Automated blood pressure measurements during exercise.
One of the critical parameters measured during exercise is blood pressure. However, the accurate measurement of systolic and diastolic blood pressure during exercise is difficult with auscultation and impractical with direct arterial techniques. The purpose of this study was to compare an automated system (Colin, Inc. STBP-680) with auscultation in humans during rest and exercise and to compare the automated system with direct arterial blood pressure measurement in a canine model during pharmacological challenges that resulted in a wide range of blood pressure values. Compared with direct arterial blood pressure taken in the canine model, the STBP-680 gave good estimates of diastolic blood pressure and adequately monitored relative changes in systolic blood pressure, diastolic blood pressure, and mean arterial pressure (mean arterial pressures in all instances were calculated as one-third systolic plus two-thirds diastolic blood pressures). Compared with auscultation methods in humans, the STBP-680 gave similar estimates of resting diastolic blood pressure and monitored relative changes in resting systolic blood pressures, diastolic blood pressures, and mean arterial pressures. During both treadmill and cycle ergometer exercise in humans, the STBP-680 monitored changes in systolic blood pressure, phase IV diastolic blood pressure, and mean arterial pressure. Further, the STBP-680 estimated exactly and noted relative changes in heart rate in every test. However, during exercise, quantitative estimations of systolic blood pressure by the STBP-680 were higher than those found using auscultation. Where exact, quantitative measures of blood pressure are needed, direct arterial measurement continues to be the most accurate method. However, where indirect methods can be used, the STBP-680 may provide a suitable alternative that reduces many of the technical concerns of auscultation in young, healthy individuals.


An Adaptation of the Original Fresno Test to Measure Evidence-Based Practice Competence in Pediatric Bedside Nurses.
Instruments used to assess evidence-based practice (EBP) competence in nurses have been subjective, unreliable, or invalid. The Fresno test was identified as the only instrument to measure all the steps of EBP with supportive reliability and validity data. However, the items and psychometric properties of the original Fresno test are only relevant to measure EBP with medical residents. Therefore, the purpose of this paper is to describe the development of the adapted Fresno test for pediatric nurses, and provide preliminary validity and reliability data for its use with Bachelor of Science in Nursing-prepared pediatric bedside nurses. General adaptations were made to the original instrument's case studies, item content, wording, and format to meet the needs of a pediatric nursing sample. The scoring rubric was also modified to complement changes made to the instrument. Content and face validity, and intrarater reliability of the adapted Fresno test were assessed during a mixed-methods pilot study conducted from October to December 2013 with 29 Bachelor of Science in Nursing-prepared pediatric nurses. Validity data provided evidence for good content and face validity. Intrarater reliability estimates were high. The adapted Fresno test presented here appears to be a valid and reliable assessment of EBP competence in Bachelor of Science in Nursing-prepared pediatric nurses. However, further testing of this instrument is warranted using a larger sample of pediatric nurses in diverse settings. This instrument can be a starting point for evaluating the impact of EBP competence on patient outcomes.


l-Lysine based lipidated biphenyls as agents with anti-biofilm and anti-inflammatory properties that also inhibit intracellular bacteria.
l-Lysines were conjugated to lipidated biphenyls using simple synthetic chemistry to obtain selective membrane-active antibacterial agents that inhibit cell-wall biosynthesis. The most selective compound bore promising activity against biofilm-related infections and intracellular bacteria, and also suppressed the stimulation of TNF-α induced by lipoteichoic acid. Belligerent to resistance development, it was active in a murine model of MRSA infection.


[Pathophysiology and biochemistry of platelets].
Although their central role is to control bleeding and to induce thrombosis, platelets are important inflammatory and immune cells as well as modulators of angiogenesis. This review focuses on the different roles of platelets in hemostasis, thrombosis, inflammation, arteriosclerosis, angiogenesis, antimicrobial host defense and hematogenous tumor metastasis. Platelets are the central regulators of hemostasis. On their surface the important thrombin burst takes place. Platelets cause atherothrombotic vascular occlusions. However, they are probably involved in early stages of arteriosclerosis, e.g. extravasation of leukocytes at sites of vascular injury, formation of foam cells and proliferation of smooth muscle cells. These processes are triggered by secretion of proinflammatory substances and growth factors as well as by platelet-cell interactions via specific adhesive axes. During infections platelets kill pathogens through secretion of antimicrobial substances and extracellular traps or nets. Platelets facilitate the revascularisation of ischemic tissue and therefore even promote tumor growth.


Spatial and temporal dynamics of malaria in Madagascar.
Malaria is one of the primary health concerns in Madagascar. Based on the duration and intensity of transmission, Madagascar is divided into five epidemiological strata that range from low to mesoendemic transmission. In this study, the spatial and temporal dynamics of malaria within each epidemiological zone were studied. The number of reported cases of uncomplicated malaria from 112 health districts between 2010 and 2014 were compiled and analysed. First, a Standardized Incidence Ratio was calculated to detect districts with anomalous incidence compared to the stratum-level incidence. Building on this, spatial and temporal malaria clusters were identified throughout the country and their variability across zones and over time was analysed. The incidence of malaria increased from 2010 to 2014 within each stratum. A basic analysis showed that districts with more than 50 cases per 1000 inhabitants are mainly located in two strata: East and West. Lower incidence values were found in the Highlands and Fringe zones. The standardization method revealed that the number of districts with a higher than expected numbers of cases increased through time and expanded into the Highlands and Fringe zones. The cluster analysis showed that for the endemic coastal region, clusters of districts migrated southward and the incidence of malaria was the highest between January and July with some variation within strata. This study identified critical districts with low incidence that shifted to high incidence and district that were consistent clusters across each year. The current study provided a detailed description of changes in malaria epidemiology and can aid the national malaria programme to reduce and prevent the expansion of the disease by targeting the appropriate areas.


Depressive Symptoms Prior to Pregnancy and Infant Low Birth Weight in South Africa.
Despite improvements in service delivery and patient management, low birth weight among infants has been a persistent challenge in South Africa. The study aimed to explore the relationship between depression before pregnancy and the low birth weight (LBW) of infants in post-apartheid South Africa. This study utilized data from Waves 1 and 2 of the South African National Income Dynamics Study, the main outcome being a dichotomous measure of child LBW (<2500 g) drawn from the Wave 2 child questionnaire. Depressive symptoms of non-pregnant women was the main predictor drawn from the Wave 1 adult questionnaire. Depressive symptoms were screened using the 10-item four-point Likert version of the Center for Epidemiologic Studies Depression Scale (CES-D) instrument. A total score of 10 or greater on the CES-D indicates a positive screen for depressive symptoms. An adjusted logistic regression model was used to examine the relationship between women's depression before pregnancy and infant LBW. A sample size of 651 women in Wave 1 was linked to 672 newborns in Wave 2. The results of the adjusted logistic regression model indicated depressive symptoms (CES-D ≥ 10) prior to pregnancy were associated with infant LBW (adjusted OR 2.84, 95 % CI 1.08-7.46). Another significant covariate in the model was multiple childbirths. Our finding indicates that women's depressive symptoms prior to pregnancy are associated with the low birth weight of newborns and suggests that this association may not be limited to depression present during the ante-natal phase.


Disability Weights Measurement for 289 Causes of Disease Considering Disease Severity in Korea.
For the Korean Burden of Disease (KBD) 2015 study, we have amended disability weights for causes of disease adapting the methodology of the KBD disability weight 2012 study. We conducted a self-administered web-based survey in Korea using ranking five causes of disease. A total of 605 physicians and medical college students who were attending in third or fourth grade of a regular course performed the survey. We converted the ranked data into paired comparison data and ran a probit regression. The predicted probabilities for each cause of disease were calculated from the coefficient estimates of the probit regression. 'Being dead (1)' and 'Full health (0)' were utilized as anchor points to rescale the predicted probability on a scale from 0 to 1. As a result, disability weights for a total of 289 causes of disease were estimated. In particular, we calculated the disability weights of 60 causes of disease considering severity level. These results show that prejudice about the severity of cause of disease itself can affect the estimation of disability weight, when estimating the disability weight for causes of disease without consideration of severity. Furthermore, we have shown that disability weights can be estimated based on a ranking method which can maximize efficiency of data collection. Disability weights from this study can be used to estimate disability adjusted life year and healthy life expectancy. Furthermore, we expected that the use of the ranking method will increase gradually in disability weight studies.


Optothermophysical properties of demineralized human dental enamel determined using photothermally generated diffuse photon density and thermal-wave fields.
Noninvasive dental diagnostics is a growing discipline since it has been established that early detection and quantification of tooth mineral loss can reverse caries lesions in their incipient state. A theoretical coupled diffuse photon density and thermal-wave model was developed and applied to photothermal radiometric frequency responses, fitted to experimental data using a multiparameter simplex downhill minimization algorithm for the extraction of optothermophysical properties from artificially demineralized human enamel. The aim of this study was to evaluate the reliability and robustness of the advanced fitting algorithm. The results showed a select group of optical and thermal transport parameters and thicknesses were reliably extracted from the computational fitting algorithm. Theoretically derived thicknesses were accurately predicted, within about 20% error, while the estimated error in the optical and thermal property evaluation was within the values determined from early studies using destructive analyses. The high fidelity of the theoretical model illustrates its efficacy, reliability, and applicability toward the nondestructive characterization of depthwise inhomogeneous sound enamel and complex enamel caries lesions.


