuous Monitoring Detected Respiratory Depressive Episodes in Proximity to Adverse Respiratory Events During the PRODIGY Trial.
The PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial was a multicenter prospective trial conducted to develop a risk prediction score for opioid-induced respiratory depressive (OIRD) episodes. Several subjects in the PRODIGY trial developed critical respiratory depressive events, which were qualified as reportable adverse events (AEs). In this study, we determine whether those patients also had an episode of OIRD as detected by continuous capnography and pulse oximetry leading up to the critical clinical event. Blinded capnography and pulse oximetry data from PRODIGY patients who had critical respiratory depressive AE were reviewed. The occurrence and timing of OIRD episodes were recorded in relationship to the AE. Of the 1335 subjects in PRODIGY, 7 patients had 8 reportable pulmonary AE and 187 OIRDs (150 apnea episodes, 14 bradypnea episodes, 23 hypoxic episodes) with median 12 (5-19.5) OIRDs per patient. Five patients were monitored before the AE, and multiple preceding OIRD episodes were detected. One patient had 2 AE, the first (hypoxemia) was recognized upon application of pulse oximetry. This patient subsequently had multiple OIRDs until the second AE occurred (somnolence requiring naloxone administration). Another patient's AE (hypotension and bradypnea) was recognized upon monitor application and subsequently had many OIRD episodes. In the PRODIGY trial, patients who had a pulmonary AE had multiple preceding OIRDs detected by continuous capnography and pulse oximetry. When monitoring was initiated before the AE, numerous OIRDs, mostly apneic episodes preceded AE, suggesting continuous monitoring of both ventilation and oxygenation may allow for early detection and possible prediction of future clinical decompensation.


Assessing Medicaid managed care in eastern state.
This case examines the expanding role of managed care programs in improving health care for the poor while controlling runaway health care costs. The case asks what the commissioner of health in a large eastern state should do to effectively monitor Medicaid managed care programs in her state. The commissioner faces intense pressures for cost containment and strong, but not universal, support for the managed care solution to health care cost problems. The commissioner is herself concerned that the cost savings attributed to managed care may not be real and that the unintended effects on health care may be adverse. Her immediate challenge is to determine what kinds of data she should require service providers to submit to her agency so that she may effectively monitor managed care programs for health care quality, provide positive feedback to health care providers, and establish politically credible program oversight.


Reducing alcohol-impaired driving crashes through the use of social marketing.
Over the past decade there has been little decrease in the number of alcohol-related driving fatalities. During this time most interventions have been educational or legal. This paper presents the results of a field experiment that used social marketing to introduce a new ride program into three rural communities. Almost all people in the 21-34-year-old target know that they should not drive while impaired, and most agree it is not a good thing to do, but for many the opportunity to behave properly does not exist. The Road Crew program was developed using new product development techniques and implemented by developing broad coalitions within the communities. A key feature of the program included rides to, between, and home from bars in older luxury vehicles. Results showed a significant shift in riding/driving behavior, especially among 21-34-year olds, a projected 17% decline in alcohol-related crashes in the first year, no increase in drinking behavior, and large savings between the reactive cost of cleaning up after a crash and the proactive cost of avoiding a crash. Programs have become self-sustaining based on fares and tavern contributions, and have become part of the life style in the treatment communities.


First principles calculations on lithium diffusion near the surface and in the bulk of Fe-doped LiCoPO4.
The olivine phosphate LiCoPO4 is a prospective cathode material in high-voltage lithium-ion batteries. During lithium diffusion, the ions must overcome the diffusion energy barrier near the surface and in the bulk. Experimental studies have shown that Fe doping can enhance the electrochemical performance of LiCoPO4 with a doping concentration of x = 0.2 (LiFe0.2Co0.8PO4). DFT calculations can provide detailed understanding of the lithium diffusion mechanism, structural stability, and electronic properties for Fe-doped LiCoPO4 and elucidate the origins for this improvement from a microscopic viewpoint. In this study, the electronic structure of Fe-doped LiCoPO4 was calculated via first principles and compared with that of pristine LiCoPO4. To investigate the surface properties of LiCoPO4, surface energies with low indices were calculated. The results showed that the (010) surface has the lowest surface energy. Minimum energy diffusion pathways and energy barriers were calculated using the NEB method. Our calculations showed that the energy barrier for lithium-ion diffusion can be reduced by Fe doping modification. Furthermore, we investigated the diffusion processes of polarons and lithium ions migrating simultaneously. This study has implications for further application of LiCoPO4 as a cathode material.


Channelled porous TiO2 synthesized with a water-in-oil microemulsion.
Porous titanium dioxide synthesized with a bicontinuous surfactant template is a promising method that leads to a high active surface area electrode. The template used is based on a water/isooctane/dioctyl sodium sulfosuccinate salt together with lecithin. Several parameters were varied during the synthesis to understand and optimize channel formation mechanisms. The material is patterned in stacked conical channels, widening towards the centre of the grains. The active surface area increased by 116 % when the concentration of alkoxide precursors was decreased and increased by 241 % when the template formation temperature was decreased to 10 °C. Increasing the oil phase viscosity tends to widen the pore aperture, thus decreasing the overall active surface area. Changing the phase proportions alters the microemulsion integrity and disrupts channel formation.


[The polychemotherapy and combined treatment of patients with stage-I and -II lymphogranulomatosis and unfavorable prognosis].
As many as 104 patients with lymphogranulomatosis, clinical stages I-II, having an unfavourable prognosis were examined for the efficacy of polychemotherapy and combined treatment. Polychemotherapy was received by 47 patients, combined treatment (chemo- plus radiotherapy) by 57 patients. Complete remissions were attained significantly more often in patients given combined treatment (92%) as compared to patients on polychemotherapy alone (64%). After complete remissions relapses occurred in 60% of the patients on polychemotherapy and in 13% of the patients receiving combined treatment. The 7-year survival without any relapses was significantly higher (85%) in patients on combined therapy as compared to patients given polychemotherapy (36%). However, the 10-year survival appeared the same in both the groups (87 and 88%). Splenectomy affected neither the rate of relapses in both the groups nor the immediate treatment efficacy or survival.


