Mast cells are evolutionarily ancient sentinel cells. Like basophils,
mast cells express the high-affinity IgE receptor and are implicated in host
defense and diverse immune-mediated diseases. To better characterize the
function of these cells, we assessed the transcriptional profiles of mast cells
isolated from peripheral connective tissues and basophils isolated from spleen
and blood. We found that mast cells were transcriptionally distinct, clustering
independently from all other profiled cells, and that mast cells demonstrated
considerably greater heterogeneity across tissues than previously appreciated.
We observed minimal homology between mast cells and basophils, which share more
overlap with other circulating granulocytes than with mast cells. Derivation of
mast cell and basophil transcriptional signatures underscores their differential
capacity to detect environmental signals and influence the inflammatory
Background and Aims Quantifying relationships between snow cover duration and plant community properties remains an important challenge in alpine ecology. This study develops a method to estimate spatial variation in energy availability in the context of a topographically complex, high-elevation watershed, which was used to test the explanatory power of environmental gradients both with and without snow cover in relation to taxonomic and functional plant diversity.
Methods Snow cover in the French Alps was mapped at 15-m resolution using Landsat imagery for five recent years, and a generalized additive model (GAM) was fitted for each year linking snow to time and topography. Predicted snow cover maps were combined with air temperature and solar radiation data at daily resolution, summed for each year and averaged across years. Equivalent growing season energy gradients were also estimated without accounting for snow cover duration. Relationships were tested between environmental gradients and diversity metrics measured for 100 plots, including species richness, community-weighted mean traits, functional diversity and hyperspectral estimates of canopy chlorophyll content.
Key Results Accounting for snow cover in environmental variables consistently led to improved predictive power as well as more ecologically meaningful characterizations of plant diversity. Model parameters differed significantly when fitted with and without snow cover. Filtering solar radiation with snow as compared without led to an average gain in R2 of 0·26 and reversed slope direction to more intuitive relationships for several diversity metrics.
Conclusions The results show that in alpine environments high-resolution data on snow cover duration are pivotal for capturing the spatial heterogeneity of both taxonomic and functional diversity. The use of climate variables without consideration of snow cover can lead to erroneous predictions of plant diversity. The results further indicate that studies seeking to predict the response of alpine plant communities to climate change need to consider shifts in both temperature and nival regimes.
Alpine grassland; climate change; French Alps; GAM; generalized additive model; growing season length; Landsat; mesotopography; plant community structure; remote sensing, snow cover
Sensitivity to temporal change places fundamental limits on object processing in the visual system. An emerging consensus from the behavioral and neuroimaging literature suggests that temporal resolution differs substantially for stimuli of different complexity and for brain areas at different levels of the cortical hierarchy. Here we used Steady-State Visual Evoked Potentials (SSVEPs) to directly measure three fundamental parameters that characterize the underlying neural response to text and face images: temporal resolution, peak temporal frequency and response latency. We presented full-screen images of text or a human face, alternated with a scrambled image, at temporal frequencies between 1 and 12 Hz. These images elicited a robust response at the first harmonic that showed differential tuning, scalp topography and delay for the text and face images. Face selective responses were maximal at 4 Hz, but text selective responses, by contrast were maximal at 1 Hz. The topography of the text image response was strongly left-lateralized at higher stimulation rates, while the response to the face image was slightly right-lateralized but nearly bilateral at all frequencies. Both text and face images elicited steady state activity at more than one apparent latency; we observed early (141ms–160ms) and late (>250ms) text and face selective responses. These differences in temporal tuning profiles are likely to reflect differences in the nature of the computations performed by word and face selective cortex. Despite the close proximity of word and face selective regions on the cortical surface, our measurements demonstrate substantial differences in the temporal dynamics of word-versus face-selective responses.
face perception; word perception; Visual Evoked Potentials; temporal resolution; temporal tuning
The history of human settlement in Southeast Asia has been complex and
involved several distinct dispersal events. Here we report the analyses of 1825
individuals from Southeast Asia including new genome-wide genotype data for 146
individuals from three Mainland Southeast Asian (Burmese, Malay and Vietnamese)
and four Island Southeast Asian (Dusun, Filipino, Kankanaey and Murut)
populations. While confirming the presence of previously recognized major
ancestry components in the Southeast Asian population structure, we highlight
the Kankanaey Igorots from the highlands of the Philippine Mountain Province as
likely the closest living representatives of the source population that may have
given rise to the Austronesian expansion. This conclusion rests on independent
evidence from various analyses of autosomal data and uniparental markers.
