Complete Mechanism of Hemithioindigo Motor Rotation.
Hemithioindigo-based molecular motors are powered by nondamaging visible light and provide very fast directional rotations at ambient conditions. Their ground state energy profile has been probed in detail, but the crucial excited state processes are completely unknown so far. In addition, very fast processes in the ground state are also still elusive to date and thus knowledge of the whole operational mechanism remains to a large extent in the dark. In this work we elucidate the complete light-driven rotation mechanism by a combination of multiscale broadband transient absorption measurements covering a time scale from fs to ms in conjunction with a high level theoretical description of the excited state. In addition to a full description of the excited state dynamics in the various time regimes, we also provide the first experimental evidence for the elusive fourth intermediate ground state of the original HTI motor. The fate of this intermediate also is followed directly proving complete unidirectionality for both 180° rotation steps. At the same time, we uncover the hitherto unknown involvement of an unproductive triplet state pathway, which slightly diminishes the quantum yield of the E to Z photoisomerization. A rate model analysis shows that increasing the speed of motor rotation is most effectively done by increasing the photoisomerization quantum yields instead of barrier reduction for the thermal ratcheting steps. Our findings are of crucial importance for improved future designs of any light-driven molecular motor in general to yield better efficiencies and applicability.


Marine picocyanobacterial PhnD1 shows specificity for various phosphorus sources but likely represents a constitutive inorganic phosphate transporter.
Despite being fundamental to multiple biological processes, phosphorus (P) availability in marine environments is often growth-limiting, with generally low surface concentrations. Picocyanobacteria strains encode a putative ABC-type phosphite/phosphate/phosphonate transporter, phnDCE, thought to provide access to an alternative phosphorus pool. This, however, is paradoxical given most picocyanobacterial strains lack known phosphite degradation or carbon-phosphate lyase pathway to utilise alternate phosphorus pools. To understand the function of the PhnDCE transport system and its ecological consequences, we characterised the PhnD1 binding proteins from four distinct marine Synechococcus isolates (CC9311, CC9605, MITS9220, and WH8102). We show the Synechococcus PhnD1 proteins selectively bind phosphorus compounds with a stronger affinity for phosphite than for phosphate or methyl phosphonate. However, based on our comprehensive ligand screening and growth experiments showing Synechococcus strains WH8102 and MITS9220 cannot utilise phosphite or methylphosphonate as a sole phosphorus source, we hypothesise that the picocyanobacterial PhnDCE transporter is a constitutively expressed, medium-affinity phosphate transporter, and the measured affinity of PhnD1 to phosphite or methyl phosphonate is fortuitous. Our MITS9220_PhnD1 structure explains the comparatively lower affinity of picocyanobacterial PhnD1 for phosphate, resulting from a more limited H-bond network. We propose two possible physiological roles for PhnD1. First, it could function in phospholipid recycling, working together with the predicted phospholipase, TesA, and alkaline phosphatase. Second, by having multiple transporters for P (PhnDCE and Pst), picocyanobacteria could balance the need for rapid transport during transient episodes of higher P availability in the environment, with the need for efficient P utilisation in typical phosphate-deplete conditions.


In vivo study of the wear of a reinforced composite used to cover implant-supported frameworks.
The goal of this study was to research the wear shown by a material (Cristobal+) offered as an alternative to ceramics in the covering of an implant-supported fixed prosthesis. Twenty-six active cusps were used in this study; the control group consisted of 12 cusps adjacent to restorations composed of Cristobal+. Five images were obtained from each sample and analyzed using computer software that creates an arch along each cusp, so each image gives the value of the radius described by that arch. If a sample showed any sign of wear, the values for the successive radii would be increasingly larger since a flattened arch would produce a larger radius. An analysis of the paired Student t test was applied. After assessing the results, a statistically significant difference in wear was noted (P < .05). Within the limitations of this study, it can be concluded that the wear of the cusps under function made with Cristobal+ reinforced composite was greater than that of the natural adjacent cusps.


The Effect of Oketani Breast Massage on Successful Breastfeeding, Mothers' Need for Breastfeeding Support, and Breastfeeding Self-Efficacy: an Experimental Study.
The negative effects of cesarean section on breastfeeding are a major global concern. This study aimed to determine the effect of Oketani breast massage on the maternal need for support during breastfeeding, breastfeeding success, and breastfeeding self-efficacy. Three hospitals affiliated to Shahid Beheshti University of Medical Sciences in Tehran, Iran, from April to July 2019. The participants in this experimental study were 113 pregnant women who were candidates for cesarean section. The mothers were selected using convenience sampling and randomly assigned. In addition to routine care, the mothers in the intervention group received Oketani breast massages twice. However, the mothers in the control group received routine care. The data were collected using the Infant Breastfeeding Assessment Tool (IBFAT), LATCH Assessment Score, and the Breastfeeding Self-Efficacy Scale (BSES). The data were analyzed with SPSS 20 software via the independent samples t test, the Mann-Whitney U test, and the chi-square test. The results of the study suggested that the breastfeeding success rate, which was evaluated with IBFAT in both the first two breastfeeding stages and the last pre-discharge breastfeeding, was significantly higher for the mothers in the intervention group (p < .001). In addition, the mother's need for support, which was evaluated with LATCH in the first two breastfeeding stages (p = .044) and the last pre-discharge breastfeeding (p < .001) in the intervention group, was less. The total number of breastfeeding sessions from birth to discharge was higher in the intervention group (p = .002). Furthermore, the mothers in the intervention group breastfed their infants in a significantly shorter time interval (p = .002). Breastfeeding self-efficacy, according to the BSES, was significantly higher in the mothers of the intervention group (p < .001). Oketani massage can be used as a care intervention by nurses to improve breastfeeding in mothers who undergo cesarean sections.


Rhizosphere Microbiomes Modulated by Pre-crops Assisted Plants in Defense Against Plant-Parasitic Nematodes.
Plant-parasitic nematodes cause considerable damage to crop plants. The rhizosphere microbiome can affect invasion and reproductive success of plant-parasitic nematodes, thus affecting plant damage. In this study, we investigated how the transplanted rhizosphere microbiome from different crops affect plant-parasitic nematodes on soybean or tomato, and whether the plant's own microbiome from the rhizosphere protects it better than the microbiome from fallow soil. Soybean plants growing in sterilized substrate were inoculated with the microbiome extracted from the rhizosphere of soybean, maize, or tomato. Controls were inoculated with extracts from bulk soil, or not inoculated. After the microbiome was established, the root lesion nematode Pratylenchus penetrans was added. Root invasion of P. penetrans was significantly reduced on soybean plants inoculated with the microbiome from maize or soybean compared to tomato or bulk soil, or the uninoculated control. In the analogous experiment with tomato plants inoculated with either P. penetrans or the root knot nematode Meloidogyne incognita, the rhizosphere microbiomes of maize and tomato reduced root invasion by P. penetrans and M. incognita compared to microbiomes from soybean or bulk soil. Reproduction of M. incognita on tomato followed the same trend, and it was best suppressed by the tomato rhizosphere microbiome. In split-root experiments with soybean and tomato plants, a systemic effect of the inoculated rhizosphere microbiomes on root invasion of P. penetrans was shown. Furthermore, some transplanted microbiomes slightly enhanced plant growth compared to uninoculated plants. The microbiomes from maize rhizosphere and bulk soil increased the fresh weights of roots and shoots of soybean plants, and microbiomes from soybean rhizosphere and bulk soil increased the fresh weights of roots and shoots of tomato plants. Nematode invasion did not affect plant growth in these short-term experiments. In conclusion, this study highlights the importance of the rhizosphere microbiome in protecting crops against plant-parasitic nematodes. An effect of pre-crops on the rhizosphere microbiome might be harnessed to enhance the resistance of crops towards plant-parasitic nematodes. However, nematode-suppressive effects of a particular microbiome may not necessarily coincide with improvement of plant growth in the absence of plant-parasitic nematodes.


A Systematic Review of Research on Autism Spectrum Disorders in Sub-Saharan Africa.
The burden of autism spectrum disorders (ASDs) in sub-Saharan Africa (SSA) is not well known. We carried out a systematic review of the literature to identify published work from SSA. We have systematically searched four databases, namely, Medline, PsycINFO, CINAHL, and Child Development & Adolescent Studies, through EBSCO and identified studies from across SSA. Based on predefined inclusion criteria, 47 studies were included in this review. Most of the identified studies (74%) were conducted in only 2 African countries, that is, South Africa and Nigeria. Additionally, most of these studies (83%) were carried out in the last decade. These studies had four major themes: development of measurement tools of ASD in Africa, examining the prevalence of ASD, identifying risk factors and risk markers, and examining psychosocial issues. We identified only a single population level study aimed at documenting the prevalence of ASD and could not identify a single case-control study aimed at examining a comprehensive set of potential risk factors. All intervention studies were based on very small sample sizes. Put together, our findings suggest that current evidence base is too scanty to provide the required information to plan adequately for effective intervention strategies for children with ASD in Africa.


Striatal dopamine D2/3 receptor availability in treatment resistant depression.
Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3) receptor (D2/3R) binding has not been investigated in TRD subjects. We used [(123)I]IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p<0.001) but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.


Sensory-Evoked Intrinsic Imaging Signals in the Olfactory Bulb Are Independent of Neurovascular Coupling.
Functional brain-imaging techniques used in humans and animals, such as functional MRI and intrinsic optical signal (IOS) imaging, are thought to largely rely on neurovascular coupling and hemodynamic responses. Here, taking advantage of the well-described micro-architecture of the mouse olfactory bulb, we dissected the nature of odor-evoked IOSs. Using in vivo pharmacology in transgenic mouse lines reporting activity in different cell types, we show that parenchymal IOSs are largely independent of neurotransmitter release and neurovascular coupling. Furthermore, our results suggest that odor-evoked parenchymal IOSs originate from changes in light scattering of olfactory sensory neuron axons, mostly due to water movement following action potential propagation. Our study sheds light on a direct correlate of neuronal activity, which may be used for large-scale functional brain imaging.


