Partner support for smoking cessation during pregnancy: a systematic review.
Pregnancy is a key time to leverage receptivity to smoking reduction or cessation in both pregnant women and their partners. A partner's smoking status and support for the pregnant/postpartum woman's efforts to reduce or quit smoking may impact her smoking behavior. A systematic literature review of interventions to enhance partner support for pregnant/postpartum women's smoking reduction or cessation and cessation treatments for the partners themselves identified 855 unique references, which were examined for relevance, yielding 9 intervention studies. This narrative review analyzed a range of interventions including mass media campaigns, ultrasound scans, video, self-help manuals, counselling, and nicotine replacement therapies (NRTs) aimed at pregnant women and/or their partners. One randomized controlled trial (RCT) showed significant results for an intervention, which included a partner-targeted component in which pregnant women received health counselling, video and printed information, while partners received a booklet explaining the importance of quitting together. Three studies (1 RCT cluster, 1 pre-post test, 1 RCT) demonstrated no effect in improving smoking cessation among pregnant women. Two RCTs included free NRTs, telephone counselling, and multiple contacts as components of effective intervention for male partners, but impact on overall quit rates may not be sustainable postpartum. Seven studies (4 pre-post test, 2 RCT, 1 RCT cluster) found no effect of the intervention on partner smoking cessation. Despite the importance of partner smoking, there are very few effective smoking cessation interventions for pregnant/postpartum women that include or target male partners, suggesting the need for further intervention development and research to establish the utility of this approach.


[Dendritic potentials in granular cells of carp olfactory bulbs].
Fast prepotentials in the granular interneurons of carp olfactory bulb were recorded by means of intracellular microelectrodes. Data are presented indicating that fast prepotentials are generated in the electrogenic membrane of granular cell dendrites. It is supposed that dendritic spikes play an important role in the inhibitory synaptic influences of granular cells upon secondary olfactory neurons.


The vitamin D system: a crosstalk between the heart and kidney.
Chronic kidney disease (CKD) independently increases the rates of cardiovascular disease, whereas the severity of kidney disease correlates with increased cardiovascular morbidity and death. Vitamin D is modified in the liver and the kidney to its active form (1,25-dihydroxyvitamin D) by the 25-hydroxy vitamin D 1-hydroxylase enzyme (CYP27B1). The activated vitamin D brings about its actions through the vitamin D receptor (VDR). The VDRs and CYP27B1 have recently been shown to be expressed in several tissues, not directly involved in mineral homeostasis, including the cardiovascular, immune, and epithelial systems. The action of vitamin D in these tissues is implicated in the regulation of endothelial, vascular smooth muscle, and cardiac cell function, the renin-angiotensin system, inflammatory and fibrotic pathways, and immune response. Impaired VDR activation and signalling results in cellular dysfunction in several organs and biological systems, which leads to reduced bone health, an increased risk for epithelial cancers, metabolic disease, and uncontrolled inflammatory responses. Failure of cardiovascular VDR activation results in hypertension, accelerated atherosclerosis and vascular calcification, cardiac hypertrophy with vascular rarification and fibrosis, and progressive renal dysfunction. An emerging body of evidence has prompted attention to the relationship between CKD, mineral bone disorder (CKD-MBD), and cardiovascular disease in the new guidelines from Kidney Disease: Improving Global Outcomes. Vitamin D receptor activators, commonly used to treat CKD-MBD, and an appropriate treatment of vitamin D hormonal system failure in patients with CKD, may help to reduce cardiovascular morbidity and mortality in these patients.


Financial sustainability of academic health centers: identifying challenges and strategic responses.
Academic health centers (AHCs) play a vital role in the health care system. The training of health care personnel and delivery of health care services, especially to the most complex and financially challenged patients, has been a responsibility increasingly shouldered by AHCs over the years. Additionally, AHCs play a significant role in researching and developing new treatment protocols, including discovering and validating new health technologies. However, AHCs face unique financial challenges in fulfilling their social mission in the health care system. Reforms being implemented under the Affordable Care Act and shifting economic patterns are threatening the financial sustainability of AHCs.The authors review challenges facing AHCs, including training new health care professionals with fewer funding resources, disproportionate clinical care of complex and costly patients, charity care to uninsured and underinsured, and reduced research funding opportunities. Then, they provide a review of some potential solutions to these challenges, including new reimbursement methods, improvements in operational efficiency, price regulation, subsidization of education, improved decision making and communication, utilization of industrial management tools, and increasing internal and external cooperation. Devising solutions to the evolving problems of AHCs is crucial to improving health care delivery in the United States. Most likely, a combination of market, government, and system reforms will be needed to improve the viability of AHCs and assist them in fulfilling their social and organizational missions.


A possible new oxidation marker for hair adulteration: Detection of PTeCA (1H-pyrrole-2,3,4,5-tetracarboxylic acid) in bleached hair.
Hair analysis has become a valuable tool in forensic toxicology to assess drug or alcohol abstinence. Yet, hair adulteration by cosmetic products presents a major challenge for forensic hair analysis. Oxidative treatments, e.g. bleaching, may lead to analyte loss and thereby to false negative results. Currently, the eumelanin degradation product 1H-pyrrole-2,3,5-tricarboxylic acid (PTCA) serves as a marker for oxidative hair treatment, but requires the definition of cut-off values. To investigate further eumelanin degradation products as markers for oxidative hair treatment, hair samples with and without in vitro bleaching (hydrogen peroxide (H2 O2 ) concentrations 1.9% up to 12%; incubation times 15 min, 30 min, 60 min) were analyzed by liquid chromatography coupled to high-resolution time of flight mass spectrometry (HPLC-HRMS). The distribution of eumelanin degradation products along the hair shaft was investigated for routine applicability after segmentation of cosmetically untreated hair samples and authentically treated hair samples. The signals of the eumelanin degradation products PTCA, 1H-pyrrole-2,3,4-tricarboxylic acid (isoPTCA), and 1H-pyrrole-2,3,4,5-tetracarboxylic acid (PTeCA) were found to be significantly elevated after in vitro bleaching already with low H2 O2 concentrations and after short incubation times. In contrast to PTCA and isoPTCA, PTeCA was not detectable in cosmetically untreated segments up to 12 cm from hair root and was only formed through the oxidation process. The results of the study show that the detection of PTeCA within the proximal 3 to 6 cm segment can be applied to reliably detect hair adulteration attempts through hair bleaching.


Posterior musculofascial reconstruction after radical prostatectomy: a systematic review of the literature.
In 2001, Rocco et al. described a surgical technique whose aim was the reconstruction of the posterior musculofascial plate after radical prostatectomy (RP) to improve early return to urinary continence. Since then, many surgeons have applied this technique-either as it was described or with some modification-to open, laparoscopic, and robot-assisted RP. To review the outcomes reported in comparative studies analysing the influence of reconstruction of the posterior aspect of the rhabdosphincter after RP. The main outcome evaluated was urinary continence at 3-7 d, 30-45 d, 90 d, 180 d, and 1 yr after catheter removal. A systematic review of the literature was performed in November 2011, searching the Medline, Embase, Scopus, and Web of Science databases. A "free-text" protocol using the terms posterior reconstruction of the rhabdosphincter, posterior rhabdosphincter, and early continence was applied. Studies published only as abstracts and reports from meetings were not included in this review. One thousand seven records were retrieved from the Medline database, 1541 from the Embase database, 1357 from the Scopus database, and 1041 from the Web of Science database. The authors reviewed the records to identify studies comparing cohorts of patients who underwent RP with or without restoration of the posterior aspect of the rhabdosphincter. Only papers evaluating use of this technique as the only technical modification among the groups were included. A cumulative analysis was conducted using Review Manager v.5.1 software (Cochrane Collaboration, Oxford, UK). Eleven studies were identified in the literature search, including two randomised controlled trials (RCTs), which were negative studies. The cumulative analysis of comparative studies showed that reconstruction of the posterior musculofascial plate improves early return of continence within the first 30 d after RP (p=0.004), while continence rates 90 d after surgery are not affected by use of the reconstruction technique. The statistical significance of the reconstruction seems to decrease when higher continence rates are reported. Use of posterior rhabdosphincter reconstruction does not seem to be related to positive surgical margin (PSM) rates or with complications like acute urinary retention (AUR) and bladder neck stricture (BNS). Some studies suggested lower anastomotic leakage rates with the posterior musculofascial plate reconstruction technique. The role of reconstruction of the posterior musculofascial plate in terms of earlier continence recovery is encouraging but still controversial. Methodological flaws and poor surgical standardisation seem to be the major causes. In two RCTs and one parallel (not randomised) group trial, posterior rhabdosphincter reconstruction offered no significant advantage for return of early continence after RP. No significant complications related to the posterior musculofascial plate reconstruction technique have been reported so far. A multicentre RCT is necessary to clarify the possible role of the technique in terms of earlier continence recovery.


Molecular selectivity in aquaporin channels studied by the 3D-RISM theory.
The three-deimensional distribution functions (3D-DFs) and potentials of mean force (PMFs) of small neutral molecules inside the two aquaporin channels, AQP1 and GlpF, are calculated based on the 3D-RISM theory, the statistical mechanics theory of molecular liquids, in order to investigate the permeability of those ligands through the channels. The ligands investigated are neon (Ne), carbon dioxide (CO(2)), nitric oxide (NO), ammonia (NH(3)), urea, and glycerol. Neon shows continuous distribution throughout the channel pore in AQP1 as is the case of water, although the PMF of Ne at the selective filter (SF) region is higher than that of water, indicating that the stability of molecules in the channel is determined not only by their size, but also by the charge distribution. The ligand molecules, CO(2), NO, urea, and glycerol, have a large barrier in PMF at the SF region in AQP1, indicating that the channel is not permeable by those ligands. On the other hand, NH(3) has only a small activation barrier, approximately 2.5 kJ/mol, to be overcome. Therefore, our theory predicts that a NH(3) molecule can be permeated through the AQP1 channel. In GlpF, all the ligands have negative PMF throughout the channel pore except for glycerol, which has a small barrier at the SF area, approximately 2.1 kJ/mol. The barrier can be readily overcome by the thermal motion. So, our results are quite consistent with the experiments for urea and glycerol, for which the corresponding data are available. The results obtained by the 3D-RISM theory show striking differences from those obtained by the MD simulations, especially in the case of GlpF. Possible causes of the difference in the results between the two methods are discussed.