Given the extensive presence of trade goods, cultural and linguistic
evidence of Indian influence in Southeast Asia starting from 2.5kya we also
detect traces of a South Asian signature in different populations in the region
dating to the last couple of thousand years.
A wider diversity of drug treatments to aid smoking cessation is needed to help tailor the most efficacious treatment for different types of smokers. This study was conducted to determine whether amitifadine, which inhibits re-uptake of dopamine, norepinephrine and serotonin, would decrease nicotine self-administration at doses that do not cause adverse side effects. Adult female Sprague-Dawley rats were trained to self-administer nicotine intravenous (IV) and were given acute doses of amitifadine in a repeated measures counterbalanced design. Effects of amitifadine on locomotor activity and food motivated responding were also evaluated. Chronic amitifadine effects were also examined. The 30 mg/kg amitifadine dose significantly reduced nicotine self-administration. The 5 and 10 mg/kg doses reduced nicotine self-administration during the first 15 min. of the session when the greatest amount of nicotine was self-administered. The 30 mg/kg amitifadine dose, but not the lower doses caused a significant reduction in locomotor activity averaged over the 1-hour session and reduced food motivated responding. The 10 mg/kg dose caused hypoactivity at the beginning of the session, but 5 mg/kg did not cause any hypoactivity. The effects of chronic amitifadine treatment (10 mg/kg) over the course of 15 sessions was also determined. Amitifadine caused a significant reduction in nicotine self-administration, which was not seen to diminish over two consecutive weeks of treatment and a week after enforced abstinence. Amitifadine significantly reduced nicotine self-administration. This prompts further research to determine if amitifadine might be an effective treatment for smoking cessation.
Amitifadine; Self-administration; Nicotine; Treatment; Dopamine; Serotonin; Norepinephrine
Mitochondrial uncoupling proteins (UCPs) are inducible and play an important role in
metabolic and redox homeostasis. Recent studies have suggested that FoxO1 controls
mitochondrial biogenesis and morphology, but it remains largely unknown how FoxO1 may
regulate mitochondrial UCPs. Here we show that FoxO1 interacted with transcription factor
EB (Tfeb), a key regulator of autophagosome and lysosome, and mediated the expression of
UCP1, UCP2 and UCP3 differentially via autophagy in adipocytes. UCP1 was down-regulated
but UCP2 and UCP3 were upregulated during adipocyte differentiation, which was associated
with increased Tfeb and autophagy activity. However, inhibition of FoxO1 suppressed Tfeb
and autophagy, attenuating UCP2 and UCP3 but increasing UCP1 expression. Pharmacological
blockade of autophagy recapitulated the effects of FoxO1 inhibition on UCPs. Chromatin
immunoprecipitation assay demonstrated that FoxO1 interacted with Tfeb by directly binding
to its promoter, and silencing FoxO1 led to drastic decrease in Tfeb transcript and
protein levels. These data provide the first line of evidence that FoxO1 interacts with
Tfeb to regulate autophagy and UCP expression in adipocytes. Dysregulation of
FoxO1→autophagy→UCP pathway may account for metabolic changes in obesity.
Qualitative methods potentially add depth to prevention research, but can produce large amounts of complex data even with small samples. Studies conducted with culturally distinct samples often produce voluminous qualitative data, but may lack sufficient sample sizes for sophisticated quantitative analysis. Currently lacking in mixed methods research are methods allowing for more fully integrating qualitative and quantitative analysis techniques. Cluster analysis can be applied to coded qualitative data to clarify the findings of prevention studies by aiding efforts to reveal such things as the motives of participants for their actions and the reasons behind counterintuitive findings. By clustering groups of participants with similar profiles of codes in a quantitative analysis, cluster analysis can serve as a key component in mixed methods research.