First Report of a Leaf Spot on Greenhouse Tomato Caused by Cladosporium oxysporum in China.
Tomato (Lycopersicon esculentum Mill.) is an important vegetable crop grown in Liaoning Province, China. In May 2012, dark brown, angular lesions were observed on lower, older leaves of 5-month-old tomato plants of cv. Bi Jiao in commercial greenhouses in Dawa County, which is administered by Panjin City in Liaoning Province. The irregularly shaped lesions varied in size from 1 to 7 mm in diameter. The necrotic lesions were usually surrounded by a yellow halo. Sporulation was rarely seen on the leaf surfaces. This contrasts with tomato leaf mold caused by Passalora fulva, in which the conidia develop as a velvety brown patch in lesions. By July 2012, the same disease was found in research greenhouses of Shenyang Agriculture University and Liaoning Academy of Agricultural Sciences. The incidence of symptoms was 30 to 40%. To identify the pathogen, leaf pieces (3 to 5 mm) with both infected and healthy portions were taken at the edge of lesions and surface-disinfected by placing them in 75% ethanol for 5 s, then transferred to a 0.1% aqueous mercuric chloride solution for 30 s and rinsed with sterilized water three times. The sections were placed on potato dextrose agar (PDA) at 25°C in the dark. Ten pure fungal cultures were obtained from single spores. For studies of microscopic morphology, isolates were grown on synthetic nutrient agar (SNA) in slide cultures. Conidia ranged in shape from subglobose or ovoid (2 to 4 × 2 to 3 μm) to subcylindrical (4.5 to 17.8 × 2.4 to 4.5 μm). Conidiophores were straight to slightly flexuous with typical nodes. The internal transcribed spacer (ITS) region from isolate PJ12-36 was amplified using primers ITS1 and ITS4 and sequenced (GenBank Accession No. KC137278). The 560-bp amplicons had 99% identity to C. oxysporum (JQ775499). On the basis of morphological characteristics (1) and nucleotide homology, the isolate was identified as C. oxysporum. Koch's postulates were fulfilled in the laboratory on fully expanded leaves of 5-week-old tomato plants 'Moneymaker' inoculated with C. oxysporum conidial suspensions (107 conidia ml-1). Eight seedlings were incubated in an illuminated incubator at 25°C for 8 to 10 days with 85% relative humidity. Characteristic lesions that developed on inoculated leaves were similar in appearance to those observed on diseased tomato plants in the greenhouse. C. oxysporum was reisolated from lesions and its identity was confirmed by morphological characteristics. C. oxysporum was previously reported as the causal agent of a leaf spot disease of pepper (2) and greenhouse tomato (4). To our knowledge, this is the first report of C. oxysporum causing disease on tomato foliage in China. It is noteworthy that C. oxysporum has led to a decline in pepper yield in northern regions of China (3). In addition, pathogenicity tests showed that the isolate W10-02 from pepper and the isolate PJ12-36 from tomato could each cause damage to the opposite host, producing symptoms similar to those observed on the host of origin. Studies are needed on strategies to manage C. oxysporum in crops, because its prevalence may cause yield loss both on tomato and pepper in northern regions of China. References: (1) K. Bensch et al. Stud. Mycol. 67:1, 2010. (2) A. M. Hammouda. Plant Dis. 76:536, 1992. (3) X. Y. Huang et al. Plant Dis. 96:1072, 2012. (4) J. S. Lamboy and H. R. Dillard. Plant Dis. 81:228, 1997.


Association between lipoprotein associated phospholipase A2 mass and subclinical coronary and carotid atherosclerosis in Retired National Football League players.
Retired National Football League (NFL) players were reported to have high prevalence of cardiovascular risk factors. Lipoprotein Associated Phospholipase A2 (LpPLA2) has shown to be associated with cardiovascular disease in the general population, but it is unknown whether such an association exists in retired NFL players. Our objective was to assess whether LpPLA2 mass was associated with coronary artery calcium (CAC) and carotid artery plaque (CAP) in retired NFL players. LpPLA2 mass was assessed using a dual monoclonal antibody immunoassay. CAC presence was defined as CAC score>0. CAP was defined as focal thickening ≥50% than that of the surrounding vessel wall with a minimal thickness of 1.2 mm on carotid ultrasound. In 832 NFL players, the median (IQR) age and LpPLA2 levels were 54 (45-63) years and 142 (109-181) ng/mL respectively. LpPLA2 mass was positively correlated with low-density lipoprotein (LDL) cholesterol and high-density lipoprotein cholesterol; negatively correlated with LDL particle concentration and body mass index; and not correlated with high-sensitivity C-reactive protein. CAC was present in 659 (79%) and CAP in 544 (65%) players. In a fully adjusted model, LpPLA2 was not associated with CAC (OR per 1-SD increase, 0.85; 95% CI 0.71-1.02) or CAP (0.90, 0.75-1.08). LpPLA2 was also not associated with CAC burden in those with CAC>0. Results were similar when highest and lowest LpPLA2 tertiles were compared, and also in various subgroups. LpPLA2 mass was not associated with coronary or carotid subclinical atherosclerosis in retired NFL players.


Post-transcriptional gene regulation by an Hfq-independent small RNA in Caulobacter crescentus.
Bacterial small RNAs (sRNAs) are a heterogeneous group of post-transcriptional regulators that often act at the heart of large networks. Hundreds of sRNAs have been discovered by genome-wide screens and most of these sRNAs exert their functions by base-pairing with target mRNAs. However, studies addressing the molecular roles of sRNAs have been largely confined to gamma-proteobacteria, such as Escherichia coli. Here we identify and characterize a novel sRNA, ChvR, from the alpha-proteobacterium Caulobacter crescentus. Transcription of chvR is controlled by the conserved two-component system ChvI-ChvG and it is expressed in response to DNA damage, low pH, and growth in minimal medium. Transient over-expression of ChvR in combination with genome-wide transcriptome profiling identified the mRNA of the TonB-dependent receptor ChvT as the sole target of ChvR. Genetic and biochemical analyses showed that ChvR represses ChvT at the post-transcriptional level through direct base-pairing. Fine-mapping of the ChvR-chvT interaction revealed the requirement of two distinct base-pairing sites for full target regulation. Finally, we show that ChvR-controlled repression of chvT is independent of the ubiquitous RNA-chaperone Hfq, and therefore distinct from previously reported mechanisms employed by prototypical bacterial sRNAs. These findings have implications for the mechanism and evolution of sRNA function across bacterial species.


Estimating the effect of multiple environmental stressors on coral bleaching and mortality.
Coral cover has been declining in recent decades due to increased temperatures and environmental stressors. However, the extent to which different stressors contribute both individually and in concert to bleaching and mortality is still very uncertain. We develop and use a novel regression approach, using non-linear parametric models that control for unobserved time invariant effects to estimate the effects on coral bleaching and mortality due to temperature, solar radiation, depth, hurricanes and anthropogenic stressors using historical data from a large bleaching event in 2005 across the Caribbean. Two separate models are created, one to predict coral bleaching, and the other to predict near-term mortality. A large ensemble of supporting data is assembled to control for omitted variable bias and improve fit, and a significant improvement in fit is observed from univariate linear regression based on temperature alone. The results suggest that climate stressors (temperature and radiation) far outweighed direct anthropogenic stressors (using distance from shore and nearby human population density as a proxy for such stressors) in driving coral health outcomes during the 2005 event. Indeed, temperature was found to play a role ~4 times greater in both the bleaching and mortality response than population density across their observed ranges. The empirical models tested in this study have large advantages over ordinary-least squares-they offer unbiased estimates for censored data, correct for spatial correlation, and are capable of handling more complex relationships between dependent and independent variables. The models offer a framework for preparing for future warming events and climate change; guiding monitoring and attribution of other bleaching and mortality events regionally and around the globe; and informing adaptive management and conservation efforts.


Release of vasoactive intestinal peptide in the dumping syndrome.
To determine the effect of gastric surgery on the plasma vasoactive intestinal peptide (VIP) concentration, 13 patients with gastrectomy and seven controls were given an oral hypertonic load (200 ml 50% glucose solution). Blood was taken at intervals during the test for measurement of VIP and blood glucose concentrations and packed cell volume. At the same time observations were made on the occurrence of dumping symptoms and a record kept of the pulse rate. VIP values in the patients with gastrectomy were significantly increased by glucose ingestion, while these did not alter in controls (p less than 0.001). There was a highly significant correlation between the rate of rise in plasma VIP concentration and the rates of rise in packed cell volume (r = 0.85; p less than 0.001) and blood glucose concentration (r = 0.76; p less than 0.01) in patients with gastrectomy. Changes in packed cell volume and blood glucose values and the occurrence of dumping symptoms during the test were significantly different when postoperative patients were compared with controls (p less than 0.001, p less than 0.005, and p less than 0.001 respectively). Furthermore, when the patients with gastrectomy were divided into those without symptoms and those with dumping after meals the latter group showed a significantly greater rise of VIP (p less than 0.05). Despite the increased plasma VIP concentrations observed during dumping, VIP cannot be taken as the sole factor in the pathogenesis of the dumping syndrome.