Comparative transcriptome analysis of NaCl and KCl stress response in Malus hupehensis Rehd. Provide insight into the regulation involved in Na+ and K+ homeostasis.
Apple is among the most widely cultivated perennial fruit crops worldwide. It is sensitive to salt stress, which seriously affects the growth and productivity of apple trees by destroying the homeostasis of Na+ and K+. Previous studies focused on the molecular mechanism underlying NaCl stress. However, signaling transduction under KCl stress has not been thoroughly studied. We comprehensively analyzed the salt tolerance of Malus hupehensis Rehd., which is a widely used rootstock in apple orchards, by using RNA-Seq. Roots and leaves were treated with NaCl and KCl. Based on mapping analyses, a total of 762 differentially expressed genes (DEGs) related to NaCl and KCl stress in the roots and leaves were identified. Furthermore, we identified seven hub genes by WGCNA Analysis. The Gene Ontology (GO) terms were enriched in ion transmembrane transporter and oxidoreductase activity under NaCl and KCl stress. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways focused on the plant hormone signal transduction and mitogen-activated protein kinase signaling pathway. We also screened out 28 candidate genes from 762 DEGs and verified their expression by quantitative reverse transcription polymerase chain reaction (qRT-PCR). All of these enriched genes were closely related to NaCl and KCl stress and take part in mediating the Na+ and K+ homeostasis in M. hupehensis. This transcriptome analysis provides a valuable resource for elucidating the signaling pathway of NaCl and KCl stress and is a substantial genetic resource for discovering genes related to the NaCl and KCl stress response.


Studies on the mechanism of action of abrin-9.2.27 immunotoxin in human melanoma cell lines.
Previously we have shown (Godal, A. et al., J. Natl. Cancer Inst., 77: 1247-1253, 1986) that the sensitivities of different melanoma cell lines to a conjugate of abrin with the anti-melanoma antibody 9.2.27 was correlated with their sensitivities to native abrin. To elucidate the underlying mechanism we have compared the binding and toxicity of the conjugate and of native abrin to two melanoma cell lines, FEMX and LOX, which differ in sensitivity to abrin. Abrin was linked by a disulfide bond to the monoclonal antibody 9.2.27, and the conjugate was purified by affinity chromatography to remove molecules with exposed galactose-binding sites on the toxin B-chain. Lactose had no effect on the binding of the immunotoxin (IT) to the cells but nevertheless reduced strongly the toxicity to the LOX cells. The differences in sensitivity to native abrin were much larger than the concurrent differences in binding. Lactose reduced the toxicity of abrin to a far greater extent than the associated reduction in binding to the cell surface. The toxicity of the immunotoxin to the FEMX cells could be prevented by pretreatment with excess 9.2.27 antibody, whereas the more abrin-sensitive LOX cells were protected only to a limited extent. Concurrent treatment of the LOX cells with antibody and lactose acted synergistically and afforded complete protection. It is suggested that the protective effect of lactose against the IT was exerted after internalization into vesicles of IT bound unspecifically to the cell surface and that the toxic moiety of the IT, the abrin A-chain, may be translocated from endocytotic vesicles to the cytosol by two alternative mechanisms, one mediated by the antibody and a second one facilitated by the B-chain and its lectin binding site. The relative significance of these mechanisms seems to differ in different target cell lines depending on their inherent sensitivities to native abrin which in turn largely reflects the ability of the cells to internalize and process surface-bound abrin.


ccrABEnt serine recombinase genes are widely distributed in the Enterococcus faecium and Enterococcus casseliflavus species groups and are expressed in E. faecium.
The presence, distribution and expression of cassette chromosome recombinase (ccr) genes, which are homologous to the staphylococcal ccrAB genes and are designated ccrAB(Ent) genes, were examined in enterococcal isolates (n=421) representing 13 different species. A total of 118 (28 %) isolates were positive for ccrAB(Ent) genes by PCR, and a number of these were confirmed by Southern hybridization with a ccrA(Ent) probe (n=76) and partial DNA sequencing of ccrA(Ent) and ccrB(Ent) genes (n=38). ccrAB(Ent) genes were present in Enterococcus faecium (58/216, 27 %), Enterococcus durans (31/38, 82 %), Enterococcus hirae (27/52, 50 %), Enterococcus casseliflavus (1/4, 25 %) and Enterococcus gallinarum (1/2, 50 %). In the eight other species tested, including Enterococcus faecalis (n=94), ccrAB(Ent) genes were not found. Thirty-eight sequenced ccrAB(Ent) genes from five different enterococcal species showed 94-100 % nucleotide sequence identity and linkage PCRs showed heterogeneity in the ccrAB(Ent) flanking chromosomal genes. Expression analysis of ccrAB(Ent) genes from the E. faecium DO strain showed constitutive expression as a bicistronic mRNA. The ccrAB(Ent) mRNA levels were lower during log phase than stationary phase in relation to total mRNA. Multilocus sequence typing was performed on 39 isolates. ccrAB(Ent) genes were detected in both hospital-related (10/29, 34 %) and non-hospital (4/10, 40 %) strains of E. faecium. Various sequence types were represented by both ccrAB(Ent) positive and negative isolates, suggesting acquisition or loss of ccrAB(Ent) in E. faecium. In summary, ccrAB(Ent) genes, potentially involved in genome plasticity, are expressed in E. faecium and are widely distributed in the E. faecium and E. casseliflavus species groups.


Intravaginal practices, vaginal infections and HIV acquisition: systematic review and meta-analysis.
Intravaginal practices are commonly used by women to manage their vaginal health and sexual life. These practices could, however, affect intravaginal mucosal integrity. The objectives of this study were to examine evidence for associations between: intravaginal practices and acquisition of HIV infection; intravaginal practices and vaginal infections; and vaginal infections and HIV acquisition. We conducted a systematic review of prospective longitudinal studies, searching 15 electronic databases of journals and abstracts from two international conferences to 31(st) January 2008. Relevant articles were selected and data extracted in duplicate. Results were examined visually in forest plots and combined using random effects meta-analysis where appropriate. Of 2120 unique references we included 22 publications from 15 different studies in sub-Saharan Africa and the USA. Seven publications from five studies examined a range of intravaginal practices and HIV infection. No specific vaginal practices showed a protective effect against HIV or vaginal infections. Insertion of products for sex was associated with HIV in unadjusted analyses; only one study gave an adjusted estimate, which showed no association (hazard ratio 1.09, 95% confidence interval, CI 0.71, 1.67). HIV incidence was higher in women reporting intravaginal cleansing but confidence intervals were wide and heterogeneity high (adjusted hazard ratio 1.88, 95%CI 0.53, 6.69, I(2) 83.2%). HIV incidence was higher in women with bacterial vaginosis (adjusted effect 1.57, 95%CI 1.26, 1.94, I(2) 19.0%) and Trichomonas vaginalis (adjusted effect 1.64, 95%CI 1.28, 2.09, I(2) 0.0%). A pathway linking intravaginal cleaning practices with vaginal infections that increase susceptibility to HIV infection is plausible but conclusive evidence is lacking. Intravaginal practices do not appear to protect women from vaginal infections or HIV and some might be harmful.