Knowledge and attitude towards personal health care and menopause among women with ischemic heart disease undergoing coronary angiography.
The aim of this study was to assess the knowledge, perception, and attitude towards personal health care and menopause among women with ischemic heart disease. The study population consisted of 100 menopausal women attending the cardiac unit for coronary angiography. All women completed a 20-item questionnaire, covering information on health-care habits, life style and attitude towards menopause. About half of the study population had ever smoked, were overweight, had never tried to lose weight and did not exercise regularly. The majority regularly underwent screening mammography, Pap smear and lipid profile measurement. There was a positive statistically significant correlation between years of education and having annual mammography, Pap smear and lipid profile, performing breast self-examinations and taking an annual vacation. Sixty eight per cent of the study population had never used hormone replacement therapy (HRT), 13.2% had used HRT in the past and 18.8% were currently using HRT. There was a negative statistically significant correlation between use of HRT and age and number of children, and a positive statistically significant correlation between use of HRT and having an annual Pap smear and mammography scan. Only a relatively small percentage of the study population safeguarded their health care or used HRT. We believe that stronger efforts are needed to promote good health-related behaviors for these women.


Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect.
We have recently reported that interferon gamma receptor deficient (IFNγR-/-) allogeneic donor T cells result in significantly less graft-versus-host disease (GvHD) than wild-type (WT) T cells, while maintaining an anti-leukemia or graft-versus-leukemia (GvL) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that IFNγR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells. Since IFNγR signaling is mediated via JAK1/JAK2, we tested the effect of JAK1/JAK2 inhibition on GvHD. While we demonstrated that pharmacologic blockade of JAK1/JAK2 in WT T cells using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), resulted in a similar effect to IFNγR-/- T cells both in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-HSCT), it remains to be determined if in vivo administration of INCB018424 will result in preservation of GvL while reducing GvHD. Here, we report that INCB018424 reduces GvHD and preserves the beneficial GvL effect in two different murine MHC-mismatched allo-HSCT models and using two different murine leukemia models (lymphoid leukemia and myeloid leukemia). In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/JAK2 inhibitors, such as TG101348 or AZD1480. These data suggest that pharmacologic inhibition of JAK1/JAK2 might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and overcome HLA-barriers in allo-HSCT. It might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases.


Risk Factors for Prolonged Opioid Use After Open Treatment of Distal Radius Fractures.
The objective of this study was to evaluate factors associated with postoperative opioid use after open treatment of distal radius fractures. The Humana insurance claims database was queried for open treatment of distal radius fractures by Current Procedural Terminology codes. The search was further refined to identify patients who filled an opioid prescription within 6 weeks after their surgery. The study's outcomes were: (1) limited postoperative opioid use, defined as filling a prescription once in the 6-week to 6-month period after surgery; and (2) persistent postoperative opioid use, defined as filling a prescription more than once in the 6-week to 6-month period after surgery. Logistic regression models were performed to identify factors associated with limited and persistent postoperative opioid use. Subgroup analyses were performed among opioid-naïve patients and those with open fractures. This study identified 9141 of 19 220 total patients with limited and persistent opioid use. Significant risk factors included nonhome discharge, inpatient surgical setting, long-term pain, tobacco abuse, and age less than 65 years. Of note, both preoperative opioid use within 1 month before surgery (odds ratio [OR], 2.6; 95% confidence interval [CI], 2.2-2.9) and preoperative opioid use between 1 and 6 months before surgery (OR, 4.0; 95% CI, 3.7-4.4) were significantly associated with persistent postoperative opioid use. This study has identified numerous risk factors associated with postoperative opioid use after open treatment of distal radius fractures. Understanding these risk factors is the first step toward reducing postoperative opioid use.


Discrete choice experiment exploring women's preferences in a novel device designed to monitor the womb environment and improve our understanding of reproductive disorders.
The study aims to determine the relative importance of key attributes of a novel intrauterine device. The device monitors uterine oxygen, pH and temperature in real time with the aim of improving our understanding and treatment of reproductive disorders. A discrete choice experiment was used to elicit preferences in this novel investigative tool. The attributes and levels used in the choice scenarios were length of time using the device (7, 14 or 28 days), information obtained to guide treatment (limited, majority or all cases), risk of complications (1% or 10%) and discreteness (completely discrete, moderately discrete or indiscrete). Secondary care hospital in Hampshire, UK. 361 women of reproductive age. Conditional logit and latent class logit regression models to determine the preference for each attribute. Conditional logit coefficients allow comparison between attributes; women placed most importance on obtaining information to guide treatment in all cases (2.771), followed by having a completely discrete device (1.104), reducing risk of complications by 1% (0.184) and decreased length of time by 1 day (0.0150). All coefficients p<0.01. Latent class conditional logit assigns participants to two classes with 27.4% in class 1 who are less likely to have higher education or qualify for National Health Service-funded in vitro fertilisation compared with class 2. Those in class 2 placed 1.7 times more importance on a device whose information guided treatment in all cases and a 1% decrease in complications risk was nearly 15 times more attractive. Women placed most importance on having a device that obtains information to guide treatment and are willing to use the device for a longer, have a device with higher risk of complications and an indiscrete device if it is able to provide answers and direction for treatment of their reproductive disorder.


[Serum testosterone and cardiovascular disease in men].
Cardiovascular diseases (CVD) represent the main cause of death in Brazil. Men die more of coronary artery disease and they have higher levels of testosterone than women. However, recent studies indicate that androgens can have beneficial and/or neutral effect in the male cardiovascular system. Low levels of endogenous testosterone have been involved with the presence of some components of the metabolic syndrome including dyslipidemia, visceral obesity, hypertension and thrombus formation process. Consistent data on the relationship between testosterone and vascular reactivity, atherosclerosis and cardiovascular mortality in men are rare, with the results of available studies presenting contradictions. Large randomized and prospective trials are needed to evaluate androgen-specific function in male CVD so that better conclusions can be established.


Bird-Inspired Self-Navigating Artificial Synaptic Compass.
Extrasensory neuromorphic devices that can recognize, memorize, and learn stimuli imperceptible to human beings are of considerable interest in interactive intelligent electronics research. This study presents an artificially intelligent magnetoreceptive synapse inspired by the magnetocognitive ability used by birds for navigation and orientation. The proposed synaptic platform is based on arrays of ferroelectric field-effect transistors with air-suspended magneto-interactive top-gates. A suspended gate of an elastomeric composite with superparamagnetic particles laminated with an electrically conductive polymer is mechanically deformed under a magnetic field, facilitating control of the magnetic-field-dependent contact area of the suspended gate with an underlying ferroelectric layer. The remanent polarization of the ferroelectric layer is electrically programmed with the deformed suspended gate, resulting in analog conductance modulation as a function of the magnitude, number, and time interval of the input magnetic pulses. The proposed extrasensory magnetoreceptive synapse may be used as an artificially intelligent synaptic compass that facilitates barrier-adaptable navigation and mapping of a moving object.


Activator protein-1 activity regulates epithelial tumor cell identity.
To examine the consequences of inhibiting activator protein-1 (AP-1) transcription factors in skin, transgenic mice were generated, which use the tetracycline system to conditionally express A-FOS, a dominant negative that inhibits AP-1 DNA binding. Older mice develop mild alopecia and hyperplasia of sebaceous glands, particularly around the eyes. When A-FOS was expressed during chemical-induced skin carcinogenesis, mice do not develop characteristic benign and malignant squamous lesions but instead develop benign sebaceous adenomas containing a signature mutation in the H-ras proto-oncogene. Inhibiting AP-1 activity after tumor formation caused squamous tumors to transdifferentiate into sebaceous tumors. Furthermore, reactivating AP-1 in sebaceous tumors results in a reciprocal transdifferentiation into squamous tumors. In both cases of transdifferentiation, individual cells express molecular markers for both cell types, indicating individual tumor cells have the capacity to express multiple lineages. Molecular characterization of cultured keratinocytes and tumor material indicates that AP-1 regulates the balance between the wnt/beta-catenin and hedgehog signaling pathways that determine squamous and sebaceous lineages, respectively. Chromatin immunoprecipitation analysis indicates that c-Jun binds several wnt promoters, which are misregulated by A-FOS expression, suggesting that members of the wnt pathway can be a primary targets of AP-1 transcriptional regulation. Thus, AP-1 activity regulates tumor cell lineage and is essential to maintain the squamous tumor cell identity.


An integrated transcriptomic and comparative genomic analysis of differential gene expression in Arctic charr (Salvelinus alpinus) following seawater exposure.
High-throughput RNA sequencing was used to compare expression profiles in two Arctic charr (Salvelinus alpinus) families post-seawater exposure to identify genes and biological processes involved in hypo-osmoregulation and regulation of salinity tolerance. To further understand the genetic architecture of hypo-osmoregulation, the genomic organization of differentially expressed (DE) genes was also analysed. Using a de novo gill transcriptome assembly we found over 2300 contigs to be DE. Major transporters from the seawater mitochondrion-rich cell (MRC) complex were up-regulated in seawater. Expression ratios for 257 differentially expressed contigs were highly correlated between families, suggesting they are strictly regulated. Based on expression profiles and known molecular pathways we inferred that seawater exposure induced changes in methylation states and elevated peroxynitrite formation in gill. We hypothesized that concomitance between DE immune genes and the transition to a hypo-osmoregulatory state could be related to Cl(-) sequestration by antimicrobial defence mechanisms. Gene ontology analysis revealed that cell division genes were up-regulated, which could reflect the proliferation of ATP1α1b-type seawater MRCs. Comparative genomics analyses suggest that hypo-osmoregulation is influenced by the relative proximities among a contingent of genes on Arctic charr linkage groups AC-4 and AC-12 that exhibit homologous affinities with a region on stickleback chromosome Ga-I. This supports the hypothesis that relative gene location along a chromosome is a property of the genetic architecture of hypo-osmoregulation. Evidence of non-random structure between hypo-osmoregulation candidate genes was found on AC-1/11 and AC-28, suggesting that interchromosomal rearrangements played a role in the evolution of hypo-osmoregulation in Arctic charr.