Localization of androgen receptor in the follicle and corpus luteum of the primate ovary during the menstrual cycle.
Ovarian androgens may act locally to modulate follicular and luteal function in various species. This study examined the distribution of androgen receptors within the primate ovary throughout the menstrual cycle. Ovaries were collected from rhesus and cynomolgus monkeys during the early, mid-, and late (n = 3-5 per stage) follicular and luteal phases of the cycle. The tissues were processed for indirect immunocytochemical localization of androgen receptors with a specific monoclonal antibody against human androgen receptor (AN1-15). In addition, ovaries (n = 3) were collected from rhesus monkeys for biochemical detection of androgen receptor using 3H-androgen and AN1-15. Specific immunocytochemical staining, as determined by comparing adjacent tissue sections incubated with either AN1-15 or a nonspecific control antibody, was exclusively nuclear. Androgen receptor was detected in the germinal epithelium and ovarian stroma at all stages of the cycle. The thecal and granulosa cells of growing follicles, and of many but not all atretic follicles, contained androgen receptors. Luteinizing granulosa cells of the periovulatory follicle and luteal cells from the early and midluteal phase stained intensely for androgen receptor. Regressing corpora lutea of the late luteal phase also stained for androgen receptor; however, fully regressed corpora lutea in the early follicular phase of the next cycle did not exhibit receptor staining. Luteal cells that were androgen receptor-positive also stained histochemically for the presence of 3 beta-hydroxysteroid dehydrogenase. Sucrose gradient analysis with radiolabeled androgen demonstrated a shift in the androgen receptor peak in monkey ovarian tissue upon addition of AN1-15, confirming the presence of androgen receptor.(ABSTRACT TRUNCATED AT 250 WORDS)


An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors.
The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples. Clin Cancer Res; 22(10); 2417-26. ©2016 AACR.


Characterization of surface proteins of Cronobacter muytjensii using monoclonal antibodies and MALDI-TOF Mass spectrometry.
Cronobacter spp. is a newly emerging pathogen that causes meningitis in infants and other diseases in elderly and immunocompromised individuals. This study was undertaken to investigate surface antigenic determinants in Cronobacter spp. using monoclonal antibodies (MAbs) and MALDI-TOF Mass spectrometry. Spleenocytes from mice that were immunized with heat-killed (20 min, 80°C) Cronobacter cells were fused with SP2 myeloma cells. Five desirable MAbs (A1, B5, 2C2, C5 and A4) were selected. MAbs A1, B5, 2C2 and C5 were of IgG2a isotype while A4 was an IgM. Specificity of the MAbs was determined by using immunoblotting with outer membrane protein preparations (OMPs) extracted from 12 Cronobacter and 6 non-Cronobacter bacteria. All MAbs recognized proteins with molecular weight ranging between 36 and 49 kDa except for one isolate (44) in which no OMPs were detected. In addition, MAbs recognized two bands (38-41 kDa) in four of the non-Cronobacter bacteria. Most of the proteins recognized by the MAbs were identified by MALDI-TOF peptide sequencing and appeared to be heterogeneous with the identities of some of them are still unknown. All MAbs recognized the same epitope as determined by an additive Index ELISA with their epitopes appeared to be conformational rather than sequential. Further, none of the MAbs recognized purified LPS from Cronobacter spp. Specificity of the MAbs toward OMPs was further confirmed by transmission electron microscopy. Results obtained in this study highlight the immunological cross-reactivity among Cronobacter OMPs and their Enterobacteriaceae counterparts. Nevertheless, the identity of the identified proteins appeared to be different as inferred from the MALDI-TOF sequencing and identification.


Comparing antibiotic self-medication in two socio-economic groups in Guatemala City: a descriptive cross-sectional study.
Self-medication with antibiotics may result in antimicrobial resistance and its high prevalence is of particular concern in Low to Middle Income Countries (LMIC) like Guatemala. A better understanding of self-medication with antibiotics may represent an opportunity to develop interventions guiding the rational use of antibiotics. We aimed to compare the magnitude of antibiotic self-medication and the characteristics of those who self-medicate in two pharmacies serving disparate socio-economic communities in Guatemala City. We conducted a descriptive, cross-sectional study in one Suburban pharmacy and one City Center pharmacy in Guatemala City. We used a questionnaire to gather information about frequency of self-medication, income and education of those who self-medicate. We compared proportions between the two pharmacies, using two-sample z-test as appropriate. Four hundred and eighteen respondents completed the survey (221 in the Suburban pharmacy and 197 in the City Center pharmacy). Most respondents in both pharmacies were female (70%). The reported monthly income in the suburban pharmacy was between $1,250.00-$2,500.00, the city-center pharmacy reported a monthly income between $125.00- $625.00 (p < 0.01). Twenty three percent of Suburban pharmacy respondents and 3% in the City Center pharmacy completed high school (p < 0.01). Proportion of self-medication was 79% in the Suburban pharmacy and 77% in City Center pharmacy. In both settings, amoxicillin was reported as the antibiotic most commonly used. High proportions of self-medication with antibiotics were reported in two pharmacies serving disparate socio-economic groups in Guatemala City. Additionally, self-medicating respondents were most often women and most commonly self-medicated with amoxicillin. Our findings support future public health interventions centered on the regulation of antibiotic sales and on the potential role of the pharmacist in guiding prescription with antibiotics in Guatemala.


Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy.
Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in early 2003 to cause a very severe acute respiratory syndrome, which eventually resulted in a 10% case-fatality rate. Owing to excellent public health measures that isolated focus cases and their contacts, and the use of supportive therapies, the epidemic was suppressed to the point that further cases have not appeared since 2005. However, despite intensive research since then (over 3500 publications), it remains an untreatable disease. The potential for re-emergence of the SARS-CoV or a similar virus with unknown but potentially serious consequences remains high. This is due in part to the extreme genetic variability of RNA viruses such as the coronaviruses, the many animal reservoirs that seem to be able host the SARS-CoV in which reassortment or recombination events could occur and the ability coronaviruses have to transmit relatively rapidly from species to species in a short period of time. Thus, it seems prudent to continue to explore and develop antiviral chemotherapies to treat SARS-CoV infections. To this end, the various efficacious anti-SARS-CoV therapies recently published from 2007 to 2010 are reviewed in this article. In addition, compounds that have been tested in various animal models and were found to reduce virus lung titers and/or were protective against death in lethal models of disease, or otherwise have been shown to ameliorate the effects of viral infection, are also reported.


Pathologists' Perspectives on Disclosing Harmful Pathology Error.
- Medical errors are unfortunately common. The US Institute of Medicine proposed guidelines for mitigating and disclosing errors. Implementing these recommendations in pathology will require a better understanding of how errors occur in pathology, the relationship between pathologists and treating clinicians in reducing error, and pathologists' experiences with and attitudes toward disclosure of medical error. - To understand pathologists' attitudes toward disclosing pathology error to treating clinicians and patients. - We conducted 5 structured focus groups in Washington State and Missouri with 45 pathologists in academic and community practice. Participants were questioned about pathology errors, how clinicians respond to pathology errors, and what roles pathologists should play in error disclosure to patients. - These pathologists believe that neither treating physicians nor patients understand the subtleties and limitations of pathologic diagnoses, which complicates discussions about pathology errors. Pathologists' lack of confidence in communication skills and fear of being misrepresented or misunderstood are major barriers to their participation in disclosure discussions. Pathologists see potential for their future involvement in disclosing error to patients, but at present advocate reliance on treating clinicians to disclose pathology errors to patients. Most group members believed that going forward pathologists should offer to participate more actively in error disclosure to patients. - Pathologists lack confidence in error disclosure communication skills with both treating physicians and patients. Improved communication between pathologists and treating physicians could enhance transparency and promote disclosure of pathology errors. Consensus guidelines for best practices in pathology error disclosure may be useful.


Antibodies to Conserved Surface Polysaccharides Protect Mice Against Bacterial Conjunctivitis.
Bacterial conjunctivitis is a major problem in ocular health. Little is known about protective immune effectors in the conjunctiva. We evaluated whether opsonic antibody to the conserved surface/capsular polysaccharide poly-N-acetyl glucosamine (PNAG) expressed by Streptococcus pneumoniae and Staphylococcus aureus was protective against bacterial conjunctivitis, as well as an antibody to the Pseudomonas aeruginosa surface polysaccharide alginate. Bacteria were injected directly into the conjunctivae of either A/J mice or into conjunctivae of wild type C57Bl/6 mice for comparisons to responses of recombination activating gene 1-knock out (RAG 1 KO) or germ-free mice in the C57Bl/6 genetic background. Human IgG1 monoclonal antibodies (MAb) to either PNAG or alginate were administered as follows: direct injection of 10 μg into the conjunctivae or topical application onto the cornea 4, 24, and 32 hours post infection; or intraperitoneal injection of 200 μg 18 hours prior to and then 4, 24, and 32-hours postinfection. After 48 hours, eyes were scored for pathology, mice were euthanized, and CFU/conjunctiva was determined. All methods of antibody administration reduced S. pneumoniae, S. aureus, or P. aeruginosa pathology and bacterial levels in the conjunctivae. Histopathologic analysis showed severe inflammatory cell infiltrates in conjunctivae of mice treated with control MAb, whereas immune mice showed only very mild cellular infiltration. The protective effect of MAb to PNAG was abolished in RAG 1 KO and germ-free mice. Antibodies to both PNAG and alginate demonstrated therapeutic efficacy in models of S. pneumoniae, S. aureus, and P. aeruginosa conjunctivitis, validating the protective capacity of antibodies to surface polysaccharides in distinct ocular tissues.