This article reports two studies. In the first study, we conduct simulations to test the accuracy of cluster assignment using three different clustering methods with binary data as produced when coding qualitative interviews. Results indicated that hierarchical clustering, K-Means clustering, and latent class analysis produced similar levels of accuracy with binary data, and that the accuracy of these methods did not decrease with samples as small as 50. Whereas the first study explores the feasibility of using common clustering methods with binary data, the second study provides a “real-world” example using data from a qualitative study of community leadership connected with a drug abuse prevention project. We discuss the implications of this approach for conducting prevention research, especially with small samples and culturally distinct communities.
Prostate cancer remains among the most commonly diagnosed malignancies worldwide. Early diagnosis and curative treatment appear to improve survival in men with unfavorable-risk cancers, but significant concerns exist regarding the overdiagnosis and overtreatment of men with lower-risk cancers. To this end, active surveillance (AS) has emerged as a primary management strategy in men with favorable-risk disease, and contemporary data suggest that use of AS has increased worldwide. Although published surveillance cohorts differ by protocol, reported rates of metastatic disease and prostate cancer-specific mortality are exceedingly low in the intermediate term (5–10 years). Such outcomes appear to be closely associated with program-specific criteria for selection, monitoring, and intervention, suggesting that AS – like other management strategies – could be individualized based on the level of risk acceptable to patients in light of personal preferences. Additional data are needed to better establish the risks associated with AS and to identify patient-specific characteristics that could modify prognosis.
Preterm birth (PTB) is a multifactorial disorder, and air pollution has been suggested to increase the risk of occurrence. However, large population studies controlling for multiple exposure measures in high-density settings with established commuter patterns are lacking.
We performed a geospatial analysis with the use of a publicly available database to identify whether residence during pregnancy, specifically with regard to exposure to traffic density and mobility in urban and suburban neighborhoods, may be a contributing risk factor for premature delivery.
In our cohort study, we analyzed 9004 pregnancies with as many as 4900 distinct clinical and demographic variables from Harris County, Texas. On the basis of primary residency and occupational zip code information, geospatial analysis was conducted. Data on vehicle miles traveled (VMT) and percentages of inhabitants traveling to work were collected at the zip code level and additionally grouped by the three recognized regional commuter loop high-density thoroughfares resulting from two interstate/highway belts (inner, middle, and outer loops). PTB was categorized as late (34 1/7 to 36 6/7 weeks) and early PTB (22 1/7 to 33 6/7 weeks), and unadjusted odds ratios (OR) and adjusted ORs were ascribed.
PTB prevalence in our study population was 10.1% (6.8% late and 3.3% early preterm), which is in accordance with our study and other previous studies. Prevalence of early PTB varied significantly between the regional commuter loop thoroughfares [OR for inner vs outer loop: 0.58 (95% confidence interval, 0.39–0.87), OR for middle vs outer loop, 0.74 (0.57–0.96)]. The ORs for PTB and early PTB were shown to be lower in gravidae from neighborhoods with the highest VMT/acre [OR for PTB, 0.82 (0.68–0.98), OR for early PTB, 0.78 (0.62–0.98)]. Conversely, risk of PTB and early PTB among subjects living in neighborhoods with a high percentage of inhabitants traveling to work over a greater distance demonstrated a contrary tendency [OR for PTB, 1.18 (1.03–1.35), OR for early PTB, 1.48 (1.17–1.86)]. In logistic regression models, the described association between PTB and residence withstood and could not be explained by differences in maternal age, gravidity or ethnicity, tobacco use, or history of PTB.