Prostatic inflammation induces urinary frequency in adult mice.
Lower urinary tract symptoms (LUTS) including urinary frequency and nocturia are common in aging men. Recent studies have revealed a strong association of prostatic inflammation with LUTS. We developed an animal model of bacterial induced, isolated prostatic inflammation and examined the effect of prostatic inflammation on voiding behavior in adult C57BL/6J mice. Prostatic inflammation was induced by transurethral inoculation of uropathogenic E. coli-1677. Bacterial cystitis was prevented by continuous administration of nitrofurantoin. Hematoxylin and eosin (H&E) staining and bacterial culture were preformed to validate our animal model. Voiding behavior was examined by metabolic cage testing on post-instillation day 1 (PID 1), PID 4, PID 7 and PID 14 and both voiding frequency and volume per void were determined. Mice with prostatic inflammation showed significantly increased voiding frequency at PID 1, 7 and 14, and decreased volume per void at all time points, as compared to mice instilled with saline and receiving nitrofurantoin (NTF). Linked analysis of voiding frequency and voided volumes revealed an overwhelming preponderance of high frequency, low volume voiding in mice with prostatic inflammation. These observations suggest that prostatic inflammation may be causal for symptoms of urinary frequency and nocturia.


Spectrum of severity of multisystem inflammatory syndrome in children: an EHR-based cohort study from the RECOVER program.
Multi-system inflammatory syndrome in children (MIS-C) is a severe post-acute sequela of SARS-CoV-2 infection in children, and there is a critical need to unfold its highly heterogeneous disease patterns. Our objective was to characterize the illness spectrum of MIS-C for improved recognition and management. We conducted a retrospective cohort study using data from March 1, 2020-September 30, 2022, in 8 pediatric medical centers from PEDSnet. We included 1139 children hospitalized with MIS-C and used their demographics, symptoms, conditions, laboratory values, and medications for analyses. We applied heterogeneity-adaptive latent class analyses and identified three latent classes. We further characterized the sociodemographic and clinical characteristics of the latent classes and evaluated their temporal patterns. Class 1 (47.9%) represented children with the most severe presentation, with more admission to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 (23.3%) represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 (28.8%) represented a mild presentation. Our results indicated that MIS-C has a spectrum of clinical severity ranging from mild to severe and the proportion of severe or critical MIS-C decreased over time.


Thresholdless quantum dot nanolaser.
Thresholdless lasing is an outstanding challenge in laser science and is achievable only in devices having near unity quantum efficiency even when not lasing. Such lasers are expected to exhibit featureless linear light output curves. However, such thresholdless behavior hinders identification of the laser transition, triggering a long-lasting argument on how to identify the lasing. Here, we demonstrate thresholdless lasing in a semiconductor quantum dot nanolaser with a photonic crystal nanocavity. We employ cavity resonant excitation for enabling the thresholdless operation via focused carrier injection into high cavity field regions. Under conventional (above bandgap) excitation, the same nanolaser exhibits a typical thresholded lasing transition, thereby facilitating a systematic comparison between the thresholdless and thresholded laser transitions in the single device. Our approach enables a clear verification of the thresholdless lasing and reveals core elements for its realization using quantum dots, paving the way to the development of ultimately energy-efficient nanolasers.


The Role of Oxalic Acid in New Particle Formation from Methanesulfonic Acid, Methylamine, and Water.
Atmospheric particles are notorious for their effects on human health and visibility and are known to influence climate. Though sulfuric acid and ammonia/amines are recognized as main contributors to new particle formation (NPF), models and observations have indicated that other species may be involved. It has been shown that nucleation from methanesulfonic acid (MSA) and amines, which is enhanced with added water, can also contribute to NPF. While organics are ubiquitous in air and likely to be involved in NPF by stabilizing small clusters for further growth, their effects on the MSA-amine system are not known. This work investigates the effect of oxalic acid (OxA) on NPF from the reaction of MSA and methylamine (MA) at 1 atm and 294 K in the presence and absence of water vapor using an aerosol flow reactor. OxA and MA do not efficiently form particles even in the presence of water, but NPF is enhanced when adding MSA to OxA-MA with and without water. The addition of OxA to MSA-MA mixtures yields a modest NPF enhancement, whereas the addition of OxA to MSA-MA-H2O has no effect. Possible reasons for these effects are discussed.


The relevance and application of disease management and pharmacoeconomics to migraine.
Disease management is a comprehensive approach to improving the outcomes for patients suffering from chronic disease. It has frequently been applied to diseases like diabetes and asthma but, to date, has not widely been regarded as particularly relevant to migraine. Yet a number of factors suggest that this view might usefully be reconsidered, notably the dissatisfaction with migraine control expressed by many patients and the inconsistencies in treatment patterns observed across clinical practice. Another factor is the growing range of therapeutic options available to manage the disorder. In this latter respect, decision-making must not only be governed by individual patient needs, but also by considerations of clinical cost effectiveness. Pharmacoeconomic analysis can play a useful role in determining the relative value for money offered by different treatments and is increasingly being applied in migraine. It is clear, however, that full realisation of its potential contribution requires progress to be made in a number of key areas, perhaps most importantly agreement on the definition of successful treatment.


Humans with traumatic brain injuries show place-learning deficits in computer-generated virtual space.
Spatial learning and memory has been linked to the hippocampus and temporal lobes and though these areas are often damaged in traumatic brain injury (TBI), spatial learning deficits after TBI have not received much attention. In the present study, a virtual environment was used to challenge people with TBI to solve a task comparable to the Morris water maze, which in turn has been shown to be highly sensitive to hippocampal and frontal lobe dysfunction in laboratory animals. A regular computer monitor was used to present 12 participants with TBI and 12 age- and sex-matched comparison participants with a computer-generated, three-dimensional "virtual arena maze," consisting of a large round arena within a very large square room. Participants were required to learn the place of an invisible target on the floor of the room based solely on distal cues on the walls of the room. Eight of the 12 participants with moderate to severe TBI showed substantial place-learning deficits in comparison to the uninjured participants. Performance in the virtual environment correlated with self-reported frequency of wayfinding problems in everyday life and with scores on a test of episodic memory, the Rivermead Behavioural Memory Task. These data confirm that deficits in spatial learning and memory follow TBI, and suggest that the virtual arena maze may provide a new method for objectively assessing them.


MicroRNA-based regulation of Aurora A kinase in breast cancer.
The involvement of non-coding RNAs (ncRNAs) in cellular physiology and disease pathogenesis is becoming increasingly relevant in recent years specifically in cancer research. Breast cancer (BC) has become a health concern and accounts for most of the cancer-related incidences and mortalities reported amongst females. In spite of the presence of promising tools for BC therapy, the mortality rate of metastatic BC cases is still high. Therefore, the genomic exploration of the BC subtype and the use of ncRNAs for possible regulation is pivotal. The expression and prognostic values of AURKA gene were assessed by Oncomine, GEPIA, KM-plotter, and bc-GenExMiner v4.4, respectively. Associated proteins and functional enrichment were evaluated by Cytoscape and DAVID databases. Additionally, molecular docking approach was employed to investigate the regulatory role of hsa-miR-32-3p assisted argonaute (AGO) protein of AURKA gene in BC. AURKA gene was highly expressed in patients with BC relative to normal counterpart and significantly correlated with poor survival. The docking result suggested that AURKA could be regulated by hsa-miR-32-3p as confirmed by the reported binding energy and specific interactions. The study gives some insights into role of AURKA and its regulation by microRNAs through AGO protein. It also provides exciting opportunities for cancer therapeutic intervention.


Sperm velocity and longevity trade off each other and influence fertilization in the sea urchin Lytechinus variegatus.
The theoretical prediction that fast sperm should be more effective at fertilizing eggs has never been documented empirically. Interspecific comparisons suggest an inverse relationship between sperm velocity and sperm longevity but this trade-off has never been demonstrated within a species. Here I investigate how sperm velocity and sperm longevity influence the patterns of fertilization in the sea urchin Lytechinus variegatus. In the laboratory I examined 11 male female pairs of sea urchins for variation in sperm velocity and sperm longevity, and determined the correlations of these traits with the percentage of eggs fertilized with serially diluted sperm. Males with faster sperm had higher rates of fertilization than males with slower sperm. Within individual males, as sperm aged they slowed down and showed a reduced percentage activity and lower rates of fertilization. Across males, the average velocity of freshly spawned sperm was inversely related to sperm longevity. These results establish the possibility that sperm traits are adapted for varying conditions along a continuum from sperm limitation to sperm competition.


Application of bio-orthogonal proteome labeling to cell transplantation and heterochronic parabiosis.
Studies of heterochronic parabiosis demonstrated that with age, the composition of the circulatory milieu changes in ways that broadly inhibit tissue regenerative capacity. In addition, local tissue niches have age-specific influences on their resident stem cells. Here we use bio-orthogonal proteome labeling for detecting in vivo proteins present only in transplanted myoblasts, but not in host tissue, and proteins exclusive to one young mouse and transferred during parabiosis to its old partner. We use a transgenic mouse strain that ubiquitously expresses a modified tRNA methionine synthase, metRS, which preferentially incorporates the methionine surrogate azido-nor-leucine (ANL) into newly generated proteins. Using click chemistry and a modified antibody array to detect ANL-labeled proteins, we identify several 'young' systemic factors in old regenerating muscle of the heterochronic parabiotic partners. Our approach enables the selective profiling of mammalian proteomes in mixed biological environments such as cell and tissue transplantation, apheresis or parabiosis.Clarifying the source of proteins in mixed biological environments, such as after transplantation or parabiosis, remains a challenge. Here, the authors address this need with a mouse strain that incorporates a methionine derivate into proteins, allowing for their detection using click chemistry and antibody arrays.