Topological transitions in metamaterials.
Light-matter interactions can be controlled by manipulating the photonic environment. We uncovered an optical topological transition in strongly anisotropic metamaterials that results in a dramatic increase in the photon density of states-an effect that can be used to engineer this interaction. We describe a transition in the topology of the iso-frequency surface from a closed ellipsoid to an open hyperboloid by use of artificially nanostructured metamaterials. We show that this topological transition manifests itself in increased rates of spontaneous emission of emitters positioned near the metamaterial. Altering the topology of the iso-frequency surface by using metamaterials provides a fundamentally new route to manipulating light-matter interactions.


Regulatory O-GlcNAcylation sites on FoxO1 are yet to be identified.
O-GlcNAcylation is a reversible post-translational modification that regulates cytosolic and nuclear proteins. We and others previously demonstrated that FoxO1 is O-GlcNAcylated in different cell types, resulting in an increase in its transcriptional activity. Four O-GlcNAcylation sites were identified in human FOXO1 but directed mutagenesis of each site individually had modest (T317) or no effect (S550, T648, S654) on its O-GlcNAcylation status and transcriptional activity. Moreover, the consequences of mutating all four sites had not been investigated. In the present work, we mutated these sites in the mouse Foxo1 and found that mutation of all four sites did not decrease Foxo1 O-GlcNAcylation status and transcriptional activity, and would even tend to increase them. In an attempt to identify other O-GlcNAcylation sites, we immunoprecipitated wild-type O-GlcNAcylated Foxo1 and analysed the tryptic digest peptides by mass spectrometry using High-energy Collisional Dissociation. We identified T646 as a new O-GlcNAcylation site on Foxo1. However, site directed mutagenesis of this site individually or together with all four previously identified residues did not impair Foxo1 O-GlcNAcylation and transcriptional activity. These results suggest that residues important for the control of Foxo1 activity by O-GlcNAcylation still remain to be identified.


A three-layered electrospun matrix to mimic native arterial architecture using polycaprolactone, elastin, and collagen: a preliminary study.
Throughout native artery, collagen, and elastin play an important role, providing a mechanical backbone, preventing vessel rupture, and promoting recovery under pulsatile deformations. The goal of this study was to mimic the structure of native artery by fabricating a multi-layered electrospun conduit composed of poly(caprolactone) (PCL) with the addition of elastin and collagen with blends of 45-45-10, 55-35-10, and 65-25-10 PCL-ELAS-COL to demonstrate mechanical properties indicative of native arterial tissue, while remaining conducive to tissue regeneration. Whole grafts and individual layers were analyzed using uniaxial tensile testing, dynamic compliance, suture retention, and burst strength. Compliance results revealed that changes to the middle/medial layer changed overall graft behavior with whole graft compliance values ranging from 0.8 to 2.8%/100 mm Hg, while uniaxial results demonstrated an average modulus range of 2.0-11.8 MPa. Both modulus and compliance data displayed values within the range of native artery. Mathematical modeling was implemented to show how changes in layer stiffness affect the overall circumferential wall stress, and as a design aid to achieve the best mechanical combination of materials. Overall, the results indicated that a graft can be designed to mimic a tri-layered structure by altering layer properties.


Infectious Japanese encephalitis virus RNA can be synthesized from in vitro-ligated cDNA templates.
Japanese encephalitis virus (JEV) is a positive-stranded enveloped RNA virus that belongs to the family Flaviviridae. Genomic JEV RNA is approximately 11 kb long and encodes 10 proteins, 3 structural and 7 nonstructural. A full-length cDNA copy of the JEV genome was constructed by in vitro ligation of two cDNA fragments which encode the 5' (nucleotide positions 1 to 5576) and 3' (nucleotide positions 5577 to 10976) halves of the genome. T7 RNA polymerase transcripts of the ligated full-length cDNA template were infectious when transfected into BHK-21 cells. To identify the recombinant virus, a silent mutation was introduced into the clone encoding the 3' half of the genome, which abolished an XbaI site at nucleotide position 9131. Virus recovered by transfection with the transcripts contained this silent mutation, confirming its identity. Recombinant and parent viruses were identical with respect to growth and plaque production in BHK-21 cells, envelope protein expression in C6/36 cells, and neurovirulence and immunogenicity in mice. Repeated attempts to obtain infectious RNA by transcription from full-length JEV genome cDNA templates cloned into plasmid vectors were unsuccessful. Synthesis of infectious JEV RNA from in vitro-ligated JEV cDNA templates will be useful for molecular and genetic studies of flavivirus replication and virulence.


Insight across mental disorders: A multifaceted metacognitive phenomenon.
There is now general agreement that lack of insight is not merely a fundamental aspect of delusions and hallucinations, or just a symptom of psychotic disorders but rather a multi-dimensional construct. Several different components of insight have been proposed and empirically examined during the last three decades, such as the ability to recognize that one has a mental illness, the capacity to relabel unusual mental events as pathological, the specific attribution of one's symptoms to having a mental illness, awareness of illness' consequences, and compliance with treatment.1 Insight impairment is an important prognostic factor in schizophrenia, impacting negatively on medication adherence, treatment outcome, and social functioning.2 Although largely investigated in schizophrenia and other psychoses, insight impairments are observed in many, if not all, mental disorders. Varying levels of awareness of mental illness and/or of specific symptoms are expected in patients with bipolar disorders, Alzheimer disease and other neurocognitive disorders, obsessive-compulsive (OCD) and related disorders.1,3 While in DSM-5 an "insight" specifier was incorporated for OCD, body dysmorphic and hoarding disorder, patients' insight has been found ranging from good to absent in other disorders, such as depressive disorders,4 eating disorders,5 and even specific6 and social7 phobias. Moreover, impaired insight is a common reason that many people with clinical depression or anxiety disorders never seek appropriate treatment and most of the people with addictions and personality disorders fail to recognize and address their problems even when the consequences are devastating: personal suffering, broken relationships, and physical health problems. Depending on the disorder and reflecting different conceptual approaches, many different terms are used to describe lack of insight, such as poor self-awareness, denial, anosognosia (mainly in neurological deficits, e.g. hemiplegia), ego-syntonic symptoms, or even self-deception. At any rate, as an aspect of self-knowledge, insight has psychological (defense mechanisms, coping strategies), social and cultural facets. On the other hand, the attitudes and behaviours towards one's illness are products of inference processes and therefore can be influenced by cognitive dysfunctions. Previous research in schizophrenia showed correlations between neurocognitive functions and insight measures but the strength of this association is rather weak.8 Social cognition may be a crucial cognitive determinant of impaired insight in schizophrenia. The correct attitude toward morbid change in oneself relies on the capacity to reflect upon self from the perspective of the other (i.e., "to see ourselves as others see us"). This capacity is clearly linked to the ability to understand mental states (e.g., beliefs, knowledge, and intentions) of others, that is, theory of mind or mentalizing. Recent research has shown that mentalizing deficits may substantially contribute to insight impairment in schizophrenia.9 This effect could be further examined in the broader context of patient's failures in metacognition, i.e. the general ability to think about thinking, and their relationships with insight impairment in schizophrenia. Mentalizing and introspection are closely related developmentally and it is yet unclear which one is the primary ability: we are able to understand others and then apply this understanding to ourselves or we are able to reflect on ourselves and then apply this reflection to others. A recent line of research in schizophrenia is based on the distinction introduced by Beck et al10 between clinical insight (i.e., awareness of illness) and cognitive insight, which describes a metacognitive ability, specifically patients' flexibility towards their beliefs, judgements and experiences. The self-report Beck Cognitive Insight Scale (BCIS) examines two subcomponents: self-certainty, assessing overconfidence about being right (e.g. "I know better than anyone else what mycomponents: self-certainty, assessing overconfidence about being right (e.g. "I know better than anyone else what my problems are"), and self-reflectiveness, assessing willingness to accept external feedback and recognition of dysfunctionalreasoning style (e.g. "Some of the ideas I was certain were true turned out to be false"). Cognitive insight in thisform describes two related but distinct aspects of metacognition in patients with psychosis, differentially associated withclinical insight, symptoms, treatment outcomes, and functioning.11 Another method for assessment of similar metacognitiveskills also used in schizophrenia is a scale (Metacognition Assessment Scale - Abbreviated, MAS-A) that is administeredthrough a specific interview and examines the capacities of self-reflectivity, understanding of the other individuals'mental states, and using metacognitive knowledge to respond to psychosocial challenges. Lysaker and colleaguesfound recently that metacognitive deficits assessed with MAS-A predict impaired insight in schizophrenia independentof symptoms.12 It is questionable whether BCIS and other methods used so far to assess self-reflection in psychoses arevalid and useful for patients with non-psychotic disorders.11 However, the metacognitive conceptualization of insightmight contribute to a new research framework for insight impairments across mental disorders. According to this approach, poor insight is in part a failure of self-reflection, i.e. the process by which we synthesizeand comprehend ideas about ourselves. This may be due to general deficits in metacognitive abilities (self-reflectivity,mentalizing) or may represent limited, domain-specific, or transient dysfunctions in metacognitive processes. Insight hasto be thought of as a relational concept, that is insight into something: insight into illness, current syndrome, specificsymptoms, pathological personality traits, social difficulties etc.1,3 In an integrated model of insight across mental disorders,aspects of metacognition interacting with multiple other (clinical, neurocognitive, emotional, and social) factorsdetermine patient's ability to correctly process information into self-awareness. The identification of these factors andtheir interactions may be a fruitful field in the research of insight.