Molecular determinants of binding of non-oxime bispyridinium nerve agent antidote compounds to the adult muscle nAChR.
Organophosphorus nerve agents (NAs) are the most lethal chemical warfare agents and have been used by state and non-state actors since their discovery in the 1930s. They covalently modify acetylcholinesterase, preventing the breakdown of acetylcholine (ACh) with subsequent loss of synaptic transmission, which can result in death. Despite the availability of several antidotes for OPNA exposure, none directly targets the nicotinic acetylcholine receptor (nAChR) mediated component of toxicity. Non-oxime bispyridinium compounds (BPDs) have been shown previously to partially counteract the effects of NAs at skeletal muscle tissue, and this has been attributed to inhibition of the muscle nAChR. Functional data indicate that, by increasing the length of the alkyl linker between the pyridinium moieties of BPDs, the antagonistic activity at nAChRs can be improved. Molecular dynamics simulations of the adult muscle nAChR in the presence of BPDs identified key residues likely to be involved in binding. Subsequent two-electrode voltage clamp recordings showed that one of the residues, εY131, acts as an allosteric determinant of BPD binding, and that longer BPDs have a greater stabilizing effect on the orthosteric loop C than shorter ones. The work reported will inform future design work on novel antidotes for treating NA exposure.


Orlistat reverse fatty infiltration and improves hepatic fibrosis in obese patients with nonalcoholic steatohepatitis (NASH).
Nonalcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Treatment, thus far, has been restricted to diet and weight loss, but without compelling results. In this study we aimed to evaluate the efficacy of orlistat therapy in obese patients with NASH. Fourteen obese patients with NASH underwent liver biopsy prior to and subsequent to 6 months treatment with orlistat (120 mg tid). Hepatic fat extension was graded as normal, mild, moderate, or severe. Hepatic fibrosis was scored on a scale from 0 to 4, with 0 denoting no fibrosis and 4, cirrhosis. Portal inflammation was scored as 0-3, with 0 = normal, 1 = mild, 2 = moderate, and 3 = severe inflammation. Fourteen patients had NASH associated with diabetes, hyperlipidemia, or obesity. Orlistat reduced fatty infiltration in 10 patients (70%; P<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. Five patients (35%) returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in three patients (21%) and by 1 grade in seven patients (50%). There was no change in four patients (28%). Orlistat lowered aminotransferases levels, total cholesterol, triglycerides and low-density lipoprotein, respectively. Insulin resistance index and malonyl dialdehyde levels improved significantly after orlistat therapy, whereas HbAic remained unchanged. In conclusion, in obese patients with NASH, liver fibrosis and inflammation improved after therapy with orlistat.


Self-insurance and the potential effects of health reform on the small-group market.
The Patient Protection and Affordable Care Act (PPACA) as amended by the Health Care Education Reconciliation Act of 2010 makes landmark changes to health insurance markets. Individual and small-group insurance plans and markets will see the biggest changes, but PPACA also affects large employer and self-insured plans by imposing rules for benefit design and health plan practices. Over half of workers--most often those in very large firms--are covered by self-insured health plans in which employers (or employee groups) bear all or some of the risk of providing insurance coverage to a defined population of workers and their dependents. As PPACA provisions become effective, some have argued that smaller firms that offer insurance may opt to self-insure their health benefits because of new small-group market rules. Such a shift could affect risk pooling in the small-group market. This paper examines the definition and prevalence of self-insured health plans, the application of PPACA provisions to these plans, and the possible effects on the broader health insurance market, should many more employers decide to self-insure.


Nuclear magnetic resonance structure and IgE epitopes of Blo t 5, a major dust mite allergen.
A high incidence of sensitization to Blomia tropicalis, the predominant house dust mite species in tropical regions, is strongly associated with allergic diseases in Singapore, Malaysia, and Brazil. IgE binding to the group 5 allergen, Blo t 5, is found to be the most prevalent among all B. tropicalis allergens. The NMR structure of Blo t 5 determined represents a novel helical bundle structure consisting of three antiparallel alpha-helices. Based on the structure and sequence alignment with other known group 5 dust mite allergens, surface-exposed charged residues have been identified for site-directed mutagenesis and IgE binding assays. Four charged residues, Glu76, Asp81, Glu86, and Glu91 at around the turn region connecting helices alpha2 and alpha3 have been identified to be involved in the IgE binding. Using overlapping peptides, we have confirmed that these charged residues are located on a major putative linear IgE epitope of Blo t 5 from residues 76-91 comprising the sequence ELKRTDLNILERFNYE. Triple and quadruple mutants have been generated and found to exhibit significantly lower IgE binding and reduced responses in skin prick tests. The mutants induced similar PBMC proliferation as the wild-type protein but with reduced Th2:Th1 cytokines ratio. Mass screening on a quadruple mutant showed a 40% reduction in IgE binding in 35 of 42 sera of atopic individuals. Findings in this study further stressed the importance of surface-charged residues on IgE binding and have implications in the cross-reactivity and use of Blo t 5 mutants as a hypoallergen for immunotherapy.


Understanding the delayed prescribing of antibiotics for respiratory tract infection in primary care: a qualitative analysis.
To identify general practitioner (GP) views and understanding on the use of delayed prescribing in primary care. Qualitative semistructured telephone interview study. Primary care general practices in England. 32 GPs from identified high-prescribing and low-prescribing general practices in England. Semistructured telephone interviews were conducted with GPs identified from practices within clinical commissioning groups with the highest and lowest prescribing rates in England. A thematic analysis of the data was conducted to generate themes. All GPs had a good understanding of respiratory tract infection (RTI) management and how the delayed prescribing approach could be used in primary care. However, GPs highlighted factors that were influential as to whether delayed prescribing was successfully carried out during the consultation. These included the increase in evidence of antimicrobial resistance, and GPs' prior experiences of using delayed prescribing during the consultation. The patient-practitioner relationship could also influence treatment outcomes for RTI, and a lack of an agreed prescribing strategy within and between practices was considered to be of significance to GPs. Participants expressed that a lack of feedback on prescribing data at an individual and practice level made it difficult to know if delayed prescribing strategies were successful in reducing unnecessary consumption. GPs agreed that coherent and uniform training and guidelines would be of some benefit to ensure consistent prescribing throughout the UK. Delayed prescribing is encouraged in primary care, but is not always implemented successfully. Greater uniformity within and between practices in the UK is needed to operationalise delayed prescribing, as well as providing feedback on the uptake of antibiotics. Finally, GPs may need further guidance on how to answer the concerns of patients without interpreting these questions as a demand for antibiotics, as well as educating the patient about antimicrobial resistance and supporting a good patient-practitioner relationship.


The effect of estrogen replacement on early Parkinson's disease.
To determine the effect of estrogen in postmenopausal women with early PD. The role of estrogen in PD is highly disputed, with some studies suggesting a prodopaminergic effect and others suggesting an antidopaminergic effect. Owing to controversy and the small sample sizes of prior studies, further investigation is warranted. A retrospective chart review was carried out from a computerized database of patients at Columbia-Presbyterian, including only women who had symptoms of presumed PD for less than 5 years and who had not yet been on L-dopa at their first visit. Multiple regression was performed to assess the effects of estrogen on disease, measured by total Unified Parkinson's Disease Rating Scale (UPDRS) score, as a function of symptom duration, age at onset, education, smoking, dopamine agonist, and deprenyl use. Of the women who were not on L-dopa and had PD for less than 5 years at their first visit, 34 were found to have received estrogen at some time and 104 had never received estrogen. Excluding the women who had taken dopamine agonists, analysis yielded a multiple regression coefficient of 0.52 (p < 0.001). Estrogen use was negatively correlated with UPDRS score; age at onset and symptom duration were positively correlated (p < 0.05). We found a positive association between estrogen use and lower symptom severity in women with early PD not yet taking L-dopa. These results indicate that estrogen therapy should not be avoided and may be beneficial in early PD, at least prior to the initiation of L-dopa.


Life cycle assessment of a household solid waste source separation programme: a Swedish case study.
The environmental impact of an extended property close source-separation system for solid household waste (i.e., a systems for collection of recyclables from domestic properties) is investigated in a residential area in southern Sweden. Since 2001, households have been able to source-separate waste into six fractions of dry recyclables and food waste sorting. The current system was evaluated using the EASEWASTE life cycle assessment tool. Current status is compared with an ideal scenario in which households display perfect source-separation behaviour and a scenario without any material recycling. Results show that current recycling provides substantial environmental benefits compared to a non-recycling alternative. The environmental benefit varies greatly between recyclable fractions, and the recyclables currently most frequently source-separated by households are often not the most beneficial from an environmental perspective. With optimal source-separation of all recyclables, the current net contribution to global warming could be changed to a net-avoidance while current avoidance of nutrient enrichment, acidification and photochemical ozone formation could be doubled. Sensitivity analyses show that the type of energy substituted by incineration of non-recycled waste, as well as energy used in recycling processes and in the production of materials substituted by waste recycling, is of high relevance for the attained results.


Experience sampling during fMRI reveals default network and executive system contributions to mind wandering.
Although mind wandering occupies a large proportion of our waking life, its neural basis and relation to ongoing behavior remain controversial. We report an fMRI study that used experience sampling to provide an online measure of mind wandering during a concurrent task. Analyses focused on the interval of time immediately preceding experience sampling probes demonstrate activation of default network regions during mind wandering, a finding consistent with theoretical accounts of default network functions. Activation in medial prefrontal default network regions was observed both in association with subjective self-reports of mind wandering and an independent behavioral measure (performance errors on the concurrent task). In addition to default network activation, mind wandering was associated with executive network recruitment, a finding predicted by behavioral theories of off-task thought and its relation to executive resources. Finally, neural recruitment in both default and executive network regions was strongest when subjects were unaware of their own mind wandering, suggesting that mind wandering is most pronounced when it lacks meta-awareness. The observed parallel recruitment of executive and default network regions--two brain systems that so far have been assumed to work in opposition--suggests that mind wandering may evoke a unique mental state that may allow otherwise opposing networks to work in cooperation. The ability of this study to reveal a number of crucial aspects of the neural recruitment associated with mind wandering underscores the value of combining subjective self-reports with online measures of brain function for advancing our understanding of the neurophenomenology of subjective experience.