Hyperfibrinolysis in Patients with Solid Malignant Neoplasms: A Systematic Review.
Solid malignant neoplasms have the capability of disturbing the fibrinolytic system, leading to primary hyperfibrinolysis, a paraneoplastic syndrome that potentially results in severe bleeding. Yet, the full extent of primary hyperfibrinolysis in solid malignant neoplasms is unknown. Thus, the purpose of this study was to systematically review the current literature regarding clinical manifestations, biochemical diagnosis, and treatment of primary hyperfibrinolysis in patients with solid malignant neoplasms. The review was performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Embase, Scopus, and Web of Science were searched on December 5, 2019, without time limits. Studies were included if they comprised at least one biochemical marker of fibrinolysis in addition to fibrinogen degradation products such as D-dimer, and furthermore included a correlation between biochemical marker and clinical outcome. In total, 12 studies were included. All studies were case reports including a total of 21 patients. Prostate cancer was the most frequently represented cancer type (76%), and the majority of cancer patients had metastatic disease (81%). Spontaneous bleeding was the clinical presentation in the majority of patients (76%), and the most frequently localization for the bleedings was subcutaneous. Antifibrinolytic agents were the most commonly used treatment and ceased bleedings in 80% of patients. Three patients died of uncontrolled bleedings. In conclusion, primary hyperfibrinolysis induced by solid malignant neoplasms is a rare but potentially life-threatening condition that should be considered, especially in patients with metastatic disease presenting with serious, spontaneous subcutaneous bleedings. A standardized diagnostic strategy is strongly needed.


Favorable liver cancer mortality-to-incidence ratios of countries with high health expenditure.
Health expenditure is a marker associated with an advanced healthcare system, which contributes toward the good prognosis of patients. Mortality-to-incidence ratios (MIRs) are one of the predictors that reflect the prognosis of cancer patients. There remains some uncertainty on the correlation of MIRs of liver cancer with the health expenditure of countries. We therefore analyzed the correlation of MIRs from the GLOBOCAN 2012 database with the WHO rankings and the total expenditures on health/gross domestic product from WHO by linear regression analyses. A total of 29 countries were selected in this study according to the data quality and the incidence number. The results showed high rates of incidence/mortality and MIRs in less developed regions (0.92 vs. 0.96 for more vs. less developed regions). Among the continents, Asia has the highest incidence/mortality in case number, crude rate, and age-standardized rate. In terms of the MIR, Northern America has the lowest MIR and Latin America and the Caribbean have the highest MIRs (0.82 and 1.04, respectively). Finally, favorable MIRs are associated significantly with good WHO ranking and high expenditures on gross domestic product (P=0.048 and 0.025, respectively). The MIR variation for liver cancer is thus found to be associated with the health expenditure and WHO ranking.


Neutralization of placental growth factor as a novel treatment option in diabetic retinopathy.
The current standard of care in clinical practice for diabetic retinopathy (DR), anti-vascular endothelial growth factor (VEGF) therapy, has shown a significant improvement in visual acuity. However, treatment response can be variable and might be associated with potential side effects. This study was designed to investigate inhibition of placental growth factor (PlGF) as a possible alternative therapy for DR. The effect of the anti-PlGF antibody (PL5D11D4) was preclinically evaluated in various animal models by investigating different DR hallmarks, including inflammation, neurodegeneration, vascular leakage and fibrosis. The in vivo efficacy was tested in diabetic streptozotocin (STZ) and Akimba models and in the laser induced choroidal neovascularization (CNV) mouse model. Intravitreal (IVT) administration of the anti-PlGF antibody was compared to anti-VEGFR-2 antibody (DC101), anti-VEGF antibody (B20), VEGF-Trap (aflibercept) and triamcinolone acetonide (TAAC). Vascular leakage was investigated in the mouse STZ model by fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) perfusion and in the Akimba model by fluorescein angiography (FA). Repeated IVT administration of the anti-PlGF antibody reduced vascular leakage, which was comparable to a single administration of VEGFR-2 inhibition in the mouse STZ model. PL5D11D4 treatment did not alter retinal ganglion cell (RGC) density, as demonstrated by Brn3a staining, whereas DC101 significantly reduced RGC number with 20%. Immunohistological stainings were performed to investigate inflammation (CD45, F4/80) and fibrosis (collagen type 1a). In the CNV model, IVT injection(s) of PL5D11D4 dose-dependently reduced inflammation and fibrosis, as compared to PBS treatment. Equimolar single administration of the anti-PlGF antibody and aflibercept (21 nM) and TAAC decreased leukocyte and macrophage infiltration with 50%, whereas DC101 and B20 (21 nM) had no effect on the inflammatory response. Similar results were observed in the mouse STZ model on the number of microglia and macrophages in the retina. Repeated administration of PL5D11D4 (21 nM) and TAAC similarly reduced fibrosis, while no effect was observed after equimolar DC101, B20 nor aflibercept administration (21 nM). In summary, the anti-PlGF antibody showed comparable efficacy as well-characterized VEGF-inhibitor on the process of vascular leakage, but differentiates itself by also reducing inflammation and fibrosis, without triggering a neurodegenerative response.


Decrease of hypothalamic neuropeptide Y gene expression by vanadyl sulfate in streptozotocin-induced diabetic rats.
In an attempt to elucidate the effect of vanadium compounds on the gene expression of neuropeptide Y (NPY), vanadyl sulfate (VOSO4) was orally administrated at the dose of 1 mg/kg body weight into streptozotocin-induced diabetic rats (STZ-diabetic rats) three times daily for 1 week. We found a marked lowering of plasma glucose with a significant decrease of food and water intake in these STZ-diabetic rats treated with VOSO4, although the weight gain was unaffected. The increase of hypothalamic NPY, both the mRNA level and peptide concentration, in STZ-diabetic rats was also reduced by this oral treatment of VOSO4. However, similar treatment of VOSO4 in normal rats failed to modify the feeding behavior and hypothalamic NPY gene expression. These data suggest that decrease of hypothalamic NPY gene expression by VOSO4 is related to the recovery of hyperphagia in diabetic rats lacking insulin.


Identification and prediction of molecular subtypes of atherosclerosis based on m6A immune cell infiltration.
Atherosclerosis is a complex disease with multiple molecular subtypes that are not yet fully understood. Recent studies have suggested that N6-methyladenosine (m6A) alterations may play a role in the pathogenesis of atherosclerosis. However, the relationship between m6A regulators and atherosclerosis remains unclear. In this study, we analyzed the expression levels of 25 m6A regulators in a cohort of atherosclerosis (AS) and non-AS patients using the R "limma" package. We also used machine learning models, including random forest (RF), support vector machine (SVM), generalized linear model (GLM), and extreme gradient boosting (XGB), to predict the molecular subtypes of atherosclerosis based on m6A immune cell infiltration. We found that METTL3, YTHDF2, IGFBP1, and IGF2BP1 were overexpressed in AS patients compared to non-AS patients, while the other significant m6A regulators showed no significant difference. Our machine learning models achieved high accuracy in predicting the molecular subtypes of atherosclerosis based on m6A immune cell infiltration. Our study suggests that m6A alterations may play a role in the pathogenesis of atherosclerosis, and that machine learning models can be used to predict molecular subtypes of atherosclerosis based on m6A immune cell infiltration. These findings may have important implications for the detection and management of atherosclerosis.


Photochemistry of a dual-bacteriorhodopsin system in Haloarcula marismortui: HmbRI and HmbRII.
Recently, a dual-bacteriorhodopsin system, containing HmbRI and HmbRII, has been found in Haloarcula marismortui (Mol. Microbiol. 2013, 88, 551-561), and the light-driven proton pump activities were intrinsically different in a wide pH range. Compared with bacteriorhodopsin in H. salinarum (HsbR), the identical steady-state absorption contours of HsbR and HmbRs in the visible range indicated similarities in the retinal pocket. In addition, other reactive residues, including the proton relay channel, proton release group, and proton collecting funnel at the cytoplasm, were mostly conserved. We employed transient absorption spectroscopy and global analysis to characterize the photocycle intermediates and kinetics of HmbRI and HmbRII in the pH range of 4-8. The features of the time-resolved difference spectra of HmbRI indicated that the photocycle of HmbRI mainly followed the conventional pathway, including intermediates M, N, and O. A minute bypassed pathway from intermediate M needed to be included to better match the experimental data. The corresponding intermediate M' is attributed to the all-trans deprotonated Schiff base retinal, indicating the occurrence of retinal reisomerization prior to the reprotonation of the deprotonated Schiff base following the decay of intermediate M. Regarding HmbRII, its photocycle only followed the intermediates M and N, without intermediate O. The plausible molecular mechanisms, including the effects of the lengths of the loops and the distribution of the charged residues in the bacterio-opsin interior, were proposed to explain the differences in the photocycles. The pH-dependent photocycles were also investigated, and the results supported our proposed mechanism. Unravelling the photocycles of the HmbRs in the Haloarcula marismortui provided evidence that not only expanding the functional pH ranges but also the turnover kinetics are the strategies of the dual-bR system in the evolution of microbes in extreme environments.


Risk of canine cranial cruciate ligament rupture is not associated with the major histocompatibility complex.
To investigate the association of the major histocompatability (MHC) class II allele haplotype frequencies with the diagnosis of cranial cruciate ligament (CCL) rupture in two breeds of dog. DNA samples from populations of Labrador Retrievers and Golden Retrievers with CCL rupture and general populations of the same breeds were characterised for three DLA class II loci (DRB1*, DQA1* and DQB1*) alleles using sequence-based typing or reference strand-mediated conformation analysis. Although distinct differences in haplotype types, frequencies and homozygozity were observed between the two breeds, no disease specific association could be identified for the development of the CCL rupture within either population. The risk for developing CCL rupture was not associated with DLA haplotype group(s) in Labrador Retrievers or Golden Retrievers, thus the hypothesis that there is an autoimmune basis to CCL rupture was not supported.