Duplication and Loss of Function of Genes Encoding RNA Polymerase III Subunit C4 Causes Hybrid Incompatibility in Rice.
Reproductive barriers are commonly observed in both animals and plants, in which they maintain species integrity and contribute to speciation. This report shows that a combination of loss-of-function alleles at two duplicated loci, DUPLICATED GAMETOPHYTIC STERILITY 1 (DGS1) on chromosome 4 and DGS2 on chromosome 7, causes pollen sterility in hybrid progeny derived from an interspecific cross between cultivated rice, Oryza sativa, and an Asian annual wild rice, O. nivara Male gametes carrying the DGS1 allele from O. nivara (DGS1-nivaras ) and the DGS2 allele from O. sativa (DGS2-T65s ) were sterile, but female gametes carrying the same genotype were fertile. We isolated the causal gene, which encodes a protein homologous to DNA-dependent RNA polymerase (RNAP) III subunit C4 (RPC4). RPC4 facilitates the transcription of 5S rRNAs and tRNAs. The loss-of-function alleles at DGS1-nivaras and DGS2-T65s were caused by weak or nonexpression of RPC4 and an absence of RPC4, respectively. Phylogenetic analysis demonstrated that gene duplication of RPC4 at DGS1 and DGS2 was a recent event that occurred after divergence of the ancestral population of Oryza from other Poaceae or during diversification of AA-genome species.


Microbial diversity of extreme habitats in human homes.
High-throughput sequencing techniques have opened up the world of microbial diversity to scientists, and a flurry of studies in the most remote and extreme habitats on earth have begun to elucidate the key roles of microbes in ecosystems with extreme conditions. These same environmental extremes can also be found closer to humans, even in our homes. Here, we used high-throughput sequencing techniques to assess bacterial and archaeal diversity in the extreme environments inside human homes (e.g., dishwashers, hot water heaters, washing machine bleach reservoirs, etc.). We focused on habitats in the home with extreme temperature, pH, and chemical environmental conditions. We found a lower diversity of microbes in these extreme home environments compared to less extreme habitats in the home. However, we were nonetheless able to detect sequences from a relatively diverse array of bacteria and archaea. Habitats with extreme temperatures alone appeared to be able to support a greater diversity of microbes than habitats with extreme pH or extreme chemical environments alone. Microbial diversity was lowest when habitats had both extreme temperature and one of these other extremes. In habitats with both extreme temperatures and extreme pH, taxa with known associations with extreme conditions dominated. Our findings highlight the importance of examining interactive effects of multiple environmental extremes on microbial communities. Inasmuch as taxa from extreme environments can be both beneficial and harmful to humans, our findings also suggest future work to understand both the threats and opportunities posed by the life in these habitats.


Calcitonin gene-related peptide (CGRP): a new target for migraine.
Migraine is a neurological disorder that manifests as a debilitating headache associated with altered sensory perception. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. Clinical trials carried out during the past decade have proved that CGRP receptor antagonists are effective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation. Despite this progress in the clinical arena, the mechanisms by which CGRP triggers migraine remain uncertain. This review discusses mechanisms whereby CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Future studies on epistatic and epigenetic regulators of CGRP actions are expected to shed further light on CGRP actions in migraine. In conclusion, targeting CGRP represents an approachable therapeutic strategy for migraine.


Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.
Junctophilin-2 (JPH2) is a cardiac specific member of the junctophilins, a newly characterized family of junctional membrane complex proteins important in physically approximating the plasmalemmal L-type calcium channel and the sarcoplasmic reticulum ryanodine receptor for calcium-induced calcium release. JPH2 knockout mice showed disrupted calcium transients, altered junctional membrane complex formation, cardiomyopathy, and embryonic lethality. Furthermore, JPH2 gene expression is down-regulated in murine cardiomyopathy models. To this end, we explored JPH2 as a novel candidate gene for the pathogenesis of hypertrophic cardiomyopathy (HCM) in humans. Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of JPH2 was performed on DNA obtained from 388 unrelated patients with HCM. HCM-associated JPH2 mutations were engineered and functionally characterized using immunocytochemistry, cell morphometry measurements, and live cell confocal calcium imaging. Three novel HCM-susceptibility mutations: S101R, Y141H and S165F, which localize to key functional domains, were discovered in 3/388 unrelated patients with HCM and were absent in 1000 ethnic-matched reference alleles. Functionally, each human mutation caused (i) protein reorganization of junctophilin-2, (ii) perturbations in intracellular calcium signaling, and (iii) marked cardiomyocyte hyperplasia. The molecular and functional evidence implicates defective junctophilin-2 and disrupted calcium signaling as a novel pathogenic mechanism for HCM and establishes HCM as the first human disease associated with genetic defects in JPH2. Whether susceptibility for other cardiomyopathies, such as dilated cardiomyopathy, can be conferred by mutations in JPH2 warrants investigation.


Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetes.
Insulin-dependent diabetes can occur with immune checkpoint inhibitor (ICI) therapy. We aimed to characterize the frequency, natural history and potential predictors of ICI-induced diabetes. We reviewed 1444 patients treated with ICIs over 6 years at our cancer center, and from the 1163 patients who received programmed cell death protein 1 (PD-1) inhibitors, we identified 21 such cases, 12 of which developed new-onset insulin-dependent diabetes and 9 experienced worsening of pre-existing type 2 diabetes. ICI-induced diabetes occurred most frequently with pembrolizumab (2.2%) compared with nivolumab (1%) and ipilimumab (0%). The median age was 61 years, and body mass index was 31 kg/m2, which are both higher than expected for spontaneous type 1 diabetes. Other immune-related adverse events occurred in 62%, the most common being immune mediated thyroid disease. New-onset insulin-dependent diabetes developed after a median of four cycles or 5 months; 67% presented with diabetic ketoacidosis and 83% with low or undetectable C-peptide. Autoantibodies were elevated in 5/7 (71%) at the time of new-onset diabetes. Diabetes did not resolve during a median follow-up of 1 year. PD-1 inhibitors can lead to insulin deficiency presenting as new-onset diabetes or worsening of pre-existing type 2 diabetes, with a frequency of 1.8 %. The underlying mechanism appears similar to spontaneous type 1 diabetes but there is a faster progression to severe insulin deficiency. Better characterization of ICI-induced diabetes will improve patient care and enhance our understanding of immune-mediated diabetes.


Synthesis of BiVO4@C Core-Shell Structure on Reduced Graphene Oxide with Enhanced Visible-Light Photocatalytic Activity.
Herein, a facile strategy for the controllable synthesis of BiVO4@C core-shell nanoparticles on reduced graphene oxide (RGO) is reported. The BiVO4 particle size can be controlled in the process by adjusting the volume ratio of glycerol in the sol-gel solution. The glycerol layers adsorbed on BiVO4 (BiVO4@glycerol) made it possible to form hydrogen bonds between BiVO4@glycerol and graphene oxide with the assistance of ultrasound. After thermal treatment, glycerol adsorbed on the BiVO4 particles formed amorphous carbon shells to link the particles and RGO. As a result, the obtained RGO-BiVO4@C nanocomposite showed a five times higher rate in O2 evolution from water under visible-light irradiation. Also, it demonstrated a six times higher photocatalytic performance enhancement than that of pure BiVO4 in the degradation of Rhodamine B. The enhanced performance is attributed to the carbon shells that restrict the growth of BiVO4 , the reduced graphene oxide that improves the electronic conductivity of the composite, and importantly, the bonds formed between the carbon shells and RGO that reduce the recombination loss of photogenerated charges effectively. The strategy is simple, effective, and can be extended to other ternary oxides with controlled size and high performance.


Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study.
Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01183780.ld We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4-14·5) for patients in the ramucirumab group versus 11·7 months (10·8-12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730-0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%]). Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable. Eli Lilly.


Characterization and quantification of the fungal microbiome in serial samples from individuals with cystic fibrosis.
Human-associated microbial communities include fungi, but we understand little about which fungal species are present, their relative and absolute abundances, and how antimicrobial therapy impacts fungal communities. The disease cystic fibrosis (CF) often involves chronic airway colonization by bacteria and fungi, and these infections cause irreversible lung damage. Fungi are detected more frequently in CF sputum samples upon initiation of antimicrobial therapy, and several studies have implicated the detection of fungi in sputum with worse outcomes. Thus, a more complete understanding of fungi in CF is required. We characterized the fungi and bacteria in expectorated sputa from six CF subjects. Samples were collected upon admission for systemic antibacterial therapy and upon the completion of treatment and analyzed using a pyrosequencing-based analysis of fungal internal transcribed spacer 1 (ITS1) and bacterial 16S rDNA sequences. A mixture of Candida species and Malassezia dominated the mycobiome in all samples (74%-99% of fungal reads). There was not a striking trend correlating fungal and bacterial richness, and richness showed a decline after antibiotic therapy particularly for the bacteria. The fungal communities within a sputum sample resembled other samples from that subject despite the aggressive antibacterial therapy. Quantitative PCR analysis of fungal 18S rDNA sequences to assess fungal burden showed variation in fungal density in sputum before and after antibacterial therapy but no consistent directional trend. Analysis of Candida ITS1 sequences amplified from sputum or pure culture-derived genomic DNA from individual Candida species found little (<0.5%) or no variation in ITS1 sequences within or between strains, thereby validating this locus for the purpose of Candida species identification. We also report the enhancement of the publically available Visualization and Analysis of Microbial Population Structures (VAMPS) tool for the analysis of fungal communities in clinical samples. Fungi are present in CF respiratory sputum. In CF, the use of intravenous antibiotic therapy often does not profoundly impact bacterial community structure, and we observed a similar stability in fungal species composition. Further studies are required to predict the effects of antibacterials on fungal burden in CF and fungal community stability in non-CF populations.