800 MHz single-photon detection at 1550-nm using an InGaAs/InP avalanche photodiode operated with a sine wave gating.
Single-photon detection at 1550-nm with a high repetition rate was realized using an InGaAs/InP avalanche photodiode operated with a sine wave gating. Removing the AC noise due to the transferred gate signal usingband elimination filters, we have discriminated the avalanche signal which is much smaller than that in the conventional gating, which results in the suppression of the afterpulsing. At the repetition frequency of 800MHz, the overall afterpulsing probability was 6.0% with the detection efficiency of 8.5% and the dark count probability of 9.2X10(-6).


Oral lactoferrin influences psychological stress in humans: A single-dose administration crossover study.
Lactoferrin is a secretory protein with various physiological functions. Bovine lactoferrin has been demonstrated to alleviate psychological stresses in rats, but this effect in humans has not yet been assessed. The present study aimed to investigate the changes in psychological stress markers following a calculation task, with either lactoferrin or a placebo orally administered prior to the task. A total of 16 healthy female college students visited Juntendo University, Inzai, Japan following an overnight fast. Subjects were quietly seated for 15 min to stabilize the respiratory rate at 0.25 Hz (one breath every 4 sec). Then, subjects provided saliva, ingested either lactoferrin (800 mg of lactoferrin + soy milk) or a placebo (soy milk), remained seated for another 15 min with respiration rate at 0.25 Hz, and performed a calculation task. The task comprised two sets of 15-min calculations, with a 5-min interval between sets. Each calculation set consisted of various multiplications and divisions using pairs of three-digit numbers. Following the calculation task, saliva was collected again. Heart rate was also monitored to identify the frequency domain of heart-rate variability. The calculation task resulted in increased activity of salivary amylase, and decreased concentration of chromogranin A for both lactoferrin (P=0.028 and P<0.001, respectively) and placebo (P=0.003 and P<0.001, respectively) treatments. The degrees of changes in these salivary markers were similar between the two treatments. Heart rate variability exhibited an increase in the high-frequency (HF) component (P=0.022) and a decrease in low-frequency (LF)/HF and LF/(LF+HF) ratios (both P<0.001) following the calculation task under the placebo condition, demonstrating an upregulation of parasympathetic and a downregulation of sympathetic nervous activities. These changes in parasympathetic (HF) and sympathetic (LF/HF) activities, however, were alleviated by lactoferrin compared with the placebo (P=0.007 and P=0.026, respectively). Collectively these results suggest that oral lactoferrin may mitigate psychological stress in humans.


Implications of Misclassification Errors in Empirical Studies of Adolescent Smoking Behaviours.
Misclassification errors in a dependent variable can introduce attenuation bias to covariate effects in a binary choice model. Misreporting of smoking behaviours by adolescents has been widely documented. However, the consequence in empirical studies of adolescent smoking participation has received little attention. This study uses the Health Survey for England (HSE) to investigate the extent and implication of misclassification errors in self-reported smoking among adolescents aged 11-15 years. The HSE contains both a self-reported smoking component and an objective measure of smoking obtained from saliva cotinine assays. Saliva cotinine concentration ≥12 ng/ml is considered the 'true' indicator of adolescent smoking participation against which self-reported smoking is compared. The findings show that smoking is misreported in this age group, resulting in a downwards bias of marginal effect estimates. Given the widespread use of self-reported smoking data, this study explores the performance of the Hausman, Abrevaya and Scott-Morton-modified maximum likelihood estimation (HAS approach) in recovering true estimates of covariate effects. In this context, the HAS approach performs better when the misclassification probabilities are treated as constants compared with when they are treated as conditionally dependent parameters. Copyright © 2016 John Wiley & Sons, Ltd.


Far-field superresolution imaging with dual-dye-doped nanoparticles.
We propose to achieve superresolution in far-field fluorescence imaging by use of silica nanoparticles codoped with Cy3 and Cy5 molecules at a controllable ratio. Owing to the short distances between the dye molecules confined in the nanoparticles, Förster resonant energy transfer can efficiently occur between the Cy3 and Cy5 molecules. Therefore, the Cy5 molecules can quench the fluorescence emission from the Cy3 molecules in the outer region of focal spot of the excitation beam when the excitation intensity is properly chosen, thereby enhancing the resolution of imaging.


Tissue expression map of a large number of expressed sequence tags and its application to in silico screening of stress response genes in common wheat.
In order to assess global changes in gene expression patterns in stress-induced tissues, we conducted large-scale analysis of expressed sequence tags (ESTs) in common wheat. Twenty-one cDNA libraries derived from stress-induced tissues, such as callus, as well as liquid cultures and abiotic stress conditions (temperature treatment, desiccation, photoperiod, moisture and ABA) were constructed. Several thousand colonies were randomly selected from each of these 21 cDNA libraries and sequenced from both the 5' and 3' ends. By computing abundantly expressed ESTs, correlated expression patterns of genes across the tissues were monitored. Furthermore, the relationships between gene expression profiles among the stress-induced tissues were inferred from the gene expression patterns. Multi-dimensional analysis of EST data is analogous to microarray experiments. As an example, genes specifically induced and/or suppressed by cold acclimation and heat-shock treatments were selected in silico. Four hundred and ninety genes showing fivefold induction or 218 genes for suppression in comparison to the control expression level were selected. These selected genes were annotated with the BLAST search. Furthermore, gene ontology was conducted for these genes with the InterPro search. Because genes regulated in response to temperature treatment were successfully selected, this method can be applied to other stress-treated tissues. Then, the method was applied to screen genes in response to abiotic stresses such as drought and ABA treatments. In silico selection of screened genes from virtual display should provide a powerful tool for functional plant genomics.