While PTB is of multifactorial origin, the present study shows that community-based risk factors (namely urban/suburban location, differences in traffic density exposure, and need for traveling to work along highevehicle density thoroughfares) may influence risk for PTB. Further research focusing on previously unrecognized community-based risk factors may lead to innovative future prevention measures.
geospatial analysis; neighborhood; pregnancy outcome; preterm birth; traffic density exposure
Childhood adversity, characterized by abuse, neglect, and household dysfunction, is a problem that exerts a significant impact on individuals, families, and society. Growing evidence suggests that adverse childhood experiences (ACEs) are associated with health decline in adulthood, including cardiovascular disease (CVD). In the current review, we first provide an overview of the association between ACEs and CVD risk, with updates on the latest epidemiological evidence. Second, we briefly review plausible pathways by which ACEs could influence CVD risk, including traditional risk factors and novel mechanisms. Finally, we highlight the potential implications of ACEs in clinical and public health. Information gleaned from this review should help physicians and researchers in better understanding potential long-term consequences of ACEs and considering adapting current strategies in treatment or intervention for patients with ACEs.
Adverse childhood experiences; Childhood maltreatment; Cardiovascular disease; Risky behaviors; Depression; Intervention
The large and increasing volume of genomic data analyzed by comparative methods provides information about transcription factors and their binding sites that, in turn, enables statistical analysis of correlations between factors and sites, uncovering mechanisms and evolution of specific protein-DNA recognition. Here we present an online tool, Prot-DNA-Korr, designed to identify and analyze crucial protein-DNA pairs of positions in a family of transcription factors. Correlations are identified by analysis of mutual information between columns of protein and DNA alignments. The algorithm reduces the effects of common phylogenetic history and of abundance of closely related proteins and binding sites. We apply it to five closely related subfamilies of the MerR family of bacterial transcription factors that regulate heavy metal resistance systems. We validate the approach using known 3D structures of MerR-family proteins in complexes with their cognate DNA binding sites and demonstrate that a significant fraction of correlated positions indeed form specific side-chain-to-base contacts. The joint distribution of amino acids and nucleotides hence may be used to predict changes of specificity for point mutations in transcription factors.
The reporting of evaluation outcomes can be a point of contention between evaluators and policy-makers when a given reform fails to fulfil its promises. Whereas evaluators are required to report outcomes in full, policy-makers have a vested interest in framing these outcomes in a positive light–especially when they previously expressed a commitment to the reform. The current evidence base is limited to a survey of policy evaluators, a study on reporting bias in education research and several studies investigating the influence of industry sponsorship on the reporting of clinical trials. The objective of this study was twofold. Firstly, it aimed to assess the risk of outcome reporting bias (ORB or ‘spin’) in pilot evaluation reports, using seven indicators developed by clinicians. Secondly, it sought to examine how the government’s commitment to a given reform may affect the level of ORB found in the corresponding evaluation report. To answer these questions, 13 evaluation reports were content-analysed, all of which found a non-significant effect of the intervention on its stated primary outcome. These reports were systematically selected from a dataset of 233 pilot and experimental evaluations spanning three policy areas and 13 years of government-commissioned research in the UK. The results show that the risk of ORB is real. Indeed, all studies reviewed here resorted to at least one of the presentational strategies associated with a risk of spin. This study also found a small, negative association between the seniority of the reform’s champion and the risk of ORB in the evaluation of that reform. The publication of protocols and the use of reporting guidelines are recommended.
In this work, an approach to jointly estimating the tone hole configuration (fingering) and reed model parameters of a saxophone is presented. The problem isn't one of merely estimating pitch as one applied fingering can be used to produce several different pitches by bugling or overblowing. Nor can a fingering be estimated solely by the spectral envelope of the produced sound (as it might for estimation of vocal tract shape in speech) since one fingering can produce markedly different spectral envelopes depending on the player's embouchure and control of the reed. The problem is therefore addressed by jointly estimating both the reed (source) parameters and the fingering (filter) of a saxophone model using convex optimization and 1) a bank of filter frequency responses derived from measurement of the saxophone configured with all possible fingerings and 2) sample recordings of notes produced using all possible fingerings, played with different overblowing, dynamics and timbre. The saxophone model couples one of several possible frequency response pairs (corresponding to the applied fingering), and a quasi-static reed model generating input pressure at the mouthpiece, with control parameters being blowing pressure and reed stiffness. Applied fingering and reed parameters are estimated for a given recording by formalizing a minimization problem, where the cost function is the error between the recording and the synthesized sound produced by the model having incremental parameter values for blowing pressure and reed stiffness. The minimization problem is nonlinear and not differentiable and is made solvable using convex optimization. The performance of the fingering identification is evaluated with better accuracy than previous reported value.