Proteomic analysis of peach fruit mesocarp softening and chilling injury using difference gel electrophoresis (DIGE).
Peach fruit undergoes a rapid softening process that involves a number of metabolic changes. Storing fruit at low temperatures has been widely used to extend its postharvest life. However, this leads to undesired changes, such as mealiness and browning, which affect the quality of the fruit. In this study, a 2-D DIGE approach was designed to screen for differentially accumulated proteins in peach fruit during normal softening as well as under conditions that led to fruit chilling injury. The analysis allowed us to identify 43 spots -representing about 18% of the total number analyzed- that show statistically significant changes. Thirty-nine of the proteins could be identified by mass spectrometry. Some of the proteins that changed during postharvest had been related to peach fruit ripening and cold stress in the past. However, we identified other proteins that had not been linked to these processes. A graphical display of the relationship between the differentially accumulated proteins was obtained using pairwise average-linkage cluster analysis and principal component analysis. Proteins such as endopolygalacturonase, catalase, NADP-dependent isocitrate dehydrogenase, pectin methylesterase and dehydrins were found to be very important for distinguishing between healthy and chill injured fruit. A categorization of the differentially accumulated proteins was performed using Gene Ontology annotation. The results showed that the 'response to stress', 'cellular homeostasis', 'metabolism of carbohydrates' and 'amino acid metabolism' biological processes were affected the most during the postharvest. Using a comparative proteomic approach with 2-D DIGE allowed us to identify proteins that showed stage-specific changes in their accumulation pattern. Several proteins that are related to response to stress, cellular homeostasis, cellular component organization and carbohydrate metabolism were detected as being differentially accumulated. Finally, a significant proportion of the proteins identified had not been associated with softening, cold storage or chilling injury-altered fruit before; thus, comparative proteomics has proven to be a valuable tool for understanding fruit softening and postharvest.


An external validation of models to predict the onset of chronic kidney disease using population-based electronic health records from Salford, UK.
Chronic kidney disease (CKD) is a major and increasing constituent of disease burdens worldwide. Early identification of patients at increased risk of developing CKD can guide interventions to slow disease progression, initiate timely referral to appropriate kidney care services, and support targeting of care resources. Risk prediction models can extend laboratory-based CKD screening to earlier stages of disease; however, to date, only a few of them have been externally validated or directly compared outside development populations. Our objective was to validate published CKD prediction models applicable in primary care. We synthesised two recent systematic reviews of CKD risk prediction models and externally validated selected models for a 5-year horizon of disease onset. We used linked, anonymised, structured (coded) primary and secondary care data from patients resident in Salford (population ~234 k), UK. All adult patients with at least one record in 2009 were followed-up until the end of 2014, death, or CKD onset (n = 178,399). CKD onset was defined as repeated impaired eGFR measures over a period of at least 3 months, or physician diagnosis of CKD Stage 3-5. For each model, we assessed discrimination, calibration, and decision curve analysis. Seven relevant CKD risk prediction models were identified. Five models also had an associated simplified scoring system. All models discriminated well between patients developing CKD or not, with c-statistics around 0.90. Most of the models were poorly calibrated to our population, substantially over-predicting risk. The two models that did not require recalibration were also the ones that had the best performance in the decision curve analysis. Included CKD prediction models showed good discriminative ability but over-predicted the actual 5-year CKD risk in English primary care patients. QKidney, the only UK-developed model, outperformed the others. Clinical prediction models should be (re)calibrated for their intended uses.


California safety-net hospitals likely to be penalized by ACA value, readmission, and meaningful-use programs.
The Affordable Care Act includes provisions to increase the value obtained from health care spending. A growing concern among health policy experts is that new Medicare policies designed to improve the quality and efficiency of hospital care, such as value-based purchasing (VBP), the Hospital Readmissions Reduction Program (HRRP), and electronic health record (EHR) meaningful-use criteria, will disproportionately affect safety-net hospitals, which are already facing reduced disproportionate-share hospital (DSH) payments under both Medicare and Medicaid. We examined hospitals in California to determine whether safety-net institutions were more likely than others to incur penalties under these programs. To assess quality, we also examined whether mortality outcomes were different at these hospitals. Our study found that compared to non-safety-net hospitals, safety-net institutions had lower thirty-day risk-adjusted mortality rates in the period 2009-11 for acute myocardial infarction, heart failure, and pneumonia and marginally lower adjusted Medicare costs. Nonetheless, safety-net hospitals were more likely than others to be penalized under the VBP program and the HRRP and more likely not to meet EHR meaningful-use criteria. The combined effects of Medicare value-based payment policies on the financial viability of safety-net hospitals need to be considered along with DSH payment cuts as national policy makers further incorporate performance measures into the overall payment system.


Retrieval-based face annotation by weak label regularized local coordinate coding.
Auto face annotation, which aims to detect human faces from a facial image and assign them proper human names, is a fundamental research problem and beneficial to many real-world applications. In this work, we address this problem by investigating a retrieval-based annotation scheme of mining massive web facial images that are freely available over the Internet. In particular, given a facial image, we first retrieve the top $(n)$ similar instances from a large-scale web facial image database using content-based image retrieval techniques, and then use their labels for auto annotation. Such a scheme has two major challenges: 1) how to retrieve the similar facial images that truly match the query, and 2) how to exploit the noisy labels of the top similar facial images, which may be incorrect or incomplete due to the nature of web images. In this paper, we propose an effective Weak Label Regularized Local Coordinate Coding (WLRLCC) technique, which exploits the principle of local coordinate coding by learning sparse features, and employs the idea of graph-based weak label regularization to enhance the weak labels of the similar facial images. An efficient optimization algorithm is proposed to solve the WLRLCC problem. Moreover, an effective sparse reconstruction scheme is developed to perform the face annotation task. We conduct extensive empirical studies on several web facial image databases to evaluate the proposed WLRLCC algorithm from different aspects. The experimental results validate its efficacy. We share the two constructed databases "WDB" (714,454 images of 6,025 people) and "ADB" (126,070 images of 1,200 people) with the public. To further improve the efficiency and scalability, we also propose an offline approximation scheme (AWLRLCC) which generally maintains comparable results but significantly reduces the annotation time.


Identity gaps and level of depression among Korean immigrants.
Identity gaps are a new theoretical construct that provide a framework for integrating communication into the study of identity and understanding the relationship between identity and health outcomes, such as depression. Derived from the communication theory of identity, identity gaps emerge when elements of identity are inconsistent with each other. This article focuses on 2 types of identity gaps, personal-enacted and personal-relational, examining their relationships with situational variables and depression. A questionnaire was administered to a community sample of 377 Korean immigrants to test a hypothesized path model predicting that 3 situational variables (intercultural communication competence, middleperson status, and perception of racial hierarchy) would influence the identity gaps that, in turn, influence Korean immigrants' levels of depression. Results showed that all 3 situational variables predicted Korean immigrants' personal-relational identity gaps, whereas only intercultural communication competence predicted their personal-enacted identity gaps. Both types of identity gaps predicted the level of depression. The personal-relational identity gap significantly mediated the effects of all 3 situational variables on levels of depression. However, the personal-enacted identity gap mediated only the effects of intercultural communication competence on the levels of depression.


Stem-Pitting Citrus tristeza virus Predominantly Transmitted by the Brown Citrus Aphid from Mixed Infections Containing Non-Stem-Pitting and Stem-Pitting Isolates.
Citrus tristeza virus (CTV) is a phloem-limited Closterovirus that produces a variety of symptoms in various Citrus spp. One of these symptoms is stem pitting (SP). SP does not occur in all Citrus spp. but when it does it may cause low tree vigor, decline, and an economic reduction in fruit size and yield. Historically, the first appearance of CTV-SP in a citrus area often occurs after the introduction of the most efficient CTV vector, the brown citrus aphid (BCA), Toxoptera citricida. Hypotheses for this association range from the introduction of these strains in new planting materials to the increased ability of BCA to transmit SP strains from existing CTV sources. It is known that CTV often exists as a complex of isolates or subisolates. Single and multiple BCA transmissions have been used to separate different genotypes or strains of CTV from mixed CTV infected plants. This study was initiated to determine what the BCA transmits when an exotic severe SP CTV isolate B12 from Brazil or B408 from Dominican Republic are mixed with a non-SP (NSP) isolate, FS627 from Florida. Biological and molecular data was generated from grafted mixtures of these isolates and their aphid-transmitted subisolates. Single-strand conformation polymorphism patterns of the 5' terminal region of open reading frame (ORF) 1a, the overlapping region of ORF1b and ORF2, and the major coat protein gene region of NSP and SP CTV-grafted plants remained unchanged but the patterns of doubly inoculated plants varied. The haplotype diversity within SP isolates B12, B408, and mixtures of NSP and SP isolates (FS627/B12 and FS627/B408) and aphid-transmitted subisolates from doubly inoculated plants was determined by analysis of the haplotype nucleotide sequences. Aphid transmission experiments, symptoms, and molecular analyses showed that SP-CTV was more frequently transmitted with or without NSP-CTV from mixed infections.