Decomposition of the organic matter of natural and concentrated vinasse in sandy and clayey soils.
Vinasse has been used as fertilizer by sugarcane growers, due to its potential to completely replace mineral fertilizers. However, if the application is not adequate, this practice may cause environmental contamination. This study used a respirometry test to evaluate the organic matter (OM) decomposition present in natural vinasse and concentrated vinasse (CV), with or without urea addition. The experiment involved two soil types and two types of vinasse at different application rates. The vinasse chemical characterization showed high levels of pseudo-total potassium (K) in both vinasses, which are not considered in the application rates. Decomposition rates above 90% and between 70 and 80% were obtained for sandy and clayey soils, respectively, over a brief 41-day period, indicating rapid OM decomposition. Positive priming effect was observed for CV and CV + urea treatments in sandy soil. An important implication of these findings revealed that K not available in vinasse was released in the soil solution by the OM mineralization, indicating the possibility of overestimation in the vinasse application rates. Therefore, K pseudo-total values should be considered in the calculation of the vinasse application rates. However, studies involving K mobility into soil are needed to validate this hypothesis.


Expression of anaphase-promoting complex7 in fibroadenomas and phyllodes tumors of breast.
The proteolytic destruction of cyclin B is an important event during cell division. Cyclin B proteolysis is triggered by the anaphase-promoting complex. Therefore, cell cycle dysregulation due to anaphase-promoting complex loss contributes to cell transformation and human carcinogenesis. This study investigates anaphase-promoting complex7 expression in spindle cell breast tumors and also includes a comparison between the proliferation antigen Ki-67 and S-phase fraction. The average values of the anaphase-promoting complex7 and Ki-67 labeling indices increased in order from benign to malignant within the phyllodes tumor group, and the fibroadenoma and juvenile fibroadenoma exhibited lower levels of anaphase-promoting complex7 and Ki-67 expression than did the phyllodes tumor. The frequency of anaphase-promoting complex7-positive stromal cells correlated with Ki-67 expression in phyllodes tumor and in all of the examined breast tumors. The above results indicate that anaphase-promoting complex7 and Ki-67 are closely related to cell proliferation. In addition, phyllodes tumor can be differentiated from juvenile fibroadenoma with increased mitotic figures mimicking phyllodes tumor by anaphase-promoting complex7 and Ki-67 immunochemistry. Because anaphase-promoting complex7 is expressed at higher levels than is Ki-67, it may overcome the limitations of the Ki-67 labeling index with regard to the differentiation of benign phyllodes tumor from fibroadenoma.


Cellular metabolic, stress, and histological response on exposure to acute toxicity of endosulfan in tilapia (Oreochromis mossambicus).
Endosulfan is one of the most hazardous organochlorines pesticides responsible for environmental pollution, as it is very persistent and shows bio-magnification. This study evaluated the impact of acute endosulfan toxicity on metabolic enzymes, lysozyme activities, heat shock protein (Hsp) 70 expression, and histopathology in Tilapia (Oreochromis mossambicus). Among the indicators that were induced in dose dependent manner were the enzymes of amino acid metabolism (serum alanine aminotransferase and aspartate aminotransferase), carbohydrate metabolism (serum lactate dehydrogenase), pentose phosphate pathway (Glucose-6-phosphate dehydrogenase) as well as lysozyme and Hsp70 in liver and gill, while liver and gill Isocitrate dehydrogenase (TCA cycle enzyme) and marker of general energetics (Total adenosine triphosphatase) were inhibited. Histopathological alterations in gill were clubbing of secondary gill lamellae, marked hyperplasia, complete loss of secondary lamellae and atrophy of primary gill filaments. Whereas in liver, swollen hepatocyte, and degeneration with loss of cellular boundaries were distinctly noticed. Overall results clearly demonstrated the unbalanced metabolism and damage of the vital organs like liver and gill in Tilapia due to acute endosulfan exposure.


Evaluation of a short RNA within Prostate Cancer Gene 3 in the predictive role for future cancer using non-malignant prostate biopsies.
Prostate Cancer 3 (PCA3) is a long non-coding RNA (ncRNA) upregulated in prostate cancer (PCa). We recently identified a short ncRNA expressed from intron 1 of PCA3. Here we test the ability of this ncRNA to predict the presence of cancer in men with a biopsy without PCa. We selected men whose initial biopsy did not identify PCa and selected matched cohorts whose subsequent biopsies revealed PCa or benign tissue. We extracted RNA from the initial biopsy and measured PCA3-shRNA2, PCA3 and PSA (qRT-PCR). We identified 116 men with and 94 men without an eventual diagnosis of PCa in 2-5 biopsies (mean 26 months), collected from 2002-2008. The cohorts were similar for age, PSA and surveillance period. We detected PSA and PCA3-shRNA2 RNA in all samples, and PCA3 RNA in 90% of biopsies. The expression of PCA3 and PCA3-shRNA2 were correlated (Pearson's r = 0.37, p<0.01). There was upregulation of PCA3 (2.1-fold, t-test p = 0.02) and PCA3-shRNA2 (1.5-fold) in men with PCa on subsequent biopsy, although this was not significant for the latter RNA (p = 0.2). PCA3 was associated with the future detection of PCa (C-index 0.61, p = 0.01). This was not the case for PCA3-shRNA2 (C-index 0.55, p = 0.2). PCA3 and PCA3-shRNA2 expression are detectable in historic biopsies and their expression is correlated suggesting co-expression. PCA3 expression was upregulated in men with PCa diagnosed at a future date, the same did not hold for PCA3-shRNA2. Futures studies should explore expression in urine and look at a time course between biopsy and PCa detection.


Object-based analysis-synthesis coding (OBASC) based on the source model of moving flexible 3-D objects.
This correspondence investigates object-based analysis-synthesis coding (OBASC) for the encoding of moving images at very low data rates. According to the source model, each moving object of an image is described and encoded by three parameter sets defining its motion, shape, and surface color. The parameter sets of each object are obtained by model-based image analysis. They are coded by an object-dependent parameter coding. Using the coded parameter sets, an image can be synthesized by model-based image synthesis. Here, OBASC based on the source model of "moving flexible 3-D objects with 3-D motion" (F3D) is introduced. The efficiency of this source model F3D is compared to the efficiency of OBASC based on the source model of "moving rigid 3-D objects with 3-D motion" (R3D). Compared to R3D, F3D requires the additional transmission of flexible-shape parameters. Therefore, the source model F3D is only applied in those areas of the image which cannot be described by the source model R3D. The new source model F3D reduces the bit rate from 64 to 56 kb/s, providing the same picture quality measured by the SNR of the encoded color parameters.