Identification and ontogenesis of beta-adrenergic receptors in fetal and neonatal rabbit myocardium.
In adult animals, beta-adrenergic receptors are involved in the regulation of myocardial contractility and heart rate. Their properties in the fetal and early neonatal period have not been adequately investigated. We have directly characterized beta-adrenergic receptors in rabbit fetal and neonatal myocardial membranes by a radioligand binding assay utilizing 125I-hydroxybenzylpindolol (I-HYP), a potent, non-specific, beta-adrenergic antagonist, I-HYP binding sites were detected as early as the 21st day of gestation (term 31 days). The binding was rapid, saturable and reversible. The dissociation constant, KD, as determined by Scatchard plots, ranged from 30 pM to 50 pM. There was a progressive increase in the density of the receptor sites with advancing gestation. Competition studies with beta-agonists and antagonists showed that the order of potency in inhibiting I-HYP binding was consistent with a beta 1-subtype of beta-adrenergic receptors. We conclude that the progressive increase in density of beta-adrenergic receptors in rabbit fetal myocardium parallels similar maturational processes occurring in other tissues with advancing gestation. It may also account for the reported developmental changes in fetal myocardial contractility.


Alterations in regulatory T-cells: rediscovered pathways in immunotoxicology.
In addition to the effector T-cells subsets, T-cells can also differentiate into cells that play a suppressive or regulatory role in adaptive immune responses. The cell types currently identified as regulatory T-cells (T(regs)) include natural or thymic-derived T(regs), T-cells which express Foxp3(+)CD25(+)CD4(+) and can suppress immune responses to autoreactive T-cells, as well as inducible T(regs), that are generated from naïve T-cells in the periphery after interaction with antigens presented by dendritic cells. Inducible T(regs) include T(H)3 cells, T(r)1 cells, and Foxp3(+)-inducible T(regs). T(regs) have been shown to be critical in the maintenance of immune responses and T-cell homeostasis. These cells play an important role in suppressing responses to self-antigens and in controlling inappropriate responses to non-self-antigens, such as commensal bacteria or food in the gut. For example, depletion of CD4(+)CD25(+) T(regs) from mice resulted in the development of multi-organ autoimmune diseases. CD4(+)CD25(+) T(regs) and/or IL-10-producing T(r)1 cells are capable of suppressing or attenuating T(H)2 responses to allergens. Moreover, adoptive transfer of CD4(+)CD25(+) T(regs) from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10- and TGFβ-producing T(r)1 cells as well as FoxP3-expressing IL-10 T-cells, with resulting suppression of the T(H)2 cytokine milieu. Activation, expansion, or suppression of CD4(+)CD25(+) T(regs) in vivo by xenobiotics, including drugs, may therefore represent a relevant mechanism underlying immunotoxicity, including immunosuppression, allergic asthma, and autoimmune diseases.


Incidence of metabolic syndrome over 9 years follow-up; the importance of sex differences in the role of insulin resistance and other risk factors.
To determine, the predictors of incident metabolic syndrome (MetS) in a community-based cohort of West Asians, during a mean follow-up of 9.3 years, a sample of 2858 non-MetS Iranian adults aged ≥ 20 years were examined at baseline and followed at three year intervals during three consecutive phases. The MetS was defined using the joint interim statement. Cox proportional hazard regression was used to determine the independent variables associated with incident MetS. Overall, 1117 new cases MetS were identified resulting in an incidence rate of 550.9/10000 person years (95% CI: 519.5-584.2). The corresponding incidence rates among women and men were 433.5/10000 person years (95% CI: 398.8-471.2) and 749.2/10000 person years (95% CI: 689.9-813.5), respectively. Baseline-adjusted predictors of developing MetS included all of the MetS components, being overweight or obese in both gender, and family history of diabetes and age only in women. There were significant effect modifications of gender on age (P<0.001), high blood pressure (0.026), high waist circumference (P<0001) and obesity categories (all P ≤ 0.01) in multivariate analysis. After considering HOMA-IR in the model, among women, all of the MetS predictors as well as those with HOMA-IR ≥ 2.23 showed a significant risk for incident MetS [HR: 1.63 (1.16-2.28)]; however, among men all the MetS components (WC was marginally significant) as well as the fourth quartile of HOMA-IR [HR: 1.50 (1.03-2.17)] and being overweight showed a significant risk. Finally, in the pooled analysis, we showed that female gender had lower risk for incident MetS than male [HR: 0.58 (0.47-0.70)]. In the Iranian population, high incidence of MetS, especially among men, was shown. Our findings confirmed that sex- specific risk predictors should be considered in primary prevention for incident MetS.


Thalassospira sp. isolated from the oligotrophic eastern Mediterranean Sea exhibits chemotaxis toward inorganic phosphate during starvation.
The eastern Mediterranean Sea represents an ultraoligotrophic environment where soluble phosphate limits the growth of bacterioplankton. Correspondingly, genes coding for high-affinity phosphate uptake systems and for organophosphonate utilization are highly prevalent in the plankton metagenome. Chemotaxis toward inorganic phosphate constitutes an alternative strategy to cope with phosphate limitation, but so far has only been demonstrated for two bacterial pathogens and an archaeon, and not in any free-living planktonic bacterium. In the present study, bacteria affiliated with the genus Thalassospira were found to constitute a regular, low-abundance member of the bacterioplankton that can be detected throughout the water column of the eastern Mediterranean Sea. A representative (strain EM) was isolated in pure culture and exhibited a strong positive chemotaxis toward inorganic phosphate that was induced exclusively in phosphate-starved cultures. Phosphate-depleted cells were 2-fold larger than in exponentially growing cultures, and 43% of the cells retained their motility even during prolonged starvation over 10 days. In addition, Thalassospira sp. strain EM was chemotactically attracted by complex substrates (yeast extract and peptone), amino acids, and 2-aminoethylphosphonate but not by sugar monomers. Similarly to the isolate from the eastern Mediterranean, chemotaxis toward phosphate was observed in starved cultures of the other two available isolates of the genus, T. lucentensis DSM 14000T and T. profundimaris WP0211T. Although Thalassospira sp. represents only up to 1.2% of the total bacterioplankton community in the water column of the eastern Mediterranean Sea, its chemotactic behavior potentially leads to an acceleration of nutrient cycling and may also explain the persistence of marine copiotrophs in this extremely nutrient-limited environment.


The NMDA-to-AMPA ratio at synapses onto layer 2/3 pyramidal neurons is conserved across prefrontal and visual cortices.
To better understand regulation of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor complements across the cortex, and to investigate NMDA receptor (NMDAR)-based models of persistent activity, we compared NMDA/AMPA ratios in prefrontal (PFC) and visual cortex (VC) in rat. Whole cell voltage-clamp responses were recorded in brain slices from layer 2/3 pyramidal cells of the medial PFC and VC of rats aged p16-p21. Mixed miniature excitatory postsynaptic currents (mEPSCs) having AMPA receptor (AMPAR)- and NMDAR-mediated components were isolated in nominally 0 Mg2+ ACSF. Averaged mEPSCs were well-fit by double exponentials. No significant differences in the NMDA/AMPA ratio (PFC: 27 +/- 1%; VC: 28 +/- 3%), peak mEPSC amplitude (PFC: 19.1 +/- 1 pA; VC: 17.5 +/- 0.7 pA), NMDAR decay kinetics (PFC: 69 +/- 8 ms; VC: 67 +/- 6 ms), or degree of correlation between NMDAR- and AMPAR-mediated mEPSC components were found between the areas (PFC: n = 27; VC: n = 28). Recordings from older rats (p26-29) also showed no differences. EPSCs were evoked extracellularly in 2 mM Mg2+ at depolarized potentials; although the average NMDA/AMPA ratio was larger than that observed for mEPSCs, the ratio was similar in the two regions. In nominally 0 Mg2+ and in the presence of CNQX, spontaneous activation of NMDAR increased recording noise and produced a small tonic depolarization which was similar in both areas. We conclude that this basic property of excitatory transmission is conserved across PFC and VC synapses and is therefore unlikely to contribute to differences in firing patterns observed in vivo in the two regions.


Surface Chemistry Interactions of Cationorm with Films by Human Meibum and Tear Film Compounds.
Cationorm® (CN) cationic nanoemulsion was demonstrated to enhance tear film (TF) stability in vivo possibly via effects on tear film lipid layer (TFLL). Therefore the interactions of CN with human meibum (MGS) and TFLL in vitro and in vivo deserve special study. MGS and CN were spread at the air/water interface of a Langmuir surface balance to ensure a range of MGS/CN oil phase ratios: 20/1, 10/1, 5/1, 3/1, 2/1 and 1/1. The films capability to reorganize during dynamic area changes was evaluated via the surface pressure-area compression isotherms and step/relaxation dilatational rheology studies. Films structure was monitored with Brewster angle microscopy. CN/TFLL interactions at the ocular surface were monitored with non-contact specular microscopy. The in vitro studies of MGS/CN layers showed that (i) CN inclusion (at fixed MGS content) increased film elasticity and thickness and that (ii) CN can compensate for moderate meibum deficiency in MGS/CN films. In vivo CN mixed with TFLL in a manner similar to CN/MGS interactions in vitro, and resulted in enhanced thickness of TFLL. In vitro and in vivo data complement each other and facilitated the study of the composition-structure-function relationship that determines the impact of cationic nanoemulsions on TF.


Risk Factors for Lateral Ankle Sprains and Chronic Ankle Instability.
Lateral ankle sprains (LASs) are a common injury sustained by individuals who participate in recreational physical activities and sports. After an LAS, a large proportion of individuals develop long-term symptoms, which contribute to the development of chronic ankle instability (CAI). Due to the prevalence of LASs and the propensity to develop CAI, collective efforts toward reducing the risk of sustaining these injuries should be a priority of the sports medicine and sports physiotherapy communities. The comprehensive injury-causation model was developed to illustrate the interaction of internal and external risk factors in the occurrence of the inciting injury. The ability to mitigate injury risk is contingent on a comprehensive understanding of risk factors for injury. The objective of this current concepts review is to use the comprehensive injury-causation model as a framework to illustrate the risk factors for LAS and CAI based on the literature.