Effect of corticosteroids on the human monocyte IgG and complement receptors.
A quantitative in vitro assay was employed to directly assess the effect of corticosteroids on the IgG and complement receptor function of human mononuclear phagocytic cells. In this system corticosteroids were solubilized with cholesterol-phospholipid sonicated dispersions before exposure to mononuclear cells. Solubilized corticosteroids at concentrations between 10(-4) and 10(-3) M inhibited both IgG and complement receptor activity in a dose-response fashion. Inhibition was dependent upon the time of interaction of the mononuclear cells with corticosteroids and was half-maximal by 15 min. The inhibitory effect at all concentrations of hydrocortisone was partially overcome by increasing the number of IgG molecules per erythrocyte. Hydrocortisone also inhibited the binding of erythrocytes coated with both IgG and C3, despite the fact that when both were on the erythrocyte surface a synergistic effect on binding to mononuclear cells was observed. At the steroid concentrations employed, the capacity of mononuclear cells to exclude trypan blue and to take up latex particles and neutral red was unaffected. Mineralocorticoids also inhibited receptor activity, but the sex hormones were less effective. These studies demonstrate an effect of steroid hormones on cell membrane receptor function, and they suggest that an inhibition of the recognition system for IgG and C3 in vivo may explain, in part, the effect of corticosteroids in man.


Operationalizing theoretical constructs in bloodborne pathogens training curriculum.
This article describes how the protection motivation theory (PMT) was used to inform the production of video curriculum for a bloodborne pathogens training program for hospital nurses. Although hospital nurses are well acquainted with the work practices designed to prevent bloodborne pathogen exposures (universal precautions), there is evidence that they do not always follow them. First, the original PMT is adapted to reflect what is currently known about the role of affect in health behavior prediction. Second, the authors show how the four PMT message constructs-probability of occurrence, magnitude of noxiousness, response efficacy, and self-efficacy-guided the planning, shooting, and editing of the videotapes. Incidental to this process was the operationalization of these message constructs in such a way that affective reactions would result. The results show that this video curriculum successfully aroused negative affect in the target audience. Only by carefully planning and documenting how message constructs are operationalized in health education materials can one be sure of achieving theory-based (and thus the most replicable) message design.


Regional correlation among ganglion cell complex, nerve fiber layer, and visual field loss in glaucoma.
To analyze the relationship among macular ganglion cell complex (GCC) thickness, peripapillary nerve fiber layer (NFL) thickness, and visual field (VF) defects in patients with glaucoma. A Fourier-domain optical coherence tomography (FD-OCT) system was used to map the macula and peripapillary regions of the retina in 56 eyes of 38 patients with perimetric glaucoma. The macular GCC and peripapillary NFL thicknesses were mapped and standard automated perimetry (SAP) was performed. Loss of GCC and NFL were correlated with the VF map on both a point-by-point and regional basis. Correlation between GCC thickness and peripapillary NFL thickness produced a detailed correspondence map that demonstrates the arcuate course of the NFL in the macula. Corresponding regions within the GCC, NFL, and VF maps demonstrate significant correlation, once parafoveal retinal ganglion cell (RGC) displacement is taken into account. There are significant point-specific and regional correlations between GCC loss, NFL loss, and deficits on SAP. Using these different data sources together may improve our understanding of glaucomatous damage and aid in the management of patients with glaucoma.


Comparative analysis of modeling techniques for coliform organisms in streams.
The use of models for predicting changes in water quality parameters is currently considered an integral part of river basin management. The application of modeling techniques to coliform organisms is in its infancy due to the complexities involved and the lack of definitive information on coliform populations in natural environments. The purpose of this study was to make a comparative analysis of the available models for coliform organisms in order to improve on the state of the art of this subject. The available coliform models may be classified into deterministic or statistical types. In this study, six different models, three of each type, were selected for analysis and were applied to coliform data available on the Leaf River. Results of comparing the models indicated that a deterministic model was best suited for total coliform and a statistical model was best suited for fecal coliform. Ultimate selection of a model for coliform organisms is dependent not only on the accuracy of the model but on ease of implementation. Current technology would probably dictate the use of a deterministic model because of the lack of a complete data base on which to base statistical models.


Relaxed genetic control of cortical organization in human brains compared with chimpanzees.
The study of hominin brain evolution has focused largely on the neocortical expansion and reorganization undergone by humans as inferred from the endocranial fossil record. Comparisons of modern human brains with those of chimpanzees provide an additional line of evidence to define key neural traits that have emerged in human evolution and that underlie our unique behavioral specializations. In an attempt to identify fundamental developmental differences, we have estimated the genetic bases of brain size and cortical organization in chimpanzees and humans by studying phenotypic similarities between individuals with known kinship relationships. We show that, although heritability for brain size and cortical organization is high in chimpanzees, cerebral cortical anatomy is substantially less genetically heritable than brain size in humans, indicating greater plasticity and increased environmental influence on neurodevelopment in our species. This relaxed genetic control on cortical organization is especially marked in association areas and likely is related to underlying microstructural changes in neural circuitry. A major result of increased plasticity is that the development of neural circuits that underlie behavior is shaped by the environmental, social, and cultural context more intensively in humans than in other primate species, thus providing an anatomical basis for behavioral and cognitive evolution.


The regulation of osteoclast function and bone resorption by small GTPases.
Osteoclasts are multinucleated cells that are responsible for resorption of bone, and increased activity of these cells is associated with several common bone diseases, including postmenopausal osteoporosis. Upon adhesion to bone, osteoclasts become polarized and reorganise their cytoskeleton and membrane to form unique domains including the sealing zone (SZ), which is a dense ring of F-actin-rich podosomes delimiting the ruffled border (RB), where protons and proteases are secreted to demineralise and degrade the bone matrix, respectively. These processes are dependent on the activity of small GTPases. Rho GTPases are well known to control the organization of F-actin and adhesion structures of different cell types, affecting subsequently their migration. In osteoclasts, RhoA, Rac, Cdc42, RhoU and also Arf6 regulate podosome assembly and their organization into the SZ. By contrast, the formation of the RB involves vesicular trafficking pathways that are regulated by the Rab family of GTPases, in particular lysosomal Rab7. Finally, osteoclast survival is dependent on the activity of Ras GTPases. The correct function of almost all these GTPases is absolutely dependent on post-translational prenylation, which enables them to localize to specific target membranes. Bisphosphonate drugs, which are widely used in the treatment of bone diseases such as osteoporosis, act by preventing the prenylation of small GTPases, resulting in the loss of the SZ and RB and therefore inhibition of osteoclast activity, as well as inducing osteoclast apoptosis. In this review we summarize current understanding of the role of specific prenylated small GTPases in osteoclast polarization, function and survival.


Trajectories and Determinants of Elder Care in Rural China During an 8-Year Period: Why Having Sons Makes a Difference.
Using 8-year panel data for 1,355 older adults in rural Anhui province, China, this study examined the trajectories and determinants of elder care provided by adult children to their older parents. The results of two-level latent variable growth models showed that trajectories of elder care differed by the gender of children, with an increase in care from sons but a decrease in care from daughters over time. Children's life stages influenced their care provision but differed by gender. Functional impairment of parents and care provided by siblings in the family also affected the care provided by each child. The findings reflect the patrilineal nature of Chinese family systems and demonstrate the linkages between critical life events and caregiving behaviors of adult children. Findings of this study can inform the formulation of elder care policies that meet the needs of families with different structures and at different life stages.


Economic impact of an infection control education program in a specialized preschool setting.
To assess the economic impact, from a societal perspective, of a multidimensional infection control education program (ICEP) in a preschool for children with Down syndrome. Krilov et al implemented a comprehensive ICEP in a specialized preschool setting and reported a significant decrease in medical resource utilization and days absent from school. Clinical and economic data from Krilov et al and other sources were incorporated into a health-state transition (Markov) decision analysis model that estimated annual expected costs for the baseline and intervention years. Procedure and diagnosis codes were assigned to all physician office visits, emergency department visits, hospitalizations, and laboratory and diagnostic tests. Cost estimates then were derived using 1999 national reimbursement schedules and other sources. Productivity losses for parents were estimated using national wage rates. The costs of the ICEP were compared with the reduction in the costs of illness (direct medical costs plus costs associated with lost parental working time). The outcomes measured were mean annual costs of illness per child, total annual ICEP costs, and net annual costs or savings. With a comprehensive ICEP, the mean costs of illness in the baseline year was $1235 per child, of which 68% and 14% were for productivity losses and physician visits, respectively. In the intervention year, the mean costs of illness per child was $615, of which 71% and 20% were for productivity losses and physician visits, respectively. The cost of the preexisting infection control (IC) practices in place at the onset of the study (baseline year) was $716. The comprehensive ICEP cost (intervention year) was $75 627, 92% of which was spent to hire a cleaning service to decontaminate toys 3 times per week. When a secondary analysis was performed to reflect a less intensive ICEP in a nonspecialized preschool setting, the mean costs of illness in the baseline and intervention years were $962 and $614 per child, respectively, representing a total annual cost-of-illness savings of $13 224 for the 38 children who participated in the study by Krilov et al. The annual incremental cost of the less intensive ICEP was $2371; therefore, the estimated net annual savings of the less intensive ICEP in a nonspecialized preschool was $10 853. This study suggests that the reduction in the costs of illness could more than offset the cost of implementing a multidimensional ICEP in a preschool setting.