Intracellular interleukin-32γ mediates antiviral activity of cytokines against hepatitis B virus.
Cytokines are involved in early host defense against pathogen infections. In particular, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) have critical functions in non-cytopathic elimination of hepatitis B virus (HBV) in hepatocytes. However, the molecular mechanisms and mediator molecules are largely unknown. Here we show that interleukin-32 (IL-32) is induced by TNF and IFN-γ in hepatocytes, and inhibits the replication of HBV by acting intracellularly to suppress HBV transcription and replication. The gamma isoform of IL-32 (IL-32γ) inhibits viral enhancer activities by downregulating liver-enriched transcription factors. Our data are validated in both an in vivo HBV mouse model and primary human hepatocytes. This study thus suggests that IL-32γ functions as intracellular effector in hepatocytes for suppressing HBV replication to implicate a possible mechanism of non-cytopathic viral clearance.


Radon in indoor spaces: an underestimated risk factor for lung cancer in environmental medicine.
Occupational medicine has long recognized radon to be a cause of lung cancer, especially among miners working under ground. Until recently, however, little scientific evidence was available about the risk to the general population caused by indoor radon. The authors analyzed literature that they found by a selective search in the light of the recently published S1 guideline of the German Society of Occupational and Environmental Medicine (Deutsche Gesellschaft für Arbeitsmedizin und Umweltmedizin) and a recent publication of the German Commission on Radiological Protection (Strahlenschutzkommission). Exposure to indoor radon and its decay products is a major contributor to the radiation exposure of the general population. In Germany, the mean radiation exposure due to radon in living rooms and bedrooms is about 49 Bq/m(3). It is well documented in the scientific literature that indoor radon significantly increases the risk of lung cancer, probably in a linear dose-response relationship with no threshold. Every 100 Bq/m(3) increase in the radon concentration is estimated to increase the relative risk for lung cancer by 8% to 16%. After cigarette smoking, radon is the second main cause of lung cancer in the general population without occupational exposure. From the point of view of preventive environmental medicine, it is important to identify buildings with high radon concentrations, initiate appropriate measures, and minimize radon exposure, particularly in new buildings.


Crania with mutilated facial skeletons: a new ritual treatment in an early pre-pottery Neolithic B cranial cache at Tell Qarassa North (South Syria).
The removal of crania from burials, their ritual use and their disposal, generally in cranial caches, are the most particular characteristics of the funerary ritual in the transition to the Neolithic in the Near East. Despite the importance of this ritual, detailed studies of cranial caches are rare. This funerary ritual has traditionally been interpreted as a form of ancestor-veneration. However, this study of the cranial caches found at the site of Tell Qarassa North, South Syria, dated in the second half of the ninth millennium BC, questions this interpretation. The 12 crania, found in two groups arranged in two circles on the floor of a room, belonged to male individuals, apart from one child and one preadolescent. In 10 of the 11 cases, the facial skeletons were deliberately mutilated. In the context of the Pre-Pottery Neolithic B, when the symbolism of the human face played a vital role in ritual practice, this mutilation of the facial skeleton could be interpreted as an act of hostility. In the absence of indicators of social stratification or signs of violence that might indicate more coercive forms of society, the veneration of ancestors has been explained as a mechanism for social cohesion, which would have been necessary in a context of rapid growth in the population of settlements. However, data on the negative nature of some funerary rites, of punishment or indifference rather than veneration, should make us question an over-idealized view of the first Neolithic societies.


The mothering experience of women with FGM/C raising 'uncut' daughters, in Ivory Coast and in Canada.
While Female Genital Cutting (FGM/C) is a deeply entrenched cultural practice, there is now mounting evidence for a gradual decline in prevalence in a number of geographical areas in Africa and following migration to non-practicing countries. Consequently, there is now a growing number of women with FGM/C who are raising 'uncut' daughters. This study used a qualitative methodology to investigate the experience of women with FGM/C raising daughters who have not been subjected to the ritual. The aim of this study was to shed light on mothers' perception of the meaning and cultural significance of the practice and to gain insight into their mothering experience of 'uncut' girls. To this end, in-depth interviews were conducted with fifteen mothers living in Abidjan, Ivory Coast and in Montreal, Canada (8 and 7, respectively). Thirteen mothers intrinsically refused to perpetuate FGM/C onto their daughters and two diasporic mothers were in favour of FGM/C but forewent the practice for fear of legal repercussions. Whether the eschewing of FGM/C was deliberate or legally imposed, raising 'uncut' daughters had significant consequences in terms of women's mothering experiences. Mothers faced specific challenges pertaining to community and family pressure to have daughters undergo FGM/C, and expressed concerns regarding their daughters' sexuality. Conversely, women's narratives were also infused with pride and hope for their daughters, and revealed an accrued dialogue between the mother-daughter dyad about cultural norms and sexuality. Interestingly, women's mothering experience was also bolstered by the existence of informal networks of support between mothers with FGM/C whose daughters were 'uncut'. These communities of mothers engaged in open dialogue about the consequences of FGM/C and offered reciprocal solidarity and support in their decision to forego FGM/C for their children. Women with FGM/C who are raising 'uncut' daughters in their homeland and in their country of immigration vastly report a positive experience. However, they also face specific challenges related to immigration, psychosocial, and psychosexual considerations, which must be tackled from a multidisciplinary perspective.