EPIMUTESTR: a nearest neighbor machine learning approach to predict cancer driver genes from the evolutionary action of coding variants.
Discovering rare cancer driver genes is difficult because their mutational frequency is too low for statistical detection by computational methods. EPIMUTESTR is an integrative nearest-neighbor machine learning algorithm that identifies such marginal genes by modeling the fitness of their mutations with the phylogenetic Evolutionary Action (EA) score. Over cohorts of sequenced patients from The Cancer Genome Atlas representing 33 tumor types, EPIMUTESTR detected 214 previously inferred cancer driver genes and 137 new candidates never identified computationally before of which seven genes are supported in the COSMIC Cancer Gene Census. EPIMUTESTR achieved better robustness and specificity than existing methods in a number of benchmark methods and datasets.


The International Classification of Functioning, Disability and Health (ICF) in Electronic Health Records. A Systematic Literature Review.
The International Classification of Functioning, Disability and Health (ICF) is the World Health Organization's standard for describing health and health-related states. Examples of how the ICF has been used in Electronic Health Records (EHRs) have not been systematically summarized and described yet. To provide a systematic review of peer-reviewed literature about the ICF's use in EHRs, including related challenges and benefits. Peer-reviewed literature, published between January 2001 and July 2015 was retrieved from Medline®, CINAHL®, Scopus®, and ProQuest® Social Sciences using search terms related to ICF and EHR concepts. Publications were categorized according to three groups: Requirement specification, development and implementation. Information extraction was conducted according to a qualitative content analysis method, deductively informed by the evaluation framework for Health Information Systems: Human, Organization and Technology-fit (HOT-fit). Of 325 retrieved articles, 17 publications were included; 4 were categorized as requirement specification, 7 as development, and 6 as implementation publications. Information regarding the HOT-fit evaluation framework was summarized. Main benefits of using the ICF in EHRs were its unique comprehensive perspective on health and its interdisciplinary focus. Main challenges included the fact that the ICF is not structured as a formal terminology as well as the need for a reduced number of ICF codes for more feasible and practical use. Different approaches and technical solutions exist for integrating the ICF in EHRs, such as combining the ICF with other existing standards for EHR or selecting ICF codes with natural language processing. Though the use of the ICF in EHRs is beneficial as this review revealed, the ICF could profit from further improvements such as formalizing the knowledge representation in the ICF to support and enhance interoperability.


Action of humic acid on promotion of cucumber shoot growth involves nitrate-related changes associated with the root-to-shoot distribution of cytokinins, polyamines and mineral nutrients.
Numerous studies have reported the ability of humic substances to increase shoot growth in different plant species cultivated under diverse growth conditions. However, the mechanism responsible for this effect of humic substances is poorly understood. It is possible that the shoot promoting effect of humic substances involves a primary effect on root H(+)-ATPase activity and nitrate root-shoot distribution that, in turn, causes changes in the root-shoot distribution of certain cytokinins, polyamines and abscisic acid, thus affecting shoot growth. We investigated this hypothesis in the present study. The results showed that the root application of a purified humic acid causes a significant increase in shoot growth that is associated with an enhancement in root H(+)-ATPase activity, an increase in nitrate shoot concentration, and a decrease in roots. These effects were associated with significant increases in the shoot concentration of several cytokinins and polyamines (principally putrescine), concomitant with decreases in roots. Likewise, these changes in the root-shoot distribution of diverse active cytokinins correlated well to significant changes in the root-shoot distribution of several mineral nutrients. These results, taken together, indicate that the beneficial effects of humic substances on shoot development in cucumber could be directly associated with nitrate-related effects on the shoot concentration of several active cytokinins and polyamines (principally putrescine).


Efficacy of implementing a BRCA screening protocol in primary care.
Breast cancer is the second leading cause of cancer death for women, whereas ovarian cancer is the deadliest gynecological cancer. Breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2) mutations can increase the risk of developing breast and ovarian cancer. Screening can assist in prevention and early detection. This study aimed to increase provider knowledge of BRCA mutations, the use of BRCA screening tools, and genetic referrals. An Institutional Review Board-approved study was implemented for providers for training on BRCA1 and BRCA2 mutations and the importance of screening and referral for those at risk. Measures included provider confidence and knowledge after training as well as number of patient referrals. A standardized webinar was required with further education provided in multiple modalities. The number of BRCA screenings and referrals for genetic screening was monitored through the electronic health record (EHR). Eight providers including five nurse practitioners and three medical doctors participated in the complete project. As a result, 56 patients were BRCA screened, and four referrals were made to receive genetic counseling. Education enhanced knowledge, increased screening tool use, and resulted in improvement in genetic referrals through the EHR.


A hybrid coarse-grained model for structure, solvation and assembly of lipid-like peptides.
Reconstituted photosynthetic proteins which are activated upon exposure to solar energy hold enormous potential for powering future solid state devices and solar cells. The functionality and integration of these proteins into such devices has been successfully enabled by lipid-like peptides. Yet, a fundamental understanding of the organization of these peptides with respect to the photosynthetic proteins and themselves remains unknown and is critical for guiding the design of such light-activated devices. This study investigates the relative organization of one such peptide sequence V6K2 (V: valine and K: lysine) within assemblies. Given the expansive spatiotemporal scales associated with this study, a hybrid coarse-grained (CG) model which captures the structure, conformation and aggregation of the peptide is adopted. The CG model uses a combination of iterative Boltzmann inversion and force matching to provide insight into the relative organization of V6K2 in assemblies. The CG model reproduces the structure of a V6K2 peptide sequence along with its all atom (AA) solvation structure. The relative organization of multiple peptides in an assembly, as captured by CG simulations, is in agreement with corresponding results from AA simulations. Also, a backmapping procedure reintroduces the AA details of the peptides within the aggregates captured by the CG model to demonstrate the relative organization of the peptides. Furthermore, a large number of peptides self-assemble into an elongated micelle in the CG simulation, which is consistent with experimental findings. The coarse-graining procedure is tested for transferability to longer peptide sequences, and hence can be extended to other amphiphilic peptide sequences.


Child abuse: a literature review.
The following is a summary of a recently published review of Swedish and international literature concerning children exposed to abuse and neglect or manifesting failure to thrive. The review is the first report appearing from the so-called PRU group in Uppsala--Psycho-social Risk Children in Uppsala. The group is a multidisciplinary team engaged in a research project about Uppsala children exposed to mental, social and physical risks in their homes. The project is financed by the Save the Children Fund, which has also contributed to the printing costs of the book. Various professions are represented in the research team, namely social work, family therapy, child psychiatry, child psychology, paediatrics, and sociology. The complete review was published in the autumn of 1977 under the following title: Dagmar Lagerberg/PRU-gruppen: Föräldravåld mot barn. En litteraturstudie (PRU group: Child abuse by parents. A literature review). A second main report, presenting the aims, material, methods, and results of the project, is planned for publication in 1979.


The utility of gingival crevicular fluid matrix metalloproteinase-8 response patterns in prediction of site-level clinical treatment outcome.
Different gingival crevicular fluid (GCF) matrix metalloproteinase (MMP)-8 response patterns were studied among non-smoking and smoking patients with chronic periodontitis (CP) and generalized aggressive periodontitis (GAgP) to test the utility of GCF MMP-8 levels predicting the site-level treatment outcome. Data from four independent longitudinal studies were combined. Altogether, the studies included 158 periodontal sites from 67 patients with CP and 32 patients with GAgP, and GCF samples were collected at baseline, after the treatment, and during the 6-month maintenance period. All GCF samples were analyzed by immunofluorometric assay for MMP-8. Different site-level MMP-8 response patterns were explored by the cluster analysis. Most optimal MMP-8 cutoff levels were searched with receiver operating characteristic analyses, and the predictive utility of defined levels was tested. Distinct types of MMP-8 response patterns were found in both smokers and non-smokers. MMP-8 levels exceeding the optimal cutoff levels separately defined for smokers and non-smokers indicated increased risk for compromised treatment outcome at baseline and during the maintenance period. Seventy-one percent of non-smokers (positive likelihood ratio of 4.22) and 88% of smokers (positive likelihood ratio of 5.00) with positive test results at both baseline and the maintenance period had compromised treatment outcome. The double-positive result indicated 46% and 39% point risk increase for the compromised outcome, respectively. GCF MMP-8 analysis with defined cutoff levels could be used to predict the site-level treatment outcome and for longitudinal monitoring of the disease status during the maintenance period.


Severe impairment in early host defense against Candida albicans in mice deficient in myeloperoxidase.
Myeloperoxidase (MPO) catalyzes the reaction of hydrogen peroxide with chloride ion to produce hypochlorous acid (HOCl), which is used for microbial killing by phagocytic cells. Despite the important role of MPO in host defense, however, MPO deficiency is relatively common in humans, and most of these individuals are in good health. To define the in vivo role of MPO, we have generated by gene targeting mice having no MPO activity in their neutrophils and monocytes. The mice without MPO developed normally, were fertile, and showed normal clearance of intraperitoneal Staphylococcus aureus. However, they showed increased susceptibility to pneumonia and death following intratracheal infection with Candida albicans. Furthermore, the lack of MPO significantly enhanced the dissemination of intraperitoneally injected C. albicans into various organs during the first 7 days. Thus, MPO is important for early host defense against fungal infection, and the inability to generate HOCl cannot be compensated for by other oxygen-dependent systems in vivo in mice. The mutant mice serve as a model for studying pulmonary and systemic candidiasis.


Challenge of false alarms in nitroaromatic explosive detection--a detection device based on surface-enhanced Raman spectroscopy.
A challenge in the detection of explosives is the differentiation between explosives and contaminants. Synthetic musk-containing perfumes can cause false alarms, as these perfumes are nitroaromatic compounds, which can be mistaken for trinitro toluene (TNT) by some detectors. We present a detection principle based on surface-enhanced Raman scattering (SERS). A stream of the airborne compounds is focused and resublimated on a cooled nanostructured gold surface. We recorded high-resolution SERS spectra of TNT, musk xylene, and musk ketone. The nitroaromatic compounds can be identified unambiguously by their SERS spectra. Even the dominant bands containing nitro-group scissoring and symmetric stretching modes are significantly shifted by the difference in molecular structure.