Structural and functional roles of Daxx SIM phosphorylation in SUMO paralog-selective binding and apoptosis modulation.
Small ubiquitin-like modifier (SUMO) conjugation and interaction are increasingly associated with various cellular processes. However, little is known about the cellular signaling mechanisms that regulate proteins for distinct SUMO paralog conjugation and interactions. Using the transcriptional coregulator Daxx as a model, we show that SUMO paralog-selective binding and conjugation are regulated by phosphorylation of the Daxx SUMO-interacting motif (SIM). NMR structural studies show that Daxx (732)E-I-I-V-L-S-D-S-D(740) is a bona fide SIM that binds to SUMO-1 in a parallel orientation. Daxx-SIM is phosphorylated by CK2 kinase at residues S737 and S739. Phosphorylation promotes Daxx-SIM binding affinity toward SUMO-1 over SUMO-2/3, causing Daxx preference for SUMO-1 conjugation and interaction with SUMO-1-modified factors. Furthermore, Daxx-SIM phosphorylation enhances Daxx to sensitize stress-induced cell apoptosis via antiapoptotic gene repression. Our findings provide structural insights into the Daxx-SIM:SUMO-1 complex, a model of SIM phosphorylation-enhanced SUMO paralog-selective modification and interaction, and phosphorylation-regulated Daxx function in apoptosis.


Home-based pre-exposure prophylaxis (PrEP) services for gay and bisexual men: An opportunity to address barriers to PrEP uptake and persistence.
Gay, bisexual, and other men who have sex with men (GBM) are disproportionately affected by the HIV epidemic. Despite the promise of pre-exposure prophylaxis (PrEP) in reducing HIV transmission risk, barriers for uptake and persistence exist. We sought to identify whether GBM in a nationwide cohort who have not yet initiated PrEP (n = 906) would prefer to get PrEP-related care from a primary care provider (PCP) compared to a specialist clinic or provider. We then sought to identify their level of interest and factors associated with preference for using home-based PrEP services (i.e., HB-PrEP), defined to participants as conducting HIV/STI self-testing from home with PrEP prescription mailing after an initial in-person clinic visit. We examined the associations of demographics, sexual HIV transmission risk, concern about frequent medical checkups associated with PrEP, health care access, and PrEP intentions with preferences for healthcare provider type and HB-PrEP. Concern about frequent medical checkups were associated with preferring a PCP for PrEP-related care, but men who perceived a barrier to bringing up the topic of PrEP with a doctor preferred a specialist clinic or provider more than a PCP. HB-PrEP was more appealing for younger men and those engaged in sexual HIV transmission risk, suggesting HB-PrEP could help reach GBM most vulnerable to HIV and in need of PrEP. HB-PrEP expansion has potential to increase PrEP uptake and persistence among GBM, particularly for men with barriers to clinic-based care and higher intentions to initiate PrEP. Clinical guidelines regarding HB-PrEP are needed to expand its use.


A pepstatin-insensitive aspartic proteinase from a thermophilic Bacillus sp.
Bacillus sp. strain Wp22.A1 produced a cell-associated aspartic proteinase which was purified to homogeneity using phenyl-Sepharose (hydrophobic and affinity chromatography) and Mono Q. The proteinase has a molecular mass of 45 kDa by SDS/PAGE and a pI of 3.8. It is insensitive to pepstatin, but is sensitive to the other aspartic proteinase-specific inhibitors diazoacetyl-DL-norleucine methyl ester (DAN) and 1,2-epoxy-3-(p-nitrophenoxy)propane. Inactivation by DAN was only partial, suggesting that it had non-specifically modified an aspartate residue at a site other than the active site. The enzyme was not inhibited by any of the serine or cysteine proteinase inhibitors tested. Maximum proteolytic activity was observed at pH 3.5. The proteinase had a higher activity with haemoglobin, but was more specific (Vmax./Km) for cytochrome c. Substrate inhibition was observed with both these substrates. The cleavage of oxidized insulin B chain tended to occur at sites where the P1 amino acid was bulky and non-polar, and the P1' amino acid was bulky and polar, such as its primary cleavage site of Val2-Asn3. The proteinase was stable in the pH range 2.5-5.5. Thermostability was increased in the presence of Ca2+, although to a lesser extent at higher temperatures. The thermostabilities at 60, 70, 80 and 90 degrees C were 45 h, 102, 21 and 3 min respectively in the presence of Ca2+.


School-based, randomised controlled trial of an evidence-based condom promotion leaflet.
A condom use promotion leaflet was designed for use with older teenagers in schools. The text targeted a series of cognitive and behavioural antecedents of condom use identified in the literature. Given previous evidence that motivational incentives can enhance the effectiveness of health promotion leaflets, the leaflet was presented in conjunction with a quiz and prize draw. Students were randomly assigned to either the intervention condition or a (no leaflet or incentive) control condition. Measures were taken immediately, pre-intervention and 4 weeks later from 404 students. The 20-min intervention successfully promoted six of the eight measured cognitions, namely (1) attitude towards using condoms with a new partner (2) attitude towards using condoms with a steady partner (3) normative beliefs in relation to preparatory actions (4) self-efficacy in relation to both preparatory actions and (5) condom use (6) intention to use condoms, as well as three measured preparatory actions, that is, purchasing condoms, carrying condoms and discussing condom use. The intervention did not increase condom use with steady or new partners but power to test intervention impact on condom use was curtailed.


Fatal lupus pleuritis presenting in pregnancy. A case report.
Lupus, one of the most common autoimmune diseases in pregnancy, may involve multiple organ systems with varying severity. The diagnosis and treatment of the disease may be complicated by the physiologic changes of pregnancy. A 22-year-old woman presented at 29 weeks' gestation with a 4-week history of dyspnea and mild hypertension. She was found to have large bilateral pleural effusions. Her antinuclear antibody level was 1:640, with a speckled pattern, and her complement levels were low. Her urine had 2+ hemoglobin and 2+ protein with hyaline casts. Over the next three days, respiratory compromise increased despite high-dose steroids. A cesarean delivery was performed for fetal compromise. The infant did well after moderate respiratory distress. The mother developed worsening respiratory distress with adult respiratory distress syndrome, and she could not be weaned from the ventilator. Bilateral chest tubes were placed to control her effusions. Urine output remained poor despite pressors and diuretics. Staphylococcal sepsis occurred on postoperative day 5 and precluded our use of other antiinflammatory agents. Over the next 14 days the mother developed seizures, hypotension and eventual respiratory collapse. Autopsy was notable for lupus nephritis and serositis. The diagnosis and management of systemic lupus in pregnancy may be extremely difficult. Serositis and nephritis may lead to maternal compromise despite early diagnosis and treatment.


Naringenin inhibited migration and invasion of glioblastoma cells through multiple mechanisms.
Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti-inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 μM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 μM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 μM naringenin treatment. Proteins of MMP-2 and MMP-9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM.


Assessment of Patient Knowledge of Longitudinal Melanonychia: A Survey Study of Patients in Outpatient Clinics.
Subungual melanoma (SM) is a rare subtype of cutaneous melanoma but carries a worse prognosis than similarly staged cutaneous melanomas. Assessing patient knowledge of melanonychia is integral to early diagnosis of SM. The aim of this paper is to determine patient knowledge of longitudinal melanonychia (LM) and warning signs for SM, frequency of nail self-examinations, and satisfaction of patients with their physician's nail examinations. We conducted a survey-based study of 363 random patients at Weill Cornell Medicine in New York, USA, performed at 3 different clinics: a general dermatology clinic (n = 167), a nail specialty clinic (n = 44), and a primary care clinic (n = 152). Knowledge of the ABCDEF mnemonic for SM was compared to the ABCD mnemonic for cutaneous melanoma. Analyses were performed for patient behavior regarding suspicious nail changes as well as satisfaction with nail counseling and examination. Only 5% (18/363) of the patients in our study had heard of the ABCDEF mnemonic. In contrast, 9.9% (36/363) of the patients had heard of the ABCD mnemonic for cutaneous melanoma. In total, 37/363 (10.2%) patients reported having LM, 32.4% (12/37) of the patients noted changes in color or width of the band, and 10.8% (4/37) presented with pain or bleeding of the nail, with only 45.9% (17/37) seeking medical attention. Only 11.8% (43/363) of the patients stated that their physician asked them about nail changes, and 1.4% (5/363) of the patients stated that they were counseled about the ABCDEF mnemonic. In comparison, 13.8% (50/363) of the patients were advised on the ABCD mnemonic for the cutaneous melanoma mnemonic. While 70.2% (255/363) of the patients stated that they used sunscreen or wore sun-protective clothing, only 31.4% (114/363) assessed their nails for color changes, with 54.9% (128/233) of the patients categorizing themselves as "very unsatisfied" with the evaluation of their nails by their dermatologist. Our data shows that there is a lack of patient knowledge of LM and warning signs for SM. Further testing is needed to determine whether educating patients about LM, warning signs for SM, and nail self-examinations would improve patient outcomes.


Phosphoinositide 3-kinase gamma: a key modulator in inflammation and allergy.
Chronic inflammation and allergy involve the activation of tissue-resident cells and, later on, the invasion of effector cells. We have previously shown that the loss of phosphoinositide 3-kinase (PI3K) gamma impairs chemokine-dependent migration of neutrophils and macrophages both in vitro and in vivo. On the other hand, PI3K gamma is not required either during phagocytic processes or in the activation of bactericidal activities like granule secretion and particle-mediated respiratory burst in neutrophils. Tissue mast cells are key regulators in allergy and inflammation and release histamine upon clustering of their IgE receptors. We have demonstrated that murine mast cell responses are exacerbated in vitro and in vivo by autocrine signals, and require functional PI3K gamma. Adenosine, acting through the A(3) adenosine receptor, as well as other agonists of G(alpha i)-coupled receptors, transiently increased PtdIns(3,4,5) P (3) exclusively via PI3K gamma. PI3K gamma-derived PtdIns(3,4,5) P (3) was instrumental for initiation of a sustained influx of external Ca(2+) and degranulation. Mice that lacked PI3K gamma did not form oedema when challenged by passive systemic anaphylaxis. PI3K gamma thus relays inflammatory signals through various GPCRs, and is thus central to mast cell function. Taken together, this suggests that pharmaceutical targeting of PI3K gamma might alleviate inflammation at both early and late stages of the allergic response.