Atmospheric Autoxidation of Organophosphate Esters.
Organophosphate esters (OPEs), widely used as flame retardants and plasticizers, have frequently been identified in the atmosphere. However, their atmospheric fate and toxicity associated with atmospheric transformations are unclear. Here, we performed quantum chemical calculations and computational toxicology to investigate the reaction mechanism of peroxy radicals of OPEs (OPEs-RO2•), key intermediates in determining the atmospheric chemistry of OPEs, and the toxicity of the reaction products. TMP-RO2• (R1) and TCPP-RO2• (R2) derived from trimethyl phosphate and tris(2-chloroisopropyl) phosphate, respectively, are selected as model systems. The results indicate that R1 and R2 can follow an H-shift-driven autoxidation mechanism under low NO concentration ([NO]) conditions, clarifying that RO2• from esters can follow an autoxidation mechanism. The unexpected autoxidation mechanism can be attributed to the distinct role of the ─(O)3P(═O) phosphate-ester group in facilitating the H-shift of OPEs-RO2• from commonly encountered ─OC(═O)─ and ─ONO2 ester groups in the atmosphere. Under high [NO] conditions, NO can mediate the autoxidation mechanism to form organonitrates and alkoxy radical-related products. The products from the autoxidation mechanism have low volatility and aquatic toxicity compared to their corresponding parent compounds. The proposed autoxidation mechanism advances our current understanding of the atmospheric RO2• chemistry and the environmental risk of OPEs.


Pregnancy in Non-Communicating Unicornuate Uterus: Diagnosis Difficulty and Outcomes - a Case Report.
Approximately 1 in every 76,000 pregnancies develops within a unicornuate uterus with a rudimentary horn. Müllerian uterus anomalies are often asymptomatic, thus, the diagnosis is a challenge, and it is usually made during the gestation or due to its complications, such as uterine rupture, pregnancy-induced hypertension, antepartum, postpartum bleeding and intrauterine growth restriction (IUGR). In order to avoid unnecessary cesarean sections and the risks they involve, the physicians should consider the several approaches and for how long it is feasible to perform labor induction in suspected cases of pregnancy in a unicornuate uterus with a rudimentary horn, despite the rarity of the anomaly. This report describes a case of a unicornuate uterus in which a pregnancy developed in the non-communicating rudimentary horn and the consequences of the delayed diagnosis.


Synthesis of phosphoenol pyruvate (PEP) analogues and evaluation as inhibitors of PEP-utilizing enzymes.
The synthesis of 10 new phosphoenolpyruvate (PEP) analogues with modifications in the phosphate and the carboxylate function is described. Included are two potential irreversible inhibitors of PEP-utilizing enzymes. One incorporates a reactive chloromethylphosphonate function replacing the phosphate group of PEP. The second contains a chloromethyl group substituting for the carboxylate function of PEP. An improved procedure for the preparation of the known (Z)- and (E)-3-chloro-PEP is also given. The isomers were obtained as a 4 : 1 mixture, resolved by anion-exchange chromatography after the last reaction step. The stereochemistry of the two isomers was unequivocally assigned from the (3)J(H-C) coupling constants between the carboxylate carbons and the vinyl protons. All of these and other known PEP-analogues were tested as reversible and irreversible inhibitors of Mg2+- and Mn2+- activated PEP-utilizing enzymes: enzyme I of the phosphoenolpyruvate:sugar phosphotransferase system (PTS), pyruvate kinase, PEP carboxylase and enolase. Without exception, the most potent inhibitors were those with substitution of a vinyl proton. Modification of the phosphate and the carboxylate groups resulted in less effective compounds. Enzyme I was the least tolerant to such modifications. Among the carboxylate-modified analogues, only those replaced by a negatively charged group inhibited pyruvate kinase and enolase. Remarkably, the activity of PEP carboxylase was stimulated by derivatives with neutral groups at this position in the presence of Mg2+, but not with Mn2+. For the irreversible inhibition of these enzymes, (Z)-3-Cl-PEP was found to be a very fast-acting and efficient suicide inhibitor of enzyme I (t(1/2) = 0.7 min).


Review of empagliflozin monotherapy for previously untreated patients with type 2 diabetes mellitus: Comparison with sitagliptin.
This Practice Pearl provides a review and brief commentary of the 24-week, double-blind, parallel-group, randomized, Phase III study by Roden et al., which assessed the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin, 10 mg or 25 mg as monotherapy, versus placebo and the dipeptidyl peptidase-4 inhibitor sitagliptin, in previously untreated patients with type 2 diabetes mellitus (T2DM). Compared to placebo, empagliflozin improved glycemic control, with additional benefits on bodyweight and systolic blood pressure, versus placebo and sitagliptin. Treatment was well tolerated. The authors concluded that empagliflozin is a potential new approach to treat patients with T2DM who are inadequately controlled with diet and exercise alone. This paper advances our understanding of empagliflozin, which so far, appears to be a promising therapeutic option for the management of patients with T2DM.


Type one protein phosphatase regulates fixed-carbon starvation-induced autophagy in Arabidopsis.
Autophagy, a conserved pathway that carries out the bulk degradation of cytoplasmic material in eukaryotic cells, is critical for plant physiology and development. This process is tightly regulated by ATG13, a core component of the ATG1 kinase complex, which initiates autophagy. Although ATG13 is known to be dephosphorylated immediately after nutrient starvation, the phosphatase regulating this process is poorly understood. Here, we determined that the Arabidopsis (Arabidopsis thaliana) septuple mutant (topp-7m) and octuple mutant (topp-8m) of TYPE ONE PROTEIN PHOSPHATASE (TOPP) exhibited significantly reduced tolerance to fixed-carbon (C) starvation due to compromised autophagy activity. Genetic analysis placed TOPP upstream of autophagy. Interestingly, ATG13a was found to be an interactor of TOPP. TOPP directly dephosphorylated ATG13a in vitro and in vivo. We identified 18 phosphorylation sites in ATG13a by LC-MS. Phospho-dead ATG13a at these 18 sites significantly promoted autophagy and increased the tolerance of the atg13ab mutant to fixed-C starvation. The dephosphorylation of ATG13a facilitated ATG1a-ATG13a complex formation. Consistently, the recruitment of ATG13a for ATG1a was markedly inhibited in topp-7m-1. Finally, TOPP-controlled dephosphorylation of ATG13a boosted ATG1a phosphorylation. Taken together, our study reveals the crucial role of TOPP in regulating autophagy by stimulating the formation of the ATG1a-ATG13a complex by dephosphorylating ATG13a in Arabidopsis.