[Atherosclerosis and clinical examination: epidemiology of stroke and ischemic heart disease].
We discussed the risk factors for stroke and ischemic heart disease (IHD) as a main atherosclerotic disease. We showed that hypertension was the most principal risk factor for both cerebral hemorrhage and cerebral infarction, and the increase of total cholesterol (TCH) was inversely related with the incidence of cerebral hemorrhage. Many of the cerebral infarctions occurred where a large number of the cerebral hemorrhages did. We indicated that the mechanism of occurrence was different between stroke and IHD. In Japan, TCH has been recognized as a risk factor for IHD as same as western countries, but there are not many IHD. The mean of TCH was lower before one or two decade. But, it has increased in the last decade, and recently is nearing the level of American people in the thirties and forties. Death statistics of IHD became more accurate in Japan by reason for revision of the death certificate form from ICD-9 to ICD-10. The recognition of IHD death statistics will be changed. Incidence of stroke has been decreasing because of the decrease of hypertension. However, we will have to reconsider a preventive measure of IHD.


[An update on the management of Raynaud's phenomenon].
Basic knowledge of clinical management of Raynaud's phenomenon was established and reviewed. Body protection against cold weather and the avoiding of all activities which cause the setting off of the ischemic episodic trigger are the first step in the therapy for this type of patient. Medical treatment includes vasoactive drugs and other drugs which act against the different factors such as plasmapheresis, sympathectomy and electric neurostimulation must be reserved for patients with severe vascular symptoms.


The effect of gonadotropins on the production of human interferon-gamma by mononuclear cells.
Gonadotropins--follicle-stimulating hormone (FSH), luteinizing hormone (LH), and human chorionic gonadotropin (HCG)--and the related agent thyrotropin were shown to enhance yields of interferon-gamma (IFN-gamma) from human peripheral blood mononuclear cells (PBMC) significantly when calcium ionophores (ionomycin or A23187) were used as inducers. The enhancement increased the IFN yields four- to eight-fold. Induction with other inducers, (such as lectins, interleukin-2 (IL-2), and anti CD3, was not associated with enhancement of the IFN yields by gonadotropins. Concentrations of gonadotropins associated with pregnancy (HCG) or menopause (FSH and LH) were able to enhance IFN-gamma yields. Addition of the gonadotropins to the cells after the ionophore gave the greatest degree of enhancement. Perturbation of the calcium messenger system or nonspecific stimulation of adenyl cyclase failed to influence the IFN yield enhancing effect of the gonadotropins. No effect of gonadotropins was observed on IFN bioactivity.


Association of sedentary and physical activity behaviours with body composition: a genome-wide association and Mendelian randomisation study.
Studies suggest that body composition can be independently improved through physical activity (PA). We performed a Mendelian randomisation (MR) study to test the incremental benefits of sedentary behaviour and various PA exposures on body composition outcomes as assessed by anthropometric indices, lean body mass (kg), body fat (%) and visceral adipose tissue (VAT) (kg). Genetic instruments were identified for both self-reported and accelerometer-measured sedentary behaviour and PA. Outcomes included anthropometric and dual-energy X-ray absorptiometry measures of adiposity, extracted from the UK Biobank and the largest available consortia. Multivariable MR (MVMR) included educational attainment as a covariate to address potential confounding. Sensitivity analyses were evaluated for weak instrument bias and pleiotropic effects. We did not identify consistent associations between genetically predicted self-reported and accelerometer-measured sedentary behaviour and body composition outcomes. All analyses for self-reported moderate PA were null for body composition outcomes. Genetically predicted PA at higher intensities was protective against VAT in MR and MVMR analyses of both accelerometer-measured vigorous PA (MVMR β=-0.15, 95% CI: -0.24 to -0.07, p<0.001) and self-reported participation in strenuous sports or other exercises (MVMR β=-0.27, 95% CI: -0.52 to -0.01, p=0.034) was robust across several sensitivity analyses. We did not identify evidence of a causal relationship between genetically predicted PA and body composition, with the exception of a putatively protective effect of higher-intensity PA on VAT. Protective effects of PA against VAT may support prior evidence of biological pathways through which PA decreases risk of downstream cardiometabolic diseases.


Clinical observations on Babesia gibsoni and Babesia canis infections in dogs.
Thirty-five cases of Babesia gibsoni infection and 11 cases of Babesia canis infection were diagnosed and treated in dogs at Kadena Air Base in Okinawa, Japan, between April 1979 and February 1980. Diagnosis was made by demonstrating the organisms in blood smears and by serologic examination, using an indirect fluorescent antibody test. Serologic findings correlated well with the occurrence of infection in mature dogs, but poorly in young (1- to 3-month-old) dogs. Although these 2 intraerythrocytic parasites were readily distinguishable on Giemsa-stained blood smears and by the indirect fluorescent antibody test, the clinical syndromes were similar. Most dogs were anorectic and depressed and were found to have regenerative anemia. Of 37 dogs tested, 31 were Coomb's test-positive, and most of these became Coombs' test-negative after treatment and disappearance of clinical signs. Specific treatment consisted predominantly of the use of diminazene aceturate. Pentamidine isethionate also used. Although these drugs were effective in halting and reversing the clinical progression of the disease, they usually were ineffective in clearing the blood of B gibsoni organisms, and relapses commonly occurred. Both drugs appeared to be more effective against B canis. It was concluded that some of the several hundred dogs arriving in the United States annually from Okinawa are carriers of B gibsoni, a parasite only recently discovered in North America.


Leaching and transformation of chemical additives from weathered plastic deployed in the marine environment.
Plastic pollution causes detrimental environmental impacts, which are increasingly attributed to chemical additives. However, the behaviour of plastic additives in the marine environment is poorly understood. We used a marine deployment experiment to examine the impact of weathering on the extractables profile, analysed by liquid chromatography-mass spectrometry, of four plastics at two locations over nine months in Aotearoa/New Zealand. The concentration of additives in polyethylene and oxo-degradable polyethylene were strongly influenced by artificial weathering, with deployment location and time less influential. By comparison, polyamide 6 and polyethylene terephthalate were comparatively inert with minimal change in response to artificial weathering or deployment time. Non-target analysis revealed extensive differentiation between non-aged and aged polyethylene after deployment, concordant with the targeted analysis. These observations highlight the need to consider the impact of leaching and weathering on plastic composition when quantifying the potential impact and risk of plastic pollution within receiving environments.


Comparative Transcriptomic and Lipidomic Analyses of Human Male and Female Meibomian Glands Reveal Common Signature Genes of Meibogenesis.
Meibum is a lipid secretion that is produced by holocrine Meibomian glands (MGs). MGs are a specialized type of sebaceous glands that are embedded in the human eyelids. Chemically, meibum and sebum are different. A detailed characterization of lipidome and transcriptome of MG is required to deconvolute a complex and poorly characterized array of biosynthetic reactions (termed meibogenesis) that lead to formation of meibum. Changes in the composition and quality of meibum have been linked to various ocular disorders, some of which are more prevalent in males, while others in females. To establish the role of gender in meibogenesis in humans, we characterized MG transcriptomes and lipidomes of females and males, and identified signature genes of meibogenesis in both genders. Specimens of MG tissues were subjected to mRNA microarray analyses. Chemical composition of meibum samples was assessed chromatographically and mass spectrometrically. Both targeted and untargeted approaches were used. About 290 signature genes of meibogenesis were identified. The analyses of their expression patterns demonstrated no major differences between the genders. Lipid profiling of major classes of meibomian lipids, such as wax esters, cholesteryl esters, free cholesterol, (O)-acylated omega-hydroxy fatty acids (OAHFA), cholesteryl esters of OAHFA, and triacylglycerols, also demonstrated only minor (and random) differences in these lipids. The results of transcriptomic analyses correlated well with lipidomic data. Taken together, our data imply that in males and females, meibogenesis proceeds in a similar fashion, yielding secretions with similar, highly conserved, compositions. This finding is important for designing novel, gender-independent diagnostic and therapeutic approaches to various MG-related diseases and pathological conditions.


Is rotavirus still a major cause for diarrheal illness in hospitalized pediatric patients after rotavirus vaccine introduction in the Saudi national immunization program?
Previous studies in Jeddah, western Saudi Arabia, showed rotavirus (RV) prevalence around 40% in pediatric inpatients with gastroenteritis (GE) with a maximum level during cooler months. Currently, there are no data on impact of rotavirus vaccine (RVV) on RV-GE in Saudi Arabia. Therefore, this study was conducted to assess impact of RVV on incidence and severity of RV-GE in hospitalized pediatric patients; 3 years after introduction of RVV in Saudi immunization program (SIP) in January, 2013.This cross-sectional observational study included GE cases under 5 years of age admitted to 2 tertiary hospitals, in Jeddah, from October to December, 2015. All included GE-cases had RV antigen detection in stool by immunochromatographic assay, complete data collection including RVV status and severity assessment (Vesikari score) in initial admission.During study period, a total of 359 GE cases in children under 5 years of age were hospitalized with 14 (3.9%) RV-GE confirmed cases. Mean age of RV-GE patients was 13.10 ± 5.70 months. All RV cases had severe GE and 1 case received RVV. Among other 345 GE cases, 35.7% did not receive RVV and 46.1% had severe GE. Severe GE (Vesikari score > 11) was more significantly identified among RV-GE cases than in other all-cause GE (P < .001). During same period of this study in 2012, 369 RV-GE out of 1193 total GE cases (31%) were hospitalized at 2 hospitals, so, number of hospitalized pediatric patients for all-cause and RV-GE in children under 5 years of age decreased significantly in 2015 RV season (compared to 2015 RV season, odds ratio for RV-GE in 2012: 11.04, 95% CI: 6.38-19.09).Logistic regression analysis of variables of this cross-sectional, hospital-based study in Jeddah, Saudi Arabia, 3 years after introduction of RVV in SIP, showed that among the studied variables, RVV was associated with remarkable reduction of hazard of all-cause and RV-GE in vaccinated and even in unvaccinated children under 5 years of age possibly by RVV herd effect. However, RV was still associated with severe GE-related hospitalizations in unvaccinated children against RV who were younger than 2 years and particularly in the 1st year of life, indicating need for more optimum rate of RVV coverage. Hopefully, further improvement in RVV coverage rate may make RV-GE a disease of the past in Saudi children.