A genome-scale metabolic model of Arabidopsis and some of its properties.
We describe the construction and analysis of a genome-scale metabolic model of Arabidopsis (Arabidopsis thaliana) primarily derived from the annotations in the Aracyc database. We used techniques based on linear programming to demonstrate the following: (1) that the model is capable of producing biomass components (amino acids, nucleotides, lipid, starch, and cellulose) in the proportions observed experimentally in a heterotrophic suspension culture; (2) that approximately only 15% of the available reactions are needed for this purpose and that the size of this network is comparable to estimates of minimal network size for other organisms; (3) that reactions may be grouped according to the changes in flux resulting from a hypothetical stimulus (in this case demand for ATP) and that this allows the identification of potential metabolic modules; and (4) that total ATP demand for growth and maintenance can be inferred and that this is consistent with previous estimates in prokaryotes and yeast.


The multifaceted nature of catechol chemistry: bioinspired pH-initiated hyaluronic acid hydrogels with tunable cohesive and adhesive properties.
The field of hydrogels has rapidly expanded in recent years. A growing theme is the development of hydrogels that are bioinspired, with tailorable physicochemical properties. Marine mussels utilize their byssus to adhere themselves to rocks and thereby decrease the turbulent buffeting of the intertidal zone. An increase in pH is a noticeable phenomenon during the mussel byssus secretion and formation processes. In this study, by mimicking the acidic-to-basic pH switch that occurs during byssus formation, a series of bioinspired, pH-initiated hyaluronic acid (HA) hydrogels that possess tunable cohesive and adhesive properties were developed. Specifically, four different kinds of hyaluronic acid (HA) hydrogel crosslinking networks were fabricated by utilizing the multifaceted nature of catechol chemistry, including metal-catechol coordination, quinone-catechol dismutation, quinone-amine Michael addition and Schiff base reactions, or quinone-thiol Michael addition reactions. Our research demonstrated that pH, as one of the most important environmental variables for mussels, plays a vital role in regulating the cohesion and adhesion behaviors. And regarding the development of new materials, this biomimetic strategy also demonstrates alternative and tunable crosslinking approaches that can overcome the limitations of current HA hydrogels.


Increased connexin 43 expression as a potential mediator of the neuroprotective activity of the corticotropin-releasing hormone.
CRH is a major central stress mediator, but also a potent neuroprotective effector. The mechanisms by which CRH mediates its neuroprotective actions are largely unknown. Here, we describe that the gap junction molecule connexin43 (Cx43) mediates neuroprotective effects of CRH toward experimentally induced oxidative stress. An enhanced gap junction communication has been reported to contribute to neuroprotection after neurotoxic insults. We show that CRH treatment up-regulates Cx43 expression and gap junctional communication in a CRH receptor-dependent manner in IMR32 neuroblastoma cells, primary astrocytes, and organotypic hippocampal slice cultures. MAPKs and protein kinase A-cAMP response element binding protein -coupled pathways are involved in the signaling cascade from CRH to enhanced Cx43 function. Inhibition of CRH-promoted gap junction communication by the gap junction inhibitor carbenoxolone could prevent neuroprotective actions of CRH in cell and tissue culture models suggesting that gap junction molecules are involved in the neuroprotective effects of CRH. The extent of oxidative stress-induced protein carbonylation and cell death inversely correlated with Cx43 protein levels as shown by Cx43 small interfering RNA knockdown experiments. Coculture studies of primary neurons and astrocytes revealed that astrocytic Cx43 likely contributes to the neuroprotective effects of CRH. To our knowledge this is the first description of Cx43 as a potential mediator of the neuroprotective actions of CRH.


Heritability, selection, and the response to selection in the presence of phenotypic measurement error: Effects, cures, and the role of repeated measurements.
Quantitative genetic analyses require extensive measurements of phenotypic traits, a task that is often not trivial, especially in wild populations. On top of instrumental measurement error, some traits may undergo transient (i.e., nonpersistent) fluctuations that are biologically irrelevant for selection processes. These two sources of variability, which we denote here as measurement error in a broad sense, are possible causes for bias in the estimation of quantitative genetic parameters. We illustrate how in a continuous trait transient effects with a classical measurement error structure may bias estimates of heritability, selection gradients, and the predicted response to selection. We propose strategies to obtain unbiased estimates with the help of repeated measurements taken at an appropriate temporal scale. However, the fact that in quantitative genetic analyses repeated measurements are also used to isolate permanent environmental instead of transient effects requires that the information content of repeated measurements is carefully assessed. To this end, we propose to distinguish "short-term" from "long-term" repeats, where the former capture transient variability and the latter help isolate permanent effects. We show how the inclusion of the corresponding variance components in quantitative genetic models yields unbiased estimates of all quantities of interest, and we illustrate the application of the method to data from a Swiss snow vole population.


Plasma Monocyte Chemoattractant Protein-1 Level as a Predictor of the Severity of Community-Acquired Pneumonia.
Monocyte chemoattractant protein (MCP)-1 increases in the serum of immunocompetent patients with community-acquired pneumonia (CAP). However, the correlation between the circulating level of MCP-1 and severity of CAP remains unclear. This study investigated differential changes in the plasma MCP-1 levels of patients with CAP before and after an antibiotic treatment and further analyzes the association between the CAP severity and MCP-1 levels. We measured the plasma MCP-1 levels of 137 patients with CAP and 74 healthy controls by using a commercial enzyme-linked immunosorbent assay. Upon initial hospitalization, Acute Physiology and Chronic Health Evaluation II (APACHE II); confusion, urea level, respiratory rate, blood pressure, and age of >64 years (CURB-65); and pneumonia severity index (PSI) scores were determined for assessing the CAP severity in these patients. The antibiotic treatment reduced the number of white blood cells (WBCs) and neutrophils as well as the level of C-reactive protein (CRP) and MCP-1. The plasma MCP-1 level, but not the CRP level or WBC count, correlated with the CAP severity according to the PSI (r = 0.509, p < 0.001), CURB-65 (r = 0.468, p < 0.001), and APACHE II (r = 0.360, p < 0.001) scores. We concluded that MCP-1 levels act in the development of CAP and are involved in the severity of CAP.


The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette-Guérin immunization.
Bacille Calmette-Guérin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n = 53) and cellular (n = 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml(-1) [3300-11 050] in cord blood) and six weeks (0.00 ng ml(-1) [0-288]). Frequencies of PPD-specific IFN-γ-expressing CD4(+)T cells increased at one week and declined between one and six weeks (p = 0.031). Frequencies of IL-2- and TNF-α-expressing PPD-specific CD4(+)T cells increased between one and six weeks (p = 0.019, p = 0.009, respectively). At one week, the frequency of PPD-specific CD4(+)T cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses (p = 0.002) and after adjusting for confounders (mean difference, 95% CI -0.041% (-0.082, -0.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCG immunization. These findings are being explored further in a larger study.


Hydroxy decenoic acid down regulates gtfB and gtfC expression and prevents Streptococcus mutans adherence to the cell surfaces.
10-Hydroxy-2-decenoic acid, an unsaturated fatty acid is the most active and unique component to the royal jelly that has antimicrobial properties. Streptococcus mutans is associated with pathogenesis of oral cavity, gingivoperiodontal diseases and bacteremia following dental manipulations. In the oral cavity, S. mutans colonize the soft tissues including tongue, palate, and buccal mucosa. When considering the role of supragingival dental plaque in caries, the proportion of acid producing bacteria (particularly S. mutans), has direct relevance to the pathogenicity of the plaque. The genes that encode glucosyltransferases (gtfs) especially gtfB and gtfC are important in S. mutans colonization and pathogenesis. This study investigated the hydroxy-decenoic acid (HDA) effects on gtfB and gtfC expression and S. mutans adherence to cells surfaces. Streptococcus mutans was treated by different concentrations of HPLC purified HDA supplied by Iran Beekeeping and Veterinary Association. Real time RT-PCR and western blot assays were conducted to evaluate gtfB and gtfC genes transcription and translation before and after HDA treatment. The bacterial attachment to the cell surfaces was evaluated microscopically. 500 μg ml-1 of HDA inhibited gtfB and gtfC mRNA transcription and its expression. The same concentration of HDA decreased 60% the adherence of S. mutans to the surface of P19 cells. Hydroxy-decenoic acid prevents gtfB and gtfC expression efficiently in the bactericide sub-concentrations and it could effectively reduce S. mutans adherence to the cell surfaces. In the future, therapeutic approaches to affecting S. mutans could be selective and it's not necessary to put down the oral flora completely.


Corneal thickness as a predictor of corneal transplant outcome.
To assess corneal thickness (CT) and correlation with graft outcome after penetrating keratoplasty in the Cornea Donor Study. A total of 887 subjects with a corneal transplant for a moderate-risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) had postoperative CT measurements throughout a 5-year follow-up time. Relationships between baseline (recipient, donor, and operative) factors and CT were explored. Proportional hazards models were used to assess the association between CT and graft failure. Relationship between CT and cell density was assessed with a longitudinal repeated measures model and Spearman correlation estimates. Higher longitudinal CT measurements were associated with the following: diagnosis of pseudophakic or aphakic corneal edema (P < 0.001), intraocular pressure >25 mm Hg during the first postoperative month (P = 0.003), white (non-Hispanic) donor race (P = 0.002), and respiratory causes of donor death (P < 0.001). Among those without graft failure within the first postoperative year, the 5-year cumulative incidence (± 95% confidence interval) of graft failure was 5% ± 5% in those with a 1-year CT ≤ 500 μm, 5% ± 3% for CT 501 to 550 μm, 7% ± 4% for CT 551 to 600 μm, and 20% ± 11% for CT >600 μm. In a multivariate analysis, both 1-year CT and cell density were associated with subsequent graft failure (P = 0.002 and 0.009). CT increase was modestly associated with endothelial cell loss during follow-up (r = -0.29). During the first 5 years after penetrating keratoplasty, CT can serve as a predictor of graft survival. However, CT is not a substitute for cell density measurement because both measures were independently predictive of graft failure.