Ability to adapt to seasonal temperature extremes among atrial fibrillation patients. A nation-wide study of hospitalizations in Israel.
In recent years, temperature fluctuations and adverse weather events have become major concerns, influencing overall mortality and morbidity. While the association between extreme temperatures and atrial fibrillation (AF) has been supported by research, there is limited evidence on the ability of AF patients to adapt to the changing temperatures. We explored this question among AF patients in Israel featured by extreme temperature conditions. We examined the association between exposure to extreme temperatures and hospitalizations related to AF in a nationwide cohort in Israel. A case-crossover design with a distributed nonlinear model (DLNM) was applied to assess possible effects of temperature fluctuations during each season. We considered the 7 days prior to the event as the possible window period. During 2004-2018 we recorded a total of 54,909 hospitalizations for AF. Low temperatures in winter and high in summer adversely affected AF-related hospitalizations. The effect recorded for the first few weeks of each season was of higher magnitude and decreased or faded off completely as the seasons progressed (OR in winter: from 1.14, 95%CI 0.98, 1.32 to 0.90, 95%CI: 0.77, 1.06;OR in summer: from 1.95, 95%CI: 1.51, 2.52 to 1.22, 95%CI: 0.90, 1.65). Patients living in the south region and patients with low socioeconomic status were more susceptible to extreme temperatures. Although extreme hot and cold temperatures are associated with an increased risk of hospitalization for AF, the patients are likely to adapt to temperature change over the course of the first weeks of the season.


Surgical staging in endometrial cancer.
Early presentation of endometrial cancer permits effective management with excellent clinical outcome. The addition of hysteroscopy to dilatation and curettage (D&C) in the evaluation of postmenopausal bleeding adds little to the detection of malignancy. Imaging studies such as computed tomography, magnetic resonance imaging, and positron-emission tomography may be of use in determining the presence of extrauterine disease in patients medically unfit for surgical staging. However, these studies are not sufficiently sensitive to replace surgical staging and have little role in routine preoperative evaluation. Clinical staging alone is clearly inadequate, as 23% of preoperative clinical stage I/II patients are upstaged with comprehensive surgical staging. Preoperative tumor grade from D&C or office biopsy may be inaccurate and lead to an underestimate of tumor progression if used to determine which patients should be surgically staged. Clinical estimation of depth of invasion, with or without frozen section, is inaccurate and may lead to underestimation of disease status when surgical staging is not performed. The practice of resecting only clinically suspicious nodes should be discouraged as it is no substitute for comprehensive surgical staging. Comprehensive surgical staging provides proper guidance for postoperative adjuvant therapy, avoiding needless radiation in 85% of clinical stage I/II patients. Finally, resection of occult metastasis with surgical staging may improve survival.


A review of web-based support systems for students in higher education.
Recent evidence suggests that there is an increasing need for accessible and anonymous services to support higher education (HE) students suffering from psychological and/or academic difficulties. Such difficulties can lead to several negative outcomes, including poor academic performance, sub-optimal mental health, reduced study satisfaction, and dropout from study. Currently, universities in the UK lack financial resources and the on-campus mental health services traditionally offered to students are increasingly economically unsustainable. Compounded by the perceived stigma of using such services, mental health providers have been driven to address the escalating needs of students through online services. In this paper, we review online support systems identified through a literature search and a manual search of references in the identified papers. Further systems were identified through web searches, and systems still in development were identified by consultation with researchers in the field. We accessed systems online to extract relevant information, regarding the main difficulties addressed by the systems, the psychological techniques used and any relevant research evidence to support their effectiveness. A large number of web-based support systems have been developed to support mental health and wellbeing, although few specifically target HE students. Further research is necessary to establish the effectiveness of such interventions in providing a cost-effective alternative to face-to-face therapy, particularly in certain settings such as HE institutions.


EXTRACTING BIOMEDICALLY IMPORTANT INFORMATION FROM LARGE, AUTOMATED IMAGING EXPERIMENTS.
Major challenges remain in the extraction of rich information from high-throughput microscopy experiments. In this paper, I describe some of these challenges, particularly those that are the subject of ongoing research in my laboratory. The challenges include segmenting neurons, co-cultures of different cell types, and whole organisms; segmenting and tracking cells in time-lapse images; quantifying complex phenotypic changes; and discovering biologically relevant subpopulations of cells.


Insulin resistance does not impair contractile responses of cerebral arteries.
Insulin resistance (IR) impairs endothelium-mediated vasodilation in cerebral arteries as well as K+ channel function in vascular smooth muscle. Peripheral arteries also show an impaired endothelium-dependent vasodilation in IR and concomitantly show an enhanced contractile response to endothelin-1 (ET-1). However, the contractile responses of the cerebral arteries in IR have not been examined systematically. This study examined the contractile responses of pressurized isolated middle cerebral arteries (MCAs) in fructose-fed IR and control rats. IR MCAs showed no difference in pressure-mediated (80 mmHg) vasoconstriction compared to controls, either in time to develop spontaneous tone (control: 61+/-3 min, n=30; IR: 63+/-2 min, n=26) or in the degree of that tone (control: 60 min: 33+/-2%, n=22 vs. IR 60 min: 34+/-3%, n=17). MCAs treated with ET-1 (10(-8.5) M) constrict similarly in control (53+/-3%, n=14) and IR (53+/-3%, n=14) arteries. Constrictor responses to U46619 (10(-6) M) are also similar in control (48+/-9%, n=8) and IR (42+/-5%, n=6) MCAs as are responses to extraluminal uridine 5'-triphosphate (UTP; 10(-4.5) M) (control: 35+/-7%, n=11 vs. IR: 38+/-3%, n=10). These findings demonstrate that constrictor responses remain intact in IR despite a selective impairment of dilator responses and endothelial and vascular smooth muscle K+ channel function in cerebral arteries. Thus, it appears that the increased susceptibility to cerebrovascular abnormalities associated with IR and diabetes (including cerebral ischemia, stroke, vertebrobasilar transient ischemic attacks) is not due to an enhanced vasoreactivity to constrictor agents.


Imaging in pulsatile tinnitus.
Tinnitus may be continuous or pulsatile. Vascular lesions are the most frequent radiologically demonstrable cause of pulsatile tinnitus. These include congenital vascular anomalies (which may be arterial or venous), vascular tumours, and a variety of acquired vasculopathies. The choice of imaging depends on the clinical findings. If a mass is present at otoscopy, thin-section computed tomography (CT) is indicated. In the otoscopically normal patient, there is a range of possible imaging approaches. However, combined CT angiography and venography is particularly useful.