Genome-Wide Association Study on the Early-Phase Insulin Response to a Liquid Mixed Meal: Results From the NEO Study.
Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 5 × 10-8) and was also replicated successfully (β: -7.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.


Use of 11p15 mucins as prognostic factors in small adenocarcinoma of the lung.
Patients with small adenocarcinoma of the lung (SACL) generally have a good prognosis. However, some SACL cases show lymph node metastasis, with poor prognosis. The expression pattern of 11p15 mucins (clustered on the p15 arm of the chromosome 11) is known to change during carcinogenesis in lung cancer. We evaluated the expression of the 11p15 mucins (MUC2, MUC5AC, and MUC6) in 79 surgical specimens of SACL cases by immunohistochemical analysis. Lymph node metastasis was estimated by pathological staging. Six (7.6%) and 11 (13.9%) of the 79 SACL cases showed MUC2 and MUC6 expression, respectively. Three SACL cases showed both MUC2 and MUC6 expression, and a significant correlation was found between MUC2 and MUC6 expression (Fisher's test, P = 0.033). Six (7.6%) SACL cases showed MUC5AC expression. Five of the 6 cases with MUC2 expression and 6 of the 11 cases with MUC6 expression were had lymph node metastasis. SACL cases with MUC2 or MUC6 expression showed a significantly higher incidence of nodal metastasis than those without expression (P < 0.001 and P = 0.006, chi(2) test, respectively). There was no significant correlation between MUC5AC expression and nodal involvement in SACL, whereas three of the six cases with MUC5AC expression showed lymph node metastasis. The SACL cases with MUC2 expression had a significantly poorer prognosis than those without MUC2 expression (P = 0.011, log-rank test). These results suggest that 11p15 mucins MUC2 and MUC6 are related to lymph node metastasis in SACL.


[Clinical efficiency of ivabradine in patients with cardiorespiratory pathology].
Clinical efficiency of If-inhibitor ivabradin (Coraxan, Servier) in 40 patients with cardiorespiratory pathology (CRP) was studied. It was shown, that use of ivabradin in dose of 5 mg two times a day leaded to significant decrease in number of angina attacks in a week, and also in time of painless myocardial ischemia, decrease in heart rate at a day and during physical exercises, increase in 6 minutes walking distance and circadian index, oxygen saturation and partial tension, decrease in average pressure in pulmonary artery, increase in ejection fraction of left ventricle. Thus, ivabradin (Coraxan, Servier) is an effective antianginal drug for CRP patients, it improves life quality and do not has an influence on external respiration function. Ivabradin in dose of 5 mg two times a day can be used for CRP patients and as alternative to beta-adrenoblockers.


Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: cause for concern?
There are now five anti-TNF drugs available for clinical use, and it will not be long before they are joined by biosimilar drugs. Some patients treated with selective TNF drugs may develop adverse events such as infections, malignancies, acute infusion and injection reactions, autoimmunity and cardiovascular effects. Registry data consistently show that, particularly during the first 6 months, anti-TNF drugs slightly increase the risk of serious infections of the skin, soft tissues and joints, but it does not seem to increase the risk of cancer other than nonmelanoma skin cancers. A number of studies have shown that the administration of biological agents can lead to the formation of neutralizing and nonneutralizing antibodies. Lipid levels increase, but the atherogenic index remains stable and qualitative changes to lipid particles may reduce the risk of cardiovascular diseases. Patients treated with anti-TNF drugs therefore need to be monitored regularly.


Cardiac effects of prostaglandins E1 and F1 alpha.
The effects of prostaglandin E1 (PGE1) and prostaglandin F1 alpha (PGF1 alpha) were studied on perfused rat hearts and isolated rat atria. Both PGE1 and PGF1 alpha produced dose-dependent increases in right atrial rate but had no effect on left atrial tension development. PGE1 (10(-4) M) increased right atrial cyclic AMP content without changing phosphorylase a activity. PGF1 alpha (10(-4) M) did not change right atrial cyclic AMP or cyclic GMP content. Both prostaglandins had no effect on left atrial cyclic nucleotide content. When infused at a rate of 1 microgram/min, PGE1 produced a time-dependent increase in cyclic AMP content in the Langendorff perfused hearts but did not alter contractile force development or phosphorylase a activity. An infusion of PGF1 alpha produced a dose-dependent increase in tension development which was secondary to a negative chronotropic effect. PGF1 alpha (1 microgram/min) did not produce any changes in cyclic nucleotide levels or phosphorylase a activity in the Langendorff perfused hearts. These results show that PGE1 can selectively increase myocardial cyclic AMP content without altering contractile force or phosphorylase activity and that PGF1 alpha does not increase rat cardiac AMP levels.


Ambient ozone concentration and emergency department visits for panic attacks.
The effect of ambient air pollution on panic disorder in the general population has not yet been thoroughly elucidated, although the occurrence of panic disorder in workers exposed to organic solvents has been reported previously. We investigated the association of ambient air pollution with the risk of panic attack-related emergency department visits. Using health insurance claims, we collected data from emergency department visits for panic attacks in Seoul, Republic of Korea (2005-2009). Daily air pollutant concentrations were obtained using automatic monitoring system data. We conducted a time-series study using a generalized additive model with Poisson distribution, which included spline variables (date of visit, daily mean temperature, and relative humidity) and parametric variables (daily mean air pollutant concentration, national holiday, and day of the week). In addition to single lag models (lag1 to lag3), cumulative lag models (lag0-1 to lag0-3) were constructed using moving-average concentrations on the days leading up to the visit. The risk was expressed as relative risk (RR) per one standard deviation of each air pollutant and its 95% confidence interval (95% CI). A total of 2320 emergency department visits for panic attacks were observed during the study period. The adjusted RR of panic attack-related emergency department visits was 1.051 (95% CI, 1.014-1.090) for same-day exposure to ozone. In cumulative models, adjusted RRs were 1.068 (1.029-1.107) in lag0-2 and 1.074 (1.035-1.114) in lag0-3. The ambient ozone concentration was significantly associated with emergency department visits for panic attacks.


Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice.
Fibroblast growth factor (FGF) family members are involved in the regulation of articular cartilage homeostasis. The aim of this study was to investigate the function of FGF receptor 1 (FGFR-1) in the development of osteoarthritis (OA) and its underlying mechanisms. FGFR-1 was deleted from the articular chondrocytes of adult mice in a cartilage-specific and tamoxifen-inducible manner. Two OA models (aging-associated spontaneous OA, and destabilization-induced OA), as well as an antigen-induced arthritis (AIA) model, were established and tested in Fgfr1-deficient and wild-type (WT) mice. Alterations in cartilage structure and the loss of proteoglycan were assessed in the knee joints of mice of either genotype, using these 3 arthritis models. Primary chondrocytes were isolated and the expression of key regulatory molecules was assessed quantitatively. In addition, the effect of an FGFR-1 inhibitor on human articular chondrocytes was examined. The gross morphologic features of Fgfr1-deficient mice were comparable with those of WT mice at both the postnatal and adult stages. The articular cartilage of 12-month-old Fgfr1-deficient mice displayed greater aggrecan staining compared to 12-month-old WT mice. Fgfr1 deficiency conferred resistance to the proteoglycan loss induced by AIA and attenuated the development of cartilage destruction after surgically induced destabilization of the knee joint. The chondroprotective effect of FGFR-1 inhibition was largely associated with decreased expression of matrix metalloproteinase 13 (MMP-13) and up-regulation of FGFR-3 in mouse and human articular chondrocytes. Disruption of FGFR-1 in adult mouse articular chondrocytes inhibits the progression of cartilage degeneration. Down-regulation of MMP-13 expression and up-regulation of FGFR-3 levels may contribute to the phenotypic changes observed in Fgfr1-deficient mice.


Protective effects of black seed (Nigella sativa) diet supplementation in common carp (Cyprinus carpio) against immune depression, oxidative stress and metabolism dysfunction induced by glyphosate.
Sustainable aquaculture arises as key to increase food production in the coming years. However, the sector still faces many challenges such as the exposure of the cultured animals to pesticide-contaminated water. Pesticides used in agriculture can reach aquaculture systems either directly (integrated-agriculture aquaculture practices) or indirectly (soil leakage) and cause a broad range of ecotoxicological effects on cultured fish and shellfish. Here, we studied how glyphosate affects several haematological, biochemical, and immune parameters in common carp (Cyprinus carpio) fingerlings, the fourth most important cultured fish species worldwide. We also evaluated the potential of dietary supplementation with black seed (Nigella sativa, 0.25, 0.5 and 1%) to lower glyphosate-associated toxicity. Our results showed that 14-day sub-lethal exposure of common carp fingerlings to glyphosate increases oxidative stress, decreases antioxidant defences, affects several metabolic pathways, and induced immune depression. Furthermore, we showed that fish fed with N. sativa-enriched diets at 0.25, 0.5 and 1% for 60 days coped better with glyphosate exposure than control fish and displayed more stable levels of biochemical serum parameters (total protein, albumin, triglycerides, low-density lipoprotein LDL), cholesterol and high-density lipoprotein HDL), higher levels of immune defences (lysozyme and immunoglobulin) and higher antioxidant enzymes (superoxide dismutase SOD, glutathione peroxidase GPx) than control fish. Fish fed with all enriched diets also displayed lower lipid peroxidation (malondialdehyde MDA), lower metabolic enzymes (alanine aminotransferase ALT, aspartate aminotransferase AST and alkaline phosphatase ALP) levels in blood serum and lower cortisol levels than control fish. Altogether, our results show that dietary inclusion of black seed can be used as a sustainable bio-remediation strategy, mitigating many of the negative effects of glyphosate exposure in fish.