Female sex workers (FSW) have high rates of unintended pregnancy, sexually transmitted infections including HIV, and other adverse sexual and reproductive health outcomes. Few services for FSWs include contraception. This mixed-methods study aimed to determine the rate, predictors and consequences of unintended pregnancy among FSWs in Mombasa, Kenya.
A prospective cohort study of non-pregnant FSWs was conducted. Quantitative data were collected quarterly, including a structured questionnaire and testing for pregnancy and HIV. Predictors of unintended pregnancy were investigated using multivariate logistic regression. Qualitative data were gathered through focus group discussions and in-depth interviews with FSWs who became pregnant during the study, and interviews with five key informants. These data were transcribed, translated and analysed thematically.
Four hundred women were enrolled, with 92% remaining in the cohort after one year. Fifty-seven percent reported using a modern contraceptive method (including condoms when used consistently). Over one-third (36%) of women were using condoms inconsistently without another method. Twenty-four percent had an unintended pregnancy during the study. Younger age, having an emotional partner and using traditional or no contraception, or condoms only, were independent predictors of unintended pregnancy. Women attributed pregnancy to forgetting to use contraception and being pressured not to by clients and emotional partners, as well as “bad luck”. They described numerous negative consequences of unintended pregnancy.
Modern contraceptive uptake is surprisingly low in this at-risk population, which in turn has a high rate of unintended pregnancy. The latter may result in financial hardship, social stigma, risk of abandonment, or dangerous abortion practices. FSWs face considerable barriers to the adoption of dual method contraceptive use, including low levels of control in their emotional and commercial relationships. Reproductive health services need to be incorporated into programs for sexually transmitted infections and HIV, which address the socially-determined barriers to contraceptive use.
Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-α to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP.
Patients initiated on highly active antiretroviral therapy (HAART) generally remain on medication indefinitely. A modification in the HAART regimen may become necessary because of possible acute or chronic toxicities, concomitant clinical conditions, development of virological failure or the advent of adverse drug events. The study documents adverse drug events of HIV-positive Ghanaian patients with HAART modifications. It also investigates the association between documented adverse drug events and HAART modification using an unmatched case–control study design.
The study was conducted in the Fevers Unit of the Korle Bu Teaching Hospital and involved patients who attended the HIV Care Clinic between January 2004 and December 2009. Data from 298 modified therapy patients (cases) were compared with 298 continuing therapy patients (controls) who had been on treatment for at least 1 month before the end of study. Controls were sampled from the same database of a cohort of HIV-positive patients on HAART, at the time a case occurred, in terms of treatment initiation ±1 month. Data were obtained from patients’ clinical folders and the HIV clinic database linked to the pharmacy database. The nature of the documented adverse drug events of the cases was described and the association between the documented adverse drug events and HAART modification was determined by logistic regression with reported odds ratios (ORs) and their 95 % confidence interval (CI).
Among the 298 modified therapy patients sampled in this study, 52.7 % of them had at least one documented adverse drug event. The most documented adverse drug event was anaemia, recorded in 18.5 % of modified therapy patients, all of whom were on a zidovudine-based regimen. The presence of documented adverse drug events was significantly associated with HAART modification [adjusted OR = 2.71 (95 % CI 2.11–3.48), p < 0.001].
Among HIV patients on HAART, adverse drug events play a major role in treatment modification. Occurrence of adverse drug events may be used as a predictor for possible therapy modification. We recommend the institution of active pharmacovigilance in HIV treatment programmes as it permits the proper identification and characterisation of drug-related adverse events. This can help develop approaches towards their management and also justify therapy modifications.
Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP – induced osteoblast differentiation (p<10−20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.
The bones in the front, back and sides of the human skull are not fused to one another at birth in order to allow the brain to double in size during the first year of life and continue growing into adulthood. However, one in 2,000 infants is born with a condition called craniosynostosis in which some of these bones have already fused. This fusion prevents the skull from growing properly, and can lead to the brain becoming compressed. As such, surgeons routinely undo the fusion in these infants to allow the brain and skull to grow normally.
Eighty-five percent of craniosynostosis cases occur in infants with no other abnormalities, (called non-syndromic cases) and most have no other affected family member. It has therefore been unclear whether these infants have craniosynostosis due to a genetic or non-genetic cause. If the cause is genetic, it is also not clear whether a mutation in a single gene, the combined effects of many genes, or something in between is responsible.
Now, by focusing on a group of 191 infants with premature fusion of bones joined at the midline of the skull, Timberlake et al. asked if any of the approximately 20,000 genes in the human genome were altered more frequently in these infants than would be expected by chance. This search revealed that rare mutations that disable one copy of a gene called SMAD6 in combination with a common DNA variant near another gene called BMP2 account for about 7% of infants with midline forms of craniosynostosis. These genes are both known to regulate how bones form, which explains how the mutation of these genes could lead to craniosynostosis.
In all cases, the parents of these children were unaffected. This was typically because one parent had only the SMAD6 mutation while the other had only the common BMP2 variant; the transmission of both to their offspring resulted in craniosynostosis. The finding that a rare mutation’s effect is strongly modified by a common variant from another site in the genome is unprecedented. These findings will allow doctors to counsel families about the risk of having additional children with craniosynostosis.
Timberlake et al. next plan to study more patients with craniosynostosis to identify additional genes that contribute to this disease. They will also look at other diseases to see whether the combination of rare mutation and common DNA variant could be behind other unexplained disorders.
craniosynostosis; craniofacial; exome sequencing; human genetics; de novo mutation; incomplete penetrance; SMAD6; BMP2; SMURF1; SPRY1; SPRY4; Human
•Resting conidia are demonstrated to be metabolically active.•After triggering of conidial outgrowth fermentation occurs, followed by respiration.•Sorbic acid inhibits O2 uptake and delays the onset of respiration.
The early stages of development of Aspergillus niger conidia during outgrowth were explored by combining genome-wide gene expression analysis (RNAseq), proteomics, Warburg manometry and uptake studies. Resting conidia suspended in water were demonstrated for the first time to be metabolically active as low levels of oxygen uptake and the generation of carbon dioxide were detected, suggesting that low-level respiratory metabolism occurs in conidia for maintenance. Upon triggering of spore germination, generation of CO2 increased dramatically. For a short period, which coincided with mobilisation of the intracellular polyol, trehalose, there was no increase in uptake of O2 indicating that trehalose was metabolised by fermentation. Data from genome-wide mRNA profiling showed the presence of transcripts associated with fermentative and respiratory metabolism in resting conidia. Following triggering of conidial outgrowth, there was a clear switch to respiration after 25 min, confirmed by cyanide inhibition. No effect of SHAM, salicylhydroxamic acid, on respiration suggests electron flow via cytochrome c oxidase. Glucose entry into spores was not detectable before 1 h after triggering germination. The impact of sorbic acid on germination was examined and we showed that it inhibits glucose uptake. O2 uptake was also inhibited, delaying the onset of respiration and extending the period of fermentation. In conclusion, we show that conidia suspended in water are not completely dormant and that conidial outgrowth involves fermentative metabolism that precedes respiration.
Aspergillus niger; Conidial development; Manometry; RNAseq; Proteome; Sorbic acid
Evaluate the impact of radiotherapy on cause specific survival (CSS) and overall survival (OS) for stage (I–III) clear cell, mucinous, and endometriod ovarian cancer.