Policy challenges for the pediatric rheumatology workforce: Part I. Education and economics.
For children with rheumatic conditions, the available pediatric rheumatology workforce mitigates their access to care. While the subspecialty experiences steady growth, a critical workforce shortage constrains access. This three-part review proposes both national and international interim policy solutions for the multiple causes of the existing unacceptable shortfall. Part I explores the impact of current educational deficits and economic obstacles which constrain appropriate access to care. Proposed policy solutions follow each identified barrier.Challenges consequent to obsolete, limited or unavailable exposure to pediatric rheumatology include: absent or inadequate recognition or awareness of rheumatic disease; referral patterns that commonly foster delays in timely diagnosis; and primary care providers' inappropriate or outdated perception of outcomes. Varying models of pediatric rheumatology care delivery consequent to market competition, inadequate reimbursement and uneven institutional support serve as additional barriers to care.A large proportion of pediatrics residency programs offer pediatric rheumatology rotations. However, a minority of pediatrics residents participate. The current generalist pediatrician workforce has relatively poor musculoskeletal physical examination skills, lacking basic competency in musculoskeletal medicine. To compensate, many primary care providers rely on blood tests, generating referrals that divert scarce resources away from patients who merit accelerated access to care for rheumatic disease. Pediatric rheumatology exposure could be enhanced during residency by providing a mandatory musculoskeletal medicine rotation that includes related musculoskeletal subspecialties. An important step is the progressive improvement of many providers' fixed referral and laboratory testing patterns in lieu of sound physical examination skills.Changing demographics and persistent reimbursement disparities will require workplace innovation and legislative reform. Reimbursement reform is utterly essential to extending patient access to subspecialty care. In practice settings characterized by a proportion of Medicaid-subsidized patients in excess of the national average (> 41%), institutional support is vital. Accelerating access to care will require the most efficient deployment of existing, limited resources. Practice redesign of such resources can also improve access, e.g., group appointments and an escalating role for physician extenders. Multidisciplinary, team-oriented care and telemedicine have growing evidence basis as solutions to limited access to pediatric rheumatology services.


Mastoparan promotes exocytosis and increases intracellular cyclic AMP in human platelets. Evidence for the existence of a Ge-like mechanism of secretion.
Recent studies have shown that mastoparan, an amphiphilic peptide derived from wasp venom, accelerates guanine nucleotide exchange and GTPase activity of purified GTP-binding proteins. In the present study we have examined the functional consequences of exposure of intact human platelets to mastoparan. Mastoparan promoted rapid (less than or equal to 1 min) dose-dependent increases in 5-hydroxy[14C]tryptamine and beta-thromboglobulin release from dense-granule and alpha-granule populations respectively. The exocytotic response did not result from a lytic effect of mastoparan and occurred in the complete absence of platelet shape change and aggregation. Liberation of [3H]arachidonate and increases in cytosolic [Ca2+] (detected with fura 2) were not observed in platelets stimulated with mastoparan. Similarly, in platelets preloaded with [3H]inositol during reversible electroporation, mastoparan did not cause the accumulation of [3H]inositol phosphates. Mastoparan-induced secretion was unaffected by preincubation with either the protein kinase C inhibitor staurosporine (10 nM-10 microM) or prostacyclin (PGI2; 100 ng/ml) and was not accompanied by phosphorylation of the 45 kDa protein kinase C substrate or the 20 kDa protein normally associated with platelet activation. The G-protein inhibitor guanosine 5'-[beta-thio]diphosphate (GDP[S]; 1 mM) attenuated the secretion induced by mastoparan in both intact and saponin-permeabilized platelets. Encapsulation of GDP[S] during reversible permeabilization inhibited mastoparan-induced secretion, providing evidence for an intracellular action of GDP[S]. In all these studies thrombin (0.05-0.2 unit/ml) elicited characteristic responses, and thrombin-induced secretion was inhibited by staurosporine, PGI2 and GDP[S]. Mastoparan also increased intra-platelet cyclic AMP in a dose-dependent manner. Mastoparan and PGI2 increased 32P incorporation into a protein of approx. 24 kDa, whereas phosphorylation of a 50 kDa substrate was only seen in PGI2-stimulated platelets. These results indicate that mastoparan promotes secretion by a mechanism which does not involve stimulation of phospholipase C and suggest that the secretory event may result either from a direct fusogenic action of mastoparan and/or from stimulation of the putative exocytosis-linked G-protein, Ge.


Clinical presentation of tuberculosis and the degree of immunodeficiency in patients with HIV infection.
A retrospective study of 80 HIV patients diagnosed with tuberculosis was carried out in order to evaluate the clinical presentation of tuberculosis (CPT) in relation to the degree of HIV-induced immunodeficiency, as determined by the CD4 lymphocyte count and reactivity to the tuberculin and delayed-type hypersensitivity reaction (DHR) skin tests by applying 2TU of RT-23 tuberculin, and the Muiltest IMC Merieux, respectively. CPT classification was undertaken on the basis of the location of the disease: pulmonary tuberculosis (PT), distinguishing between typical pulmonary (TP) and atypical (AP) according to the radiological pattern; extrapulmonary (ET); mixed tuberculosis (MT) pulmonary and extrapulmonary; and miliary tuberculosis. The CD4 lymphocyte count was 264.6 +/- 226.8, the TP had the highest number (505), MT had 132 (p < 0.001) and the miliary tuberculosis had 148 (p < 0.001), the lowest. The tuberculin skin test was positive in 35%, of which 11% were MT (p < 0.05). In the delayed-type hypersensitivity reaction, 67% were non-normoergic, of which 95% and 100% were MT and miliary tuberculosis, respectively (p < 0.05). There was a good overlap between CD4 depletion and skin tests. TP exhibited moderate immunodeficiency, AP severe immunodeficiency, and mixed and miliary TB extremely high immunodeficiency.


Marmosets (Saguinus fuscicollis): Are Learning Sets Learned?
Confronted with a novel object, a social group of marmoset monkeys investigated it. If they found food on it they returned to it readily the next day; whoever had led in eating usually did so again. If they did not find food, day 2 responsiveness decreased. These untrained performances were sufficient for one-trial visual discrimination learning.