Network characteristics of collective chemosensing.
The collective chemosensing of nonexcitable mammalian cells involves a biochemical network that features gap junction communications and heterogeneous single cell activities. To understand the integrated multicellular chemosensing, we study the calcium dynamics of micropatterned fibroblast cell colonies in response to adenosine triphosphate (ATP) stimulation. We find that the cross-correlation function between the responses of individual cells decays with topological distance as a power law for large colonies and much faster for smaller colonies. Furthermore, the strongly correlated cell pairs tend to form clusters and are more likely to exceed the percolation threshold. At a given topological distance, the cross-correlations exhibit characteristics of Poisson distributions, which allows us to estimate the unitary conductance of a single gap junction which is in good agreement with direct experimental measurements.


Abrogation of interleukin-3 dependence of myeloid cells by the v-src oncogene requires SH2 and SH3 domains which specify activation of STATs.
The v-src oncogene encodes a nonreceptor tyrosine kinase. When this gene was expressed in the myeloblastic cell line 32Dcl3, it was found to abrogate interleukin-3 (IL-3) dependence of this cell line and to block its ability to terminally differentiate into granulocytes in response to granulocyte colony-stimulating factor (GCSF). In contrast, a highly related tyrosine kinase gene, v-fgr, fails to render this cell line IL-3 independent for growth or to block its ability to undergo terminal differentiation in the presence of GCSF. The active structural domains of v-src that are responsible for the abrogation of IL-3 dependence of myeloid cells and the mechanisms by which v-src transforms these cells are at present unclear. To identify the domains in v-src which are responsible for this activity, we constructed several chimeric recombinants between the v-src and the related Src family member v-fgr by replacing portions of v-src with corresponding domains of v-fgr. These chimeric DNAs were transfected into 32Dcl3 cells and examined for their abilities to render this cell line IL-3 independent. Our results show that only chimeras containing both the SH3 and the SH2 domains of v-src were capable of rendering the 32Dcl3 cell line IL-3 independent. To understand the possible mechanisms underlying the IL-3-independent growth of v-src-transformed 32Dcl3 cells, we examined the phosphorylation status of JAK-1, JAK-2, and JAK-3 kinases in the v-src- and v-fgr-transformed 32Dcl3 cells. Our results show that none of the JAK kinases are constitutively phosphorylated by v-src or v-fgr. We then examined the phosphorylation status of the STAT (signal transducers and activators of transcription) family of transcription factors. Our results show that STAT1, STAT3, and STAT5 exist in a constitutively phosphorylated state in v-src-transformed 32Dcl3 cells, while such constitutive phosphorylation is not seen in v-fgr-transformed cell lines. Our results also show that STAT3 coimmunoprecipitates with v-Src, suggesting that the activation of STAT3 occurs due to direct association with v-Src. However, STAT1 and STAT5, which also exist in a constitutively phosphorylated state in v-src-transformed 32Dcl3 cells, do not coimmunoprecipitate with v-Src, suggesting that these proteins either interact weakly with v-Src or are phosphorylated by a mechanism distinctive from that of STAT3.


A chemical-structural model for coherent martensite/parent interface in Mn-based antiferromagnetic shape memory alloys.
The martensite/parent coherent interface of Mn-based shape memory alloys (SMAs) is a significant part in the research of their martensitic transformation, reversible shape memory effect and magnetic shape memory effect. In the present work, a chemical-structural model was proposed to calculate the martensite/parent coherent interfacial energy of Mn-X (X = Cu, Fe) alloys. In this model, the coherent heterophase interfacial energy consists of chemical and structural parts. Resulting from the formation process of the heterophase interface, the chemical interfacial energy is expressed as the incremental value of bond energy, while the structural part is obtained by calculating the interfacial strain energy. The results show that the structural interfacial energy plays the chief role in the total interfacial energy, and the total interfacial energy decreases as the temperature rises when the alloy composition is fixed. In addition, the preferred orientation has noteworthy influence on the total interfacial energy. Using the proposed model, interfacial energy, interfacial entropy, interfacial enthalpy and interfacial heat capacity are found to be correlated with temperature and interface preferred orientation. Furthermore, the influences of alloy composition, modulus softening, and the index of the habit plane on the results were discussed.


Adaptation of the Recent Life Changes Questionnaire (RLCQ) to measure stressful life events in adults residing in an urban megapolis in Pakistan.
Contextually relevant stressful life events are integral to the quantification of stress. None such measures have been adapted for the Pakistani population. The RLCQ developed by Richard Rahe measures stress of an individual through recording the experience of life changing events. We used qualitative methodology in order to identify contextually relevant stressors in an open ended format, using serial in-depth interviews until thematic saturation of reported stressful life events was achieved. In our next phase of adaptation, our objective was to scale each item on the questionnaire, so as to weigh each of these identified events, in terms of severity of stress. This scaling exercise was performed on 200 random participants residing in the four communities of Karachi namely Kharadar, Dhorajee, Gulshan and Garden. For analysis of the scaled tool, exploratory factor analysis was used to inform structuring. Finally, to complete the process of adaption, content and face validity exercises were performed. Content validity by subject expert review and face validity was performed by translation and back translation of the adapted RLCQ. This yielded our final adapted tool. Stressful life events emerging from the qualitative phase of the study reflect daily life stressors arising from the unstable socio-political environment. Some such events were public harassment, robbery/theft, missed life opportunities due to nepotism, extortion and threats, being a victim of state sponsored brutality, lack of electricity, water, sanitation, fuel, destruction due to natural disasters and direct or media based exposure to suicide bombing in the city. Personal or societal based relevant stressors included male child preference, having an unmarried middle aged daughter, lack of empowerment and respect reported by females. The finally adapted RLCQ incorporated "Environmental Stress" as a new category. The processes of qualitative methodology, in depth interview, community based scaling and face and content validity yielded an adapted RLCQ that represents contextually relevant life stress for adults residing in urban Pakistan. Clinicaltrials.gov NCT02356263 . Registered January 28, 2015. (Observational Study Only).


Natural cyanide degradation and impact on Ili River drainage areas from a Goldmine in Xinjiang autonomous region, China.
The Ili River is a very important river to the northwest of China and Kazakhstan. The Axi Goldmine is located in the upstream of a branch of the Ili River. The cyanide from the goldmine effluent is a threat to the downstream areas. According to our study, the natural degradation of cyanide conforms to a negative exponential equation in the tailings impoundment, second wastewater pond and even in the receiving streams if the dilution action from other streams were deducted. In the combined action of dilution and natural decomposing, the cyanide from the goldmine effluent does not pose a hazard to the trunk of the Ili River in the normal producing states. The equations of cyanide degradation in the streams and the hydrology parameters could be used to assess the environmental impact on the downstream areas if accidental discharges of cyanide occurred. The available way of decreasing the cyanide impact on the streams is to increase the rate of recycled water so that the lower the wastewater level in the tailing impoundment and the second wastewater pond, the lower is the amount of leakage of wastewater to the streams.


Larix laricina, an Antidiabetic Alternative Treatment from the Cree of Northern Quebec Pharmacopoeia, Decreases Glycemia and Improves Insulin Sensitivity In Vivo.
Larix laricina K. Koch is a medicinal plant belonging to traditional pharmacopoeia of the Cree of Eeyou Istchee (Eastern James Bay area of Canada). In vitro screening studies revealed that, like metformin and rosiglitazone, it increases glucose uptake and adipogenesis, activates AMPK, and uncouples mitochondrial function. The objective of this study was to evaluate the antidiabetic and antiobesity potential of L. laricina in diet-induced obese (DIO) C57BL/6 mice. Mice were subjected for eight or sixteen weeks to a high fat diet (HFD) or HFD to which L. laricina was incorporated at 125 and 250 mg/kg either at onset (prevention study) or in the last 8 of the 16 weeks of administration of the HFD (treatment study). L. laricina effectively decreased glycemia levels, improved insulin resistance, and slightly decreased abdominal fat pad and body weights. This occurred in conjunction with increased energy expenditure as demonstrated by elevated skin temperature in the prevention study and improved mitochondrial function and ATP synthesis in the treatment protocol. L. laricina is thus a promising alternative and complementary therapeutic approach for the treatment and care of obesity and diabetes among the Cree.


Work-related asthma: A case-based guide.
Work-related asthma is common yet underdiagnosed. It is a significant cause of morbidity and socioeconomic loss. Diagnosis is often difficult, and requires a strong index of suspicion and careful investigation. The Canadian Thoracic Society has endorsed the recent American College of Chest Physicians consensus statement on work-related asthma. The present document illustrates the advised approach to diagnosis and management of work-related asthma using case-based examples of occupational asthma and work-exacerbated asthma. The main statements of advice from the American College of Chest Physicians consensus statement are reproduced with permission.