Addressing social responsibility in medical education: the African way.
Indigenous sub-Saharan societies have, over the millennia, lived and socialised within the unwritten 'rules' of the 'Ubuntu' or similar philosophies that emphasises holistic 'humanness', and which is a form of 'social responsibility'. This article looks into some relevant social responsibility aspects of medical education in the South African context, with particular emphasis on how these aspects have been addressed. Apartheid was, by its very nature, incompatible with social responsibility for the majority of South Africans, but one medical school that was a non-complicit product of apartheid succeeded in fulfilling a socially responsible mission. Thus, this article implicitly identifies what South Africa, Africa and the global Health Professions Education community could learn from these trail-blazing experiences.


DNA fingerprinting by ERIC-PCR for comparing Listeria spp. strains isolated from different sources in San Luis, Argentina.
In this study, a total of 24 Listeria spp. strains were analyzed. Twenty-two isolates were obtained in San Luis (Argentina) from human, animal, and food samples. Two types of strains, Listeria monocytogenes CLIP 22762 and Listeria innocua CLIP 74915, were included as reference strains. All isolates were biochemically identified and characterized by serotyping, phage typing, and amplification of the flaA gene by polymerase chain reaction (PCR). Repetitive intergenic consensus (ERIC) sequence-based PCR was used to generate DNA fingerprints. On the basis of ERIC-PCR fingerprints, Listeria spp. strains were divided into three major clusters matching origin of isolation. ERIC-PCR fingerprints of human and animal isolates were different from those of food isolates. In addition, groups I and II included ten L. monocytogenes strains, and only one Listeria seeligeri strain. Group III included nine L. innocua strains and four L. monocytogenes strains. Computer evaluation of ERIC-PCR fingerprints allowed discrimination between the tested serotypes 1/2b, 4b, 6a, and 6b within each major cluster. The index of discrimination calculated was 0.94. This study suggests that the ERIC-PCR technique provides an alternative method for the identification of Listeria species and the discrimination of strains within one species.


How we design feasibility studies.
Public health is moving toward the goal of implementing evidence-based interventions. To accomplish this, there is a need to select, adapt, and evaluate intervention studies. Such selection relies, in part, on making judgments about the feasibility of possible interventions and determining whether comprehensive and multilevel evaluations are justified. There exist few published standards and guides to aid these judgments. This article describes the diverse types of feasibility studies conducted in the field of cancer prevention, using a group of recently funded grants from the National Cancer Institute. The grants were submitted in response to a request for applications proposing research to identify feasible interventions for increasing the utilization of the Cancer Information Service among underserved populations.


The R2C2 Model in Residency Education: How Does It Foster Coaching and Promote Feedback Use?
The authors previously developed and tested a reflective model for facilitating performance feedback for practice improvement, the R2C2 model. It consists of four phases: relationship building, exploring reactions, exploring content, and coaching. This research studied the use and effectiveness of the model across different residency programs and the factors that influenced its effectiveness and use. From July 2014-October 2016, case study methodology was used to study R2C2 model use and the influence of context on use within and across five cases. Five residency programs (family medicine, psychiatry, internal medicine, surgery, and anesthesia) from three countries (Canada, the United States, and the Netherlands) were recruited. Data collection included audiotaped site assessment interviews, feedback sessions, and debriefing interviews with residents and supervisors, and completed learning change plans (LCPs). Content, thematic, template, and cross-case analysis were conducted. An average of nine resident-supervisor dyads per site were recruited. The R2C2 feedback model, used with an LCP, was reported to be effective in engaging residents in a reflective, goal-oriented discussion about performance data, supporting coaching, and enabling collaborative development of a change plan. Use varied across cases, influenced by six general factors: supervisor characteristics, resident characteristics, qualities of the resident-supervisor relationship, assessment approaches, program culture and context, and supports provided by the authors. The R2C2 model was reported to be effective in fostering a productive, reflective feedback conversation focused on resident development and in facilitating collaborative development of a change plan. Factors contributing to successful use were identified.


NOS3 Inhibition Confers Post-Ischemic Protection to Young and Aging White Matter Integrity by Conserving Mitochondrial Dynamics and Miro-2 Levels.
White matter (WM) damage following a stroke underlies a majority of the neurological disability that is subsequently observed. Although ischemic injury mechanisms are age-dependent, conserving axonal mitochondria provides consistent post-ischemic protection to young and aging WM. Nitric oxide synthase (NOS) activation is a major cause of oxidative and mitochondrial injury in gray matter during ischemia; therefore, we used a pure WM tract, isolated male mouse optic nerve, to investigate whether NOS inhibition provides post-ischemic functional recovery by preserving mitochondria. We show that pan-NOS inhibition applied before oxygen-glucose deprivation (OGD) promotes functional recovery of young and aging axons and preserves WM cellular architecture. This protection correlates with reduced nitric oxide (NO) generation, restored glutathione production, preserved axonal mitochondria and oligodendrocytes, and preserved ATP levels. Pan-NOS inhibition provided post-ischemic protection to only young axons, whereas selective inhibition of NOS3 conferred post-ischemic protection to both young and aging axons. Concurrently, genetic deletion of NOS3 conferred long-lasting protection to young axons against ischemia. OGD upregulated NOS3 levels in astrocytes, and we show for the first time that inhibition of NOS3 generation in glial cells prevents axonal mitochondrial fission and restores mitochondrial motility to confer protection to axons by preserving Miro-2 levels. Interestingly, NOS1 inhibition exerted post-ischemic protection selectively to aging axons, which feature age-dependent mechanisms of oxidative injury in WM. Our study provides the first evidence that inhibition of glial NOS activity confers long-lasting benefits to WM function and structure and suggests caution in defining the role of NO in cerebral ischemia at vascular and cellular levels.SIGNIFICANCE STATEMENT White matter (WM) injury during stroke is manifested as the subsequent neurological disability in surviving patients. Aging primarily impacts CNS WM and mechanisms of ischemic WM injury change with age. Nitric oxide is involved in various mitochondrial functions and we propose that inhibition of glia-specific nitric oxide synthase (NOS) isoforms promotes axon function recovery by preserving mitochondrial structure, function, integrity, and motility. Using electrophysiology and three-dimensional electron microscopy, we show that NOS3 inhibition provides a common target to improve young and aging axon function, whereas NOS1 inhibition selectively protects aging axons when applied after injury. This study provides the first evidence that inhibition of glial cell NOS activity confers long-lasting benefits to WM structure and function.


Pain and other symptoms in patients with chronic benign paroxysmal positional vertigo (BPPV).
Background and aim A diagnosis of chronic benign paroxysmal positional vertigo (BPPV) is based on brief attacks of rotatory vertigo and concomitant nystagmus elicited by rapid changes in head position relative to gravity. However, the clinical course of BPPV may vary considerably from a self-limiting to a persisting and/or recurrent disabling problem. The authors' experience is that the most common complaints of patients with chronic BPPV are nautical vertigo or dizziness with other symptoms including neck pain, headache, widespread musculoskeletal pain, fatigue, and visual disturbances. Trauma is believed to be the major cause of BPPV in individuals younger than fifty years. Chronic BPPV is associated with high morbidity. Since these patients often suffer from pain and do not have rotatory vertigo, their symptoms are often attributed to other conditions. The aim of this study was to investigate possible associations between these symptoms and chronic BPPV. Methods During 2010 a consecutive prospective cohort observational study was performed. Diagnostic criteria: (A) BPPV diagnosis confirmed by the following: (1) a specific history of vertigo/dizziness evoked by acceleration/deceleration, (2) nystagmus in the first position of otolith repositioning maneuvers, and (3) appearing and disappearing nystagmus during the repositioning maneuvers; (B) the disorder has persisted for at least six months. (C) Normal MRI of the cerebrum. (A) Any disorder of the central nervous system (CNS), (B) migraine, (C) active Ménière's disease, and (D) severe eye disorders. Symptom questionnaire ('yes or no' answers during a personal interview) and Dizziness Handicap Inventory (DHI) were used. Results We included 69 patients (20 males and 49 females) with a median age of 45 years (range 21-68 years). The median duration of the disease was five years and three months. The video-oculography confirmed BPPV in more than one semicircular canal in all patients. In 15% there was a latency of more than 1 min before nystagmus occurred. The Dizziness Handicap Inventory (DHI) median score was 55.5 (score >60 indicates a risk of fall). Seventy-five percent were on 50-100% sick leave. Eighty-one percent had a history of head or neck trauma. Nineteen percent could not recall any history of trauma. In our cohort, nautical vertigo and dizziness (81%) was far more common than rotatory vertigo (20%). The majority of patients (87%) reported pain as a major symptom: neck pain (87%), headache (75%) and widespread pain (40%). Fatigue (85%), visual disturbances (84%), and decreased concentration ability (81%) were the most frequently reported symptoms. In addition, unexpected findings such as involuntary movements of the extremities, face, neck or torso were found during otolith repositioning maneuvers (12%). We describe one case, as an example, how treatment of his BPPV also resolved his chronic, severe pain condition. Conclusion This observational study demonstrates a likely connection between chronic BPPV and the following symptoms: nautical vertigo/dizziness, neck pain, headache, widespread pain, fatigue, visual disturbances, cognitive dysfunctions, nausea, and tinnitus. Implications Patients with complex pain conditions associated with nautical vertigo and dizziness should be evaluated with the Dizziness Handicap Inventory (DHI)-questionnaire which can identify treatable balance disorders in patients with chronic musculoskeletal pain.