We analyzed incidence, survival, and treatments from the Surveillance, Epidemiology, and End Results (SEER) Program from 2004 to 2011 for clear cell, mucinous, and endometriod histologies of the ovary for stages (I–III). We examined CSS and OS for all three histologies combined and each histology with relation to the use of adjuvant radiation therapy (RT). Survival analysis was calculated by Kaplan-Meier and log-rank analysis.
CSS was higher in individuals not receiving RT at 5 years (81% vs. 74%) and 10 years (74% vs. 65%, p=0.003). OS was higher in individuals not receiving RT at 5 years (76% vs. 73%) and 10 years (64% vs. 59%, p=0.039). Stage III patients receiving RT had a higher OS at 5 years (54% vs. 44%) and 10 year intervals (36% vs. 30%, p=0.037). Stage III patients with mucinous histology receiving RT had a higher OS at 5 years (50% vs. 36%) and 10 years (45% vs. 26%, p=0.052).
Those receiving RT had a lower CSS and OS at 5 and 10 years. However, subgroup analysis revealed a benefit of RT in terms of OS for all stage III patients and for stage III patients with mucinous histology.
Ovary; Radiation; Survival; Uncommon Histology
This study aimed to investigate the perinatal mortality rate with 37 864 deliveries which occured in two different periods in a single center, to compare the components of perinatal mortality and affecting factors with the results of the study related with perinatal mortality which we conducted in 1999 and to emphasize the precautions directed to reduce mortality rates.
Material and Methods:
All live births and stillbirths which occurred in Bakırköy Obstetrics and Pediatrics Training and Research Hospital between January 2007 and December 2007 were evaluated. The results were compared with the results of the study conducted in 1999. Newborns with a weight above five hundred grams and a gestational age above 22 weeks were enrolled in the study. The stillbirth rate, early neonatal mortality rate, late neonatal mortality rate, perinatal mortality rate and corrected perinatal mortality rate were calculated. Modified Wigglesworth Classification was used for evaluating the perinatal mortality and the subjects were examined in 7 groups. The characteristics belonging to the years of 2007 and 1999 were examined, the differences were recorded and the results were discussed. When the two periods were compared, it was observed that the perinatal mortality rate increased from 23.5‰ to 26‰.
When the causes were investigated, it was observed that the stillbirth rate was increased in 2007 (84%) and especially congenital anomalies had an important role in this increment. The early neonatal mortality rate declined from 0.8% in 1999 to 0.4% in 2007. It was found that especially the premature mortality rate (Group 3) and the mortality rate related with perinatal asphyxia (Group 4) were significantly decreased.
The decrease in early neonatal mortality rate could be best explained by productive operation of the new neonatal intensive care unit which had been established after 2002.
Early neonatal mortality; late neonatal mortality; modified wigglesworth classification; stillbirth; perinatal mortality
Ultrasound-assisted examination of the cardiovascular system with focused cardiac ultrasound by the treating physician is non-invasive and changes diagnosis and management of patient’s with suspected cardiac disease. This has not been reported in a general practice setting.
To determine whether focused cardiac ultrasound performed on patients aged over 50 years changes the diagnosis and management of cardiac disease by a general practitioner.
Design and setting
A prospective observational study of 80 patients aged over 50years and who had not received echocardiography or chest CT within 12months presenting to a general practice.
Clinical assessment and management of significant cardiac disorders in patients presenting to general practitioners were recorded before and after focused cardiac ultrasound. Echocardiography was performed by a medical student with sufficient training, which was verified by an expert. Differences in diagnosis and management between conventional and ultrasound-assisted assessment were recorded.
Results and conclusion
Echocardiography and interpretation were acceptable in all patients. Significant cardiac disease was detected in 16 (20%) patients, including aortic stenosis in 9 (11%) and cardiac failure in 7 (9%), which were missed by clinical examination in 10 (62.5%) of these patients. Changes in management occurred in 12 patients (15% overall and 75% of those found to have significant cardiac disease) including referral for diagnostic echocardiography in 8 (10%), commencement of heart failure treatment in 3 (4%) and referral to a cardiologist in 1 patient (1%).