Ten years risk assessment of atherosclerotic cardiovascular disease using Astro-CHARM and pooled cohort equation in a south Asian sub-population.
Atherosclerotic cardiovascular diseases (ASCVD) are on the rise in low and middle-income countries attributed to modern sedentary lifestyle and dietary habits. This has led to the need of assessment of the burden of at-risk population so that prevention measures can be developed. The objective of this study was to assess ten years risk assessment of ASCVD using Astro-CHARM and Pooled Cohort Equation (PCE) in a South Asian sub-population. A total of 386 residents of all six districts of Karachi with no ASCVD were enrolled in the study through an exponential non-discriminative referral snowball sampling technique. The inclusion criteria consisted of age 40 years or above and either gender. Study participants were enrolled after obtaining informed written consent and those study participants who were found to have either congenital heart disease or valvular heart diseases or ischemic heart disease were excluded from the study based on initial screening. For the calculation of 10 years risk of ACVD based on Astro-CHARM and PCE, the variables were obtained including medical history and coronary artery calcium and C-reactive protein measurements. Mean estimated 10-year risk of fatal or non-fatal myocardial infarction or stroke as per the Astro-CHARM was 13.98 ± 8.01%, while mean estimated 10-year risk of fatal or non-fatal myocardial infarction or stroke as per the PCE was 22.26 ± 14.01%. Based on Astro-CHARM, 11.14% of the study participants were labeled as having high risk, while PCE estimated 20.73% of study participants as having high risk of ASCVD. Despite the fact that our findings showed substantial differences in ten-year risk of ASCVD between Astro-CHARM and PCE, both calculators can be used to develop a new population and specific risk estimators for this South Asian sub-population. Our study provides the first step towards developing a risk assessment guided decision-making protocol for primary prevention of ASCVD in this population.


Painful small fiber neuropathies.
This article reviews the clinical features, pathophysiology, and treatment of small fiber sensory neuropathy. Neuropathic pain is prevalent among patients with peripheral neuropathies of diverse etiologies. For example, in one recent study using the sensitive Neuropathic Pain Symptom Inventory as a screening tool, neuropathic pain was reported in 94% of patients with different peripheral nervous system diseases. Neuropathic pain is frequently underrecognized or inadequately treated. Furthermore, the paucity of clinical signs with small fiber neuropathy may delay recognition of an organic process. Pain, or uncomfortable symptoms, typically results from damage to small unmyelinated nerve fibers (C fibers) or thinly myelinated nerve fibers (A delta fibers). Recent research has helped discover the location of the "pain generators" within the injured peripheral nerves. Small fiber neuropathies are relatively common in clinical practice, but until recently most of the available neurodiagnostic tests focused on large caliber nerve fibers. In the past two decades, the widespread use of quantitative sensory testing and punch skin biopsies to evaluate small caliber nerve fibers has substantially changed the neurologist's ability to diagnose and manage small fiber sensory neuropathy. Neuropathic pain from small fiber neuropathy is prevalent and is caused by a wide variety of disorders, many of which are treatable, especially if recognized early in the process.


Hot and not-so-hot females: reproductive state and thermal preferences of female Arizona Bark Scorpions (Centruroides sculpturatus).
For ectotherms, environmental temperatures influence numerous life history characteristics, and the body temperatures (Tb ) selected by individuals can affect offspring fitness and parental survival. Reproductive trade-offs may therefore ensue for gravid females, because temperatures conducive to embryonic development may compromise females' body condition. We tested whether reproduction influenced thermoregulation in female Arizona Bark Scorpions (Centruroides sculpturatus). We predicted that gravid females select higher Tb and thermoregulate more precisely than nonreproductive females. Gravid C. sculpturatus gain body mass throughout gestation, which exposes larger portions of their pleural membrane, possibly increasing their rates of transcuticular water loss in arid environments. Accordingly, we tested whether gravid C. sculpturatus lose water faster than nonreproductive females. We determined the preferred Tb of female scorpions in a thermal gradient and measured water loss rates using flow-through respirometry. Gravid females preferred significantly higher Tb than nonreproductive females, suggesting that gravid C. sculpturatus alter their thermoregulatory behaviour to promote offspring fitness. However, all scorpions thermoregulated with equal precision, perhaps because arid conditions create selective pressure on all females to thermoregulate effectively. Gravid females lost water faster than nonreproductive animals, indicating that greater exposure of the pleural membrane during gestation enhances the desiccation risk of reproductive females. Our findings suggest that gravid C. sculpturatus experience a trade-off, whereby selection of higher Tb and increased mass during gestation increase females' susceptibility to water loss, and thus their mortality risk. Elucidating the mechanisms that influence thermal preferences may reveal how reproductive trade-offs shape the life history of ectotherms in arid environments.


Interactive Effects of Temperature and Leaf Wetness Duration on Sporangia Germination and Infection of Cucurbit Hosts by Pseudoperonospora cubensis.
Outbreaks of cucurbit downy mildew caused by Pseudoperonospora cubensis are dependent on the weather but effects of temperature and leaf wetness duration on infection have not been studied for different cucurbits. To determine the effects of these two weather variables on sporangia germination and infection of cucurbit host types by P. cubensis, three host types; cucumber ('Straight 8'), cantaloupe ('Kermit'), and acorn squash ('Table Queen'), were inoculated and exposed to leaf wetness durations of 2 to 24 h at six constant temperatures ranging from 5 to 30°C in growth-chamber experiments. Sporangia germination was assessed after each wetness period, and leaf area infected was assessed 5 and 7 days after inoculation. Germination of sporangia was highest on cantaloupe (16.5 to 85.7%) and lowest on squash (10.7 to 68.9%), while disease severity was highest and lowest on cucumber and cantaloupe, respectively. Host type, temperature, wetness duration and their interactions significantly (P < 0.0001) affected germination and disease severity. Germination and disease data for each host type were separately fitted to a modified form of a Weibull function that characterizes a unimodal response and monotonic increase of germination or infection with temperature and wetness duration, respectively. The effect of host type on germination and infection was characterized primarily by differences in the upper limit parameter in response to temperature. Differences among host types based on other parameters were either small or inconsistent. Temperature and wetness duration that supported a given level of germination or infection varied among host types. At 20°C, 15% leaf area infected was expected following 2, 4, and 8 h of wetness for cucumber, squash, and cantaloupe, respectively. When temperature was increased to 25°C, 15% disease severity was expected following 3, 7, and 15 h of wetness for cucumber, squash, and cantaloupe, respectively. Risk charts were constructed to estimate the potential risk of infection of cucurbit host types by P. cubensis based on prevailing or forecasted temperature and leaf wetness duration. These results will improve the timing and application of the initial fungicide spray for the control of cucurbit downy mildew.


Iowa's 1st Five Initiative: improving early childhood developmental services through public-private partnerships.
The Iowa Department of Public Health's 1st Five Healthy Mental Development Initiative is bridging public and private health care systems to improve early detection of social-emotional delays and prevention of mental health problems among young children and their families. Key features of the 1st Five model include: user-friendly mental and developmental health screening and referral forms; ongoing education and support for medical office staff on healthy development and use of screening and referral tools; specially trained care coordinators to identify and address a wide range of children's and families' needs; relationships with community resources that provide early intervention; and timely notification of outcomes to the referring physician offices. With an evaluation under way, early 1st Five experience indicates that families identified through the program have a range of unmet needs: each physician referral results in an average of three to five follow-up referrals for services.


The DEAD-box protein Dbp5 controls mRNA export by triggering specific RNA:protein remodeling events.
Messenger RNA (mRNA) export involves the unidirectional passage of ribonucleoprotein particles (RNPs) through nuclear pore complexes (NPCs), presumably driven by the ATP-dependent activity of the DEAD-box protein Dbp5. Here we report that Dbp5 functions as an RNP remodeling protein to displace the RNA-binding protein Nab2 from RNA. Strikingly, the ADP-bound form of Dbp5 and not ATP hydrolysis is required for RNP remodeling. In vivo studies with nab2 and dbp5 mutants show that a Nab2-bound mRNP is a physiological Dbp5 target. We propose that Dbp5 functions as a nucleotide-dependent switch to control mRNA export efficiency and release the mRNP from the NPC.


Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy.
Pathologists participating in the National Institutes of Health-sponsored Biliary Atresia Research Consortium (BARC) developed and then evaluated a standardized system for histologic reporting of liver biopsies from infants with cholestasis. A set of 97 anonymous liver biopsy samples was sent to 10 pathologists at BARC centers. A semiquantitative scoring system that had 16 histologic features was developed and then used by the pathologists, who had no knowledge of clinical history, imaging results, or laboratory data. Interobserver agreement was evaluated statistically. Agreement on scoring of each feature and on the pathologists' diagnosis, compared with the final clinical diagnosis, was evaluated by using weighted kappa statistics. There was moderate to substantial interobserver agreement in identification of bile plugs in ducts, giant-cell transformation, extramedullary hematopoiesis, and bile duct proliferation. The pathologists' diagnosis of obstruction in clinically proven cases of biliary atresia (BA) ranged from 79%-98%, with a positive predictive value of 90.7%. Histologic features that best predicted BA, on the basis of logistic regression, included bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis (each P<.0001). The BARC histologic assessment system identified features of liver biopsies from cholestatic infants, with good interobserver agreement, that might be used in diagnosis and determination of prognosis. The system diagnosed BA with a high level of sensitivity and identified infants with biliary obstruction with reasonable interobserver agreement. However, distinguishing between BA and disorders such as total parenteral nutrition-associated liver disease and alpha(1)-antitrypsin deficiency is not possible without adequate clinical information.


Seaweed and human health.
Seaweeds may have an important role in modulating chronic disease. Rich in unique bioactive compounds not present in terrestrial food sources, including different proteins (lectins, phycobiliproteins, peptides, and amino acids), polyphenols, and polysaccharides, seaweeds are a novel source of compounds with potential to be exploited in human health applications. Purported benefits include antiviral, anticancer, and anticoagulant properties as well as the ability to modulate gut health and risk factors for obesity and diabetes. Though the majority of studies have been performed in cell and animal models, there is evidence of the beneficial effect of seaweed and seaweed components on markers of human health and disease status. This review is the first to critically evaluate these human studies, aiming to draw attention to gaps in current knowledge, which will aid the planning and implementation of future studies.


Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.