The role of radiotracer imaging in Parkinson disease.
Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.


Marker rhythmometry with macrophage-colony stimulating factor (M-CSF).
In a patient with a debulked müllerian adenocarcinoma involving the ovary, an elevated serum concentration of macrophage-colony stimulating factor (M-CSF) (5.3 ng/ml) was lowered into the range of the age- and gender-matched controls by a 24-hour infusion of 135 mg/m2 of taxol, as was a Ca125 of 1480 U/ml by three such taxol courses given at 3-week intervals (to 14 U/ml). A downward trend of M-CSF in serum with an about-14-hour ultradian modulation during the first chemotherapy course resembles that of the concomitantly assessed Ca125. A decreasing trend modulated by an about-half-weekly component is found in M-CSF of fractionated urines collected at spontaneous voidings around the clock for 5 days. M-CSF may serve as a chronobiologic marker for optimizing, on an individualized basis, 1) the infradian scheduling of chemotherapy courses and 2) the ultradian-circadian within-course time patterns. Timing based on markers of the anticancer effect aims at teh as-yet unattained transfer from rodent to human of cancer cures that were not previously feasible without chronobiologic considerations. This goal can be pursued with M-CSF as well as Ca125 and UGP as possibly complementary chronobiologic markers in a chronotherapy trial with taxol in humans.


S100A6 Promotes B Lymphocyte Penetration Through the Blood-Brain Barrier in Autoimmune Encephalitis.
Autoimmune encephalitis (AE) is a severe neurological disease. The brain of the AE patient is attacked by a dysregulated immune system, which is caused by the excessive production of autoantibodies against neuronal receptors and synaptic proteins. AE is also characterized by the uncontrolled B lymphocyte infiltration through the blood-brain barrier (BBB) layer, and the investigation of the underlying mechanism involved in this infiltration may facilitate the discovery of novel therapies for AE. However, few AE-related studies have focused on this issue. In this study, we aimed to identify the factors involved in B lymphocyte infiltration in AE. For this purpose, we first enrolled four healthy control and five AE subjects, collecting their serum and/or total white blood cell samples. The white blood cell samples were further used for collecting RNA and DNA. Then, we simulated the in vivo B lymphocyte infiltration with an in vitro leukocyte transendothelial migration model. It turned out that AE serum treatment significantly and specifically promoted B cells to penetrate the BBB endothelial layer without affecting neutrophils. Next, through genome-wide DNA methylation assays on bisulfite-conversion DNA samples, we identified S100A6 and S100A11 as potential hypo-methylated disease genes in the AE samples. Further qPCR assays demonstrated their upregulation in AE samples, reflecting the negative correlations between gene expression and DNA methylation. Finally, recombinant S100A6 protein treatment significantly increased B lymphocyte infiltration through the BBB endothelial layer, which partially recapitulated the effect of AE serum. In summary, by using an in vitro leukocyte transendothelial migration model, we confirmed that S100A6 promoted B lymphocyte to penetrate the BBB endothelial layer, which is similar to the in vivo clinical manifestations of AE. Therefore, further studies on how the S100A6 protein facilitates B lymphocyte infiltration and on whether other factors in serum also contribute to this phenomenon are likely to improve our understanding of AE and hopefully to reveal novel therapeutic targets for this emerging treatable neurological disorder.


The socioeconomic gradient and chronic illness and associated risk factors in Australia.
OBJECTIVE: To examine the prevalence of major chronic diseases and their risk factors in different socioeconomic groups in the Australian population, in order to highlight the need for public policy initiatives to reduce socioeconomic inequalities in health. METHODS: Data were provided by the Australian Bureau of Statistics (ABS) from the 2001 National Health Survey (NHS) for selected chronic diseases and associated risk factors. Conditions selected were those, which form the National Health Priority Area (NHPA) conditions (other than injury, which has not been included in this paper, with its focus on chronic disease); plus other 'serious' chronic conditions, in line with the classification developed by Mathers; and for which sufficient cases were available for analysis by socioeconomic status. Indirectly age-standardised prevalence rates were calculated by broad age group for Australia and for five groups of socioeconomic status; rate ratios were calculated to show variations in prevalence between these groups. RESULTS: Significant socioeconomic inequalities were evident for many of the major chronic diseases; the largest was for diabetes mellitus (at ages 25 to 64 years); and for many diseases, there was also a strong, continuous socioeconomic gradient in the rates.Circulatory system diseases (in particular, hypertensive disease) and digestive system diseases also exhibited a strong differential in the 25 to 64 year age group.In the 65 years and over age group, the strongest inequalities were evident for mental and behavioural problems, diabetes (with a continuous socioeconomic gradient in rates) and respiratory system diseases.A number of risk factors for chronic diseases, namely self-reported smoking, alcohol misuse, physical inactivity and excess weight showed a striking association with socioeconomic status, in particular for people who were smokers and those who did not exercise. CONCLUSION: This analysis shows that the prevalence of chronic disease varies across the socioeconomic gradient for a number of specific diseases, as well as for important disease risk factors. Therefore, any policy interventions to address the impact of chronic disease, at a population level, need to take into account these socioeconomic inequalities.


Mixed emotions: the contribution of alexithymia to the emotional symptoms of autism.
It is widely accepted that autism is associated with disordered emotion processing and, in particular, with deficits of emotional reciprocity such as impaired emotion recognition and reduced empathy. However, a close examination of the literature reveals wide heterogeneity within the autistic population with respect to emotional competence. Here we argue that, where observed, emotional impairments are due to alexithymia-a condition that frequently co-occurs with autism-rather than a feature of autism per se. Alexithymia is a condition characterized by a reduced ability to identify and describe one's own emotion, but which results in reduced empathy and an impaired ability to recognize the emotions of others. We briefly review studies of emotion processing in alexithymia, and in autism, before describing a recent series of studies directly testing this 'alexithymia hypothesis'. If found to be correct, the alexithymia hypothesis has wide-reaching implications for the study of autism, and how we might best support subgroups of autistic individuals with, and without, accompanying alexithymia. Finally, we note the presence of elevated rates of alexithymia, and inconsistent reports of emotional impairments, in eating disorders, schizophrenia, substance abuse, Parkinson's Disease, multiple sclerosis and anxiety disorders. We speculate that examining the contribution of alexithymia to the emotional symptoms of these disorders may bear fruit in the same way that it is starting to do in autism.


Long-Term Consistency of Dominance Relations Among Female Baboons (Papio cynocephalus).
At maturity, female baboons in the Amboseli National Park of Kenya generally attain a rank position among adults near to that of their mothers. However, the age of a female's mother and the difference in ages between sisters also influence the rank acquisition process. These latter demographic variables, which are sensitive to changes in resource availability, may account for the close association both within and among primate species of specific patterns of rank organization and specific environmental conditions.


Biochemical markers of renal function and maternal hypothyroidism in early pregnancy.
Objective The physiological adaptations during a normal pregnancy affect renal and thyroid function and levels of associated biochemical markers. An association between Cystatin C (CysC), creatinine, and thyroid function has been considered in non-pregnant individuals, but not in pregnant women specifically. Methods Cohort study within the North Denmark Region Pregnancy Cohort (2011-2015) with assessment of thyroid function and autoantibodies (ADVIA Centaur XPT, Siemens Healthineers) in serum residues from the early pregnancy. Consecutive samples (n = 1,112) were selected for measurement of CysC and creatinine (Atellica CH 930, Siemens Healthineers), and results were linked to information in Danish nationwide registers for a) establishment of pregnancy-specific reference intervals for CysC and creatinine, and b) evaluation of the prevalence of maternal hypothyroidism in early pregnancy according to levels of CysC and creatinine. Results The established reference intervals (2.5-97.5 percentiles) differed by week of pregnancy (week 4-8; 9-11; 12-15) and were: CysC 0.58-0.92 mg/L; 0.54-0.91 mg/L; 0.52-0.86 mg/L; creatinine 46.9-73.0 µmol/L; 42.0-68.4 µmol/L; 38.8-66.4 µmol/L. The prevalence of maternal autoimmune hypothyroidism in early pregnancy differed by the level of CysC and creatinine (<25th percentile; 25th-75th percentile; > 75th percentile) and was for CysC 1.7%; 3.8%; 7.4% and for creatinine 2.5%; 4.1%; 7.1%. Conclusions Reference intervals for CysC and creatinine were dynamic in early pregnancy and decreased with increasing gestational age. Furthermore, higher levels of CysC and creatinine associated with a higher prevalence of maternal autoimmune hypothyroidism. Results encourage considerations on the underlying mechanisms for the association between markers of renal and thyroid function.


Sex-specific parent-of-origin allelic expression in the mouse brain.
Genomic imprinting results in preferential gene expression from paternally versus maternally inherited chromosomes. We used a genome-wide approach to uncover sex-specific parent-of-origin allelic effects in the adult mouse brain. Our study identified preferential selection of the maternally inherited X chromosome in glutamatergic neurons of the female cortex. Moreover, analysis of the cortex and hypothalamus identified 347 autosomal genes with sex-specific imprinting features. In the hypothalamus, sex-specific imprinted genes were mostly found in females, which suggests parental influence over the hypothalamic function of daughters. We show that interleukin-18, a gene linked to diseases with sex-specific prevalence, is subject to complex, regional, and sex-specific parental effects in the brain. Parent-of-origin effects thus provide new avenues for investigation of sexual dimorphism in brain function and disease.