Routine focused cardiac ultrasound is feasible and frequently alters the diagnosis and management of cardiac disease in patients aged over 50years presenting to a general practice.
echocardiography; diagnosis; echocardiography and management; feasibility; hand-carried ultrasound
Cardiotoxicity from anthracycline-based chemotherapy is an important cause of early and late morbidity and mortality in breast cancer patients. Left ventricular (LV) function is assessed for patients receiving anthracycline-based chemotherapy to identify cardiotoxicity. However, animal studies suggest that right ventricular (RV) function may be a more sensitive measure to detect LV dysfunction. The purpose of this pilot study was to determine if breast cancer patients undergoing anthracycline-based chemotherapy experience RV dysfunction.
Forty-nine breast cancer patients undergoing anthracycline-based chemotherapy at the Ottawa Hospital between November 2007 and March 2013 and who had 2 echocardiograms performed at least 3months apart were retrospectively identified. Right atrial area (RAA), right ventricular fractional area change (RV FAC) and RV longitudinal strain of the free wall (RV LSFW) were evaluated according to the American Society of Echocardiography guidelines.
The majority (48/49) of patients were females with an average age of 53.4 (95% CI: 50.1–56.7years). From baseline to follow-up study, average LV ejection fraction (LVEF) decreased from 62.22 (95% CI: 59.1–65.4) to 57.4% (95% CI: 54.0–60.9) (P=0.04). During the same time period, the mean RAA increased from 12.1cm2 (95% CI: 11.1–13.0cm2) to 13.8cm2 (95% CI: 12.7–14.9cm2) (P=0.02), mean RV FAC decreased (P=0.01) from 48.3% (95% CI: 44.8–51.74) to 42.1% (95% CI: 38.5–45.6%), and mean RV LSFW worsened from −16.2% (95% CI: −18.1 to −14.4%) to −13.81% (95% CI: −15.1 to −12.5%) (P=0.04).
This study demonstrates that breast cancer patients receiving anthracycline-based chemotherapy experience adverse effects on both right atrial size and RV function. Further studies are required to determine the impact of these adverse effects on right heart function and whether this represents an earlier marker of cardiotoxicity.
right heart function; chemotherapy; cardiotoxicity; echocardiography
To assess the impact of mitral geometry, left ventricular (LV) remodelling and global LV afterload on mitral regurgitation (MR) after trans-catheter aortic valve implantation (TAVI).
In this study, 60 patients who underwent TAVI were evaluated by 3D echocardiography at baseline, 1 month and 6 months after procedure. The proportional change in MR following TAVI was determined by examining the percentage change in vena contracta (VC) at 6 months. Patients having a significant reduction of at least 30% in VC were defined as good responders (GR) and the remaining patients were defined as poor responders (PR).
After 6 months of TAVI, 27 (45%) patients were GR and 33 (55%) were PR. There was a significant decrease in 3DE-derived mitral annular diameter and area (P = 0.001), mitral valve tenting area (TA) (P = 0.05), and mitral papillary muscle dyssynchrony index (DSI) (P = 0.05) in the GR group. 3DE-derived LVESV (P = 0.016), LV mass (P = 0.001) and LV DSI, (P = 0.001) were also improved 6 months after TAVI. In addition, valvulo-arterial impedance (ZVA) was significantly higher at baseline in patients with PR (P = 0.028). 3DE-derived mitral annular area (β: 0.47, P = 0.04), mitral papillary DSI (β: −0.65, P = 0.012) and ZVA (β: 0.45, P = 0.028) were the strongest independent parameters that could predict the reduction of functional MR after TAVI.
GR patients demonstrate more regression in mitral annulus area and diameter after significant decrease in high LVEDP and trans-aortic gradients with TAVI. PR patients appear to have increased baseline ZVA, mitral valve tenting and restriction in mitral valve coaptation. These factors are important for predicting the impact of TAVI on pre-existing MR.
mitral regurgitation; TAVI; valvulo-arterial incompetence; mitral valve geometry
Several severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose.
We conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration.
Compared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30–60) and 18 % (90 % CI 108–129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63–75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study.
Although it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.