Functional analysis of the O antigen glucosylation gene cluster of Shigella flexneri bacteriophage SfX.
Previous studies have shown that Shigella flexneri bacteriophage X (SfX) encodes a glucosyltransferase (GtrX, formerly Gtr), which is involved in O antigen modification (serotype Y to serotype X). However, GtrX alone can only mediate a partial conversion. More recently, a three-gene cluster has been identified next to the attachment site in the genome of two other S. flexneri bacteriophages (i.e. SfV and SfII). This gene cluster was postulated to be responsible for a full O antigen conversion. Here it is reported that besides the gtrX gene, the other two genes in the gtr locus of SfX were also involved in the O antigen modification process. The first gene in the cluster (gtrA) encodes a small highly hydrophobic protein which appears to be involved in the translocation of lipid-linked glucose across the cytoplasmic membrane. The second gene in the cluster (gtrB) encodes an enzyme catalysing the transfer of the glucose residue from UDP-glucose to a lipid carrier. The third gene (gtrX) encodes a bacteriophage-specific glucosyltransferase which is largely responsible for the final step, i.e. attaching the glucosyl molecules onto the correct sugar residue of the O antigen repeating unit. A three-step model for the glucosylation of bacterial O antigen has been proposed.


Potentiation of total horizontal activity and ambulation in rats treated with combinations of beta-phenylethylamine and naloxone.
The effects of beta-phenylethylamine (PEA) (6.25-50 mg kg-1) and of naloxone (1-10 mg kg-1), administered alone and in combination, were studied in the rat. Adult, male rats were individually tested in a novel enclosure over a 30 min period, after administration of drugs. Measures of total horizontal activity, ambulation and rearing activity were counted automatically on the basis of interruptions of photobeams. In addition, observational data were collected, using behavioural categories which have previously been used to characterize the behavioural stereotypy syndrome induced by phenylethylamine in large doses. The results showed that certain combinations of phenylethylamine and naloxone produced striking increases in total horizontal activity and ambulation scores, but not in vertical activity scores. Furthermore, naloxone antagonized hyperreactivity and splayed-hindlimb components of the stereotypy syndrome induced by phenylethylamine, but not the head-weaving component. The behavioural specificity of the potentiation of total horizontal activity and ambulation by phenylethylamine in combination with naloxone is emphasized, and the enhancement of activity is contrasted with previous reports of the effects of naloxone administered in conjunction with d-amphetamine.


Behavioral Induction of a High Beta State in Sensorimotor Cortex Leads to Movement Slowing.
The sensorimotor beta rhythm (∼13-30 Hz) is commonly seen in relation to movement. It is important to understand its functional/behavioral significance in both health and disease. Sorting out competing theories of sensorimotor beta is hampered by a paucity of experimental protocols in humans that manipulate/induce beta oscillations and test their putative effects on concurrent behavior. Here, we developed a novel behavioral paradigm to generate beta and then test its functional relevance. In two human experiments with scalp EEG (n = 11 and 15), we show that a movement instruction generates a high beta state (postmovement beta rebound), which then slows down subsequent movements required during that state. We also show that this high initial beta rebound related to reduced mu-beta desynchronization for the subsequent movement and, further, that the temporal features of the beta state, that is, the beta bursts, related to the degree of slowing. These results suggest that increased sensorimotor beta in the postmovement period corresponds to an inhibitory state-insofar as it retards subsequent movement. By demonstrating a behavioral method by which people can proactively create a high beta state, our paradigm provides opportunities to test the effect of this state on sensations and affordances. It also suggests related experiments using motor imagery rather than actual movement, and this could later be clinically relevant, for example, in tic disorder.


Acupuncture for benign prostatic hyperplasia: A systematic review and meta-analysis.
This systematic review and meta-analysis aims to assess the therapeutic and adverse effects of acupuncture for benign prostatic hyperplasia (BPH) in randomized controlled trials (RCTs). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, the Chinese Biomedical Database, the China National Knowledge Infrastructure, the VIP Database and the Wanfang Database. Parallel-group RCTs of acupuncture for men with symptomatic BPH were included. Data from the included trials were extracted by two independent reviewers and were analyzed with The Cochrane Collaboration Review Manager software (RevMan 5.3.5) after risk of bias judgments. The primary outcome measure of this review was a change in urological symptoms. Eight RCTs, which involved 661 men with BPH, were included. Follow-up varied from 4 weeks to 18 months. Pooling of the data from three trials that compared acupuncture with sham-acupuncture revealed that in the short term (4-6 weeks), acupuncture can significantly improve IPSS (MD -1.90, 95% CI -3.58 to -0.21). A sensitivity analysis of the short-term endpoint showed the same result (MD -3.01, 95% CI -5.19 to -0.84) with a borderline minimal clinical important difference (MCID). Qmax of the short-term endpoint indicated statistically positive beneficial effects of acupuncture (MD -1.78, 95%CI -3.43, -0.14). A meta-analysis after medium-term follow-up (12-18 weeks) indicated no significant effect on IPSS when the data from two trials were combined (MD -2.04, 95% CI -4.19, 0.10). Statistically significant changes were observed in favor of acupuncture in moderate to severe BPH with respect to short-term follow-up endpoints. The clinical significance of these changes needs to be tested by further studies with rigorous designs and longer follow-up times. PROSPERO CRD42014013645.


Protection of mice against the Lyme disease agent by immunizing with recombinant OspA.
Lyme borreliosis is a tick-borne illness caused by Borrelia burgdorferi. The gene for outer surface protein A (OspA) from B. burgdorferi strain N40 was cloned into an expression vector and expressed in Escherichia coli. C3H/HeJ mice actively immunized with live transformed E. coli or purified recombinant OspA protein produced antibodies to OspA and were protected from challenge with several strains of B. burgdorferi. Recombinant OspA is a candidate for a vaccine for Lyme borreliosis.


Innovations in infant milk feeding: from the past to the future.
Innovation is important for life science and economy, but the value of innovation for public health depends on its impact on promoting health. Breastfeeding is not innovative but evolved slowly over 250-300 million years, yet its total benefits are not surpassed by more innovative ways of infant feeding. Until the 19th century, infants fed inadequate breast milk substitutes suffered from high mortality. In 1865 a major improvement was von Liebig's 'soup for infants', the first breast milk substitute based on chemical human milk analysis, soon followed by commercial applications. Other early innovations include whey protein-dominant formula, addition of specific carbohydrates to promote bifidobacteria ('prebiotic') and of live bacteria ('probiotic'), predecessors of apparently recent innovations. Opportunities for innovations exist since many outcomes in formula-fed infants do not match those in breastfed populations. Of concern, expected economic benefits through innovations may override scientific arguments. Business and marketing desires must be counterbalanced by independent pediatric and scientific evaluation. Developing innovations with relevant outcome effects is complex, costly and cannot be expected to occur every few years. Cooperation between academic investigators, small and medium enterprises with high innovative potential, and large industries promotes progress and should be facilitated, e.g. by public research funding.


Transient misfolding dominates multidomain protein folding.
Neighbouring domains of multidomain proteins with homologous tandem repeats have divergent sequences, probably as a result of evolutionary pressure to avoid misfolding and aggregation, particularly at the high cellular protein concentrations. Here we combine microfluidic-mixing single-molecule kinetics, ensemble experiments and molecular simulations to investigate how misfolding between the immunoglobulin-like domains of titin is prevented. Surprisingly, we find that during refolding of tandem repeats, independent of sequence identity, more than half of all molecules transiently form a wide range of misfolded conformations. Simulations suggest that a large fraction of these misfolds resemble an intramolecular amyloid-like state reported in computational studies. However, for naturally occurring neighbours with low sequence identity, these transient misfolds disappear much more rapidly than for identical neighbours. We thus propose that evolutionary sequence divergence between domains is required to suppress the population of long-lived, potentially harmful misfolded states, whereas large populations of transient misfolded states appear to be tolerated.


Tuberculosis in liver transplant patients.
Tuberculosis has been increasing especially in urban areas and in immunosuppressed patients; however, the incidence and factors associated with tuberculosis in OLT patients are unknown. Five of 550 patients who underwent OLT at the Mount Sinai Medical Center during a 5-year period were noted to have tuberculosis. The mean age of the patients was 49.2 years; there were 3 males and 2 females and 3 were foreign born. One of 5 had a prior history of tuberculosis. Tuberculin skin tests performed before transplant revealed 1 positive and 2 anergic reactions. The preoperative chest x-ray revealed apical fibrosis in 2 patients and bilateral apical disease with a nodule in 1 patient. Tuberculosis developed from 2 to 57 months after surgery in 4/5 patients. One had miliary lesions of the peritoneum discovered at the time of OLT. One patient had recent contact with a patient with pulmonary tuberculosis. At presentation, fever was present in 4 of 5 patients, pulmonary lesions in 3 patients, meningitis in 2; during hospitalization, 1 had a liver abscess and disseminated intravascular coagulation and peripheral gangrene. Lymphocytosis was noted in the pleural (1), peritoneal (1), and cerebrospinal fluid (1). Acid-fast smears were positive in bronchoalveolar lavage fluid (1), peritoneal isolates (1), and liver biopsy (1). All patients had positive cultures for Mycobacterium tuberculosis. These isolates were all sensitive to isoniazid, streptomycin, rifampin, ethambutol, and pyrazinamide. Four of 5 patients were treated with isoniazid and rifampin, 2 received pyrazinamide, 2, amikacin, 2, ofloxacin, and 2, ethambutol. Three of 5 patients are doing well on antituberculous therapy and 2 expired with tuberculosis as the cause of death. In OLT patients with unexplained fever, tuberculosis including extrapulmonary and disseminated disease should be considered since the mortality rate is very high. Liver transplantation can be performed in the presence of active peritoneal tuberculosis with the use of judicious antituberculous therapy. The role of preventive therapy is controversial, though use in certain high risk patients is suggested.