Subclinical hypothyroidism and cardiovascular risk factors.
Thyroid hormones have multiple effects on lipid metabolism as well as on the cardiovascular system function. These negative cardiovascular effects have long been recognized in overt hypothyroidism but can be reversed by treatment with levothyroxine. We performed on PubMed a literature search for the articles published until March 2019 by using the search terms "subclinical hypothyroidism," "cardiovascular disease," "cholesterol," "LDL," "HDL," "triglycerides," "coronary heart disease," "heart failure," "atherosclerosis," "all-cause mortality," "levothyroxine." Subclinical hypothyroidism, defined as an elevated thyrotropin (TSH) with a normal free thyroxine (FT4), is frequent in the general population and increase with age. Subclinical hypothyroidism has been linked to cardiovascular risk factors, dyslipidemia and increased atherosclerosis. Although some studies have demonstrated that lipids are elevated in subclinical hypothyroidism, other studies did not confirm these data. Clinical trials have also demonstrated there is no clear evidence that levothyroxine therapy in subjects with milder form (TSH<10 mU/L) of subclinical hypothyroidism could improve lipid status and the other cardiovascular risk factors. Nevertheless, TSH level seems the best predictor of cardiovascular disease, in particular when its levels are above 10 mU/L. Prospective studies are necessary to clarify the cardiovascular risk in patients with mild subclinical hypothyroidism and to assess the importance of treating elderly people in order to improve or counteract the correlated risks. However, until clinical recommendations will be updated, the decision to treat or not treat patients with subclinical hypothyroidism will still base on clinical judgment, clinical practice guidelines, and expert opinion.


Detection and effects of harmful algal toxins in Scottish harbour seals and potential links to population decline.
Over the past 15 years or so, several Scottish harbour seal (Phoca vitulina) populations have declined in abundance and several factors have been considered as possible causes, including toxins from harmful algae. Here we explore whether a link could be established between two groups of toxins, domoic acid (DA) and saxitoxins (STXs), and the decline in the harbour seal populations in Scotland. We document the first evidence that harbour seals are exposed to both DA and STXs from consuming contaminated fish. Both groups of toxins were found in urine and faeces sampled from live captured (n = 162) and stranded animals (n = 23) and in faecal samples collected from seal haul-out sites (n = 214) between 2008 and 2013. The proportion of positive samples and the toxins levels measured in the excreta were significantly higher in areas where harbour seal abundance is in decline. There is also evidence that DA has immunomodulatory effects in harbour seals, including lymphocytopenia and monocytosis. Scottish harbour seals are exposed to DA and STXs through contaminated prey at potentially lethal levels and with this evidence we suggest that exposure to these toxins are likely to be important factors driving the harbour seal decline in some regions of Scotland.


Treatment options for deep vein thrombosis.
Anticoagulation is the main therapy for acute deep vein thrombosis (DVT) of the limbs. Over the last five decades, there has been little progress in the development of oral anticoagulant therapies. More recently, we have been experiencing a rapidly changing situation thanks to the development of new orally active anticoagulants. The aim of this review is to highlight main published data on direct thrombin and FXa inhibitors. The electronic database PubMed website and abstract proceedings were used to identify studies. The main characteristics of these new classes of anticoagulant drugs, the development program of the most advanced molecules and the most recent published data on Phase III trials on DVT treatment for both the acute phase and the secondary prevention of the disease are reviewed. Oral administration, predictable anticoagulant responses, low potential for drug-drug interactions and first published clinical data render direct thrombin and factor Xa inhibitors good candidates to replace oral vitamin K antagonist and low molecular weight heparins for DVT treatment.


Model-based aberration correction in a closed-loop wavefront-sensor-less adaptive optics system.
In many scientific and medical applications, such as laser systems and microscopes, wavefront-sensor-less (WFSless) adaptive optics (AO) systems are used to improve the laser beam quality or the image resolution by correcting the wavefront aberration in the optical path. The lack of direct wavefront measurement in WFSless AO systems imposes a challenge to achieve efficient aberration correction. This paper presents an aberration correction approach for WFSlss AO systems based on the model of the WFSless AO system and a small number of intensity measurements, where the model is identified from the input-output data of the WFSless AO system by black-box identification. This approach is validated in an experimental setup with 20 static aberrations having Kolmogorov spatial distributions. By correcting N=9 Zernike modes (N is the number of aberration modes), an intensity improvement from 49% of the maximum value to 89% has been achieved in average based on N+5=14 intensity measurements. With the worst initial intensity, an improvement from 17% of the maximum value to 86% has been achieved based on N+4=13 intensity measurements.


A qualitative examination of perceived barriers and facilitators of physical activity for urban and rural youth.
Many adolescents, both rural and urban, are not meeting the recommended levels for physical activity (PA). This investigation was designed to elicit socioecologic barriers and facilitators for PA in rural and urban middle school youth and their parents. Thirteen focus groups were conducted with 41 youth and 50 parents from eastern North Carolina. Distance, cost, crime/danger and television were mentioned as the primary barriers among parents. Youth mentioned school policies related to PA and crime/danger as the main PA barriers. The most salient facilitators discussed by parents were social/peer facilitators, facilities available and parental role modeling of PA. The primary facilitators mentioned by youth were social outlets and facilities available. Results indicate that intrapersonal, interpersonal, environmental and policy factors related to PA resonated with both youth and parents. Since rural and urban residents often perceive and interact differently with PA environments, more research is needed to properly adapt interventions.


On the mechanism of selective inhibition of herpesvirus replication by (E)-5-(2-bromovinyl)-2'-deoxyuridine.
Bromovinyldeoxyuridine (BVdUrd) is a potent antiherpesvirus compound with low cytotoxicity. To gain an insight into its selectivity and mechanism of inhibition, we chemically synthesized the 5'-triphosphate of BVdUrd, BVdUTP, and tested its effect on the activities of DNA polymerases [DNA nucleotidyltransferase (DNA directed), EC 126.96.36.199] of two herpesviruses--i.e., herpes simplex virus type 1 (HSV-1) and Epstein-Barr virus (EBV)--as well as cellular DNA polymerases alpha, beta, and gamma. The effects on the DNA polymerases were determined under assay conditions optimal for the individual polymerases. We found that the BVdUTP was considerably more inhibityory to the utilization of dTTP by the HSV-1 DNA polymerase then by the cellular DNA polymerases. For instance, as little as 1 microM BVdUTP inhibited the utilization of dTTP by HSV-1 DNA polymerase 50%, whereas the same concentration inhibited the DNA polymerase alpha and the DNA polymerase beta activities only 9% and 3%, respectively. The BVdUTP inhibited DNA synthesis by competing with the natural substrate, dTTP. The Km for dTTP and the Ki for the BVdUTP of the HSV-1 DNA polymerase were 0.66 and 0.25 microM, respectively. Kinetic analyses with the DNA polymerases alpha and beta and the EBV DNA polymerase also reflected a similar difference in sensitivity between the HSV-1 enzyme and other enzymes. Increasing the concentration of either the DNA template or the enzyme in the reaction mixture did not bring about a significant change in the extent of inhibition. Preincubation of the inhibitor with the enzyme was not necessary for inhibition. Studies on time course of inhibition revealed that the compound is inhibitory even after the initiation of DNA synthesis. These studies indicate that the ability of BVdUTP to preferentially inhibit the HSV-1 DNA polymerase may contribute towards its selective inhibition of the viral DNA replication in infected cells.


Magnetic resonance imaging for the diagnosis of stress fractures in a horse.
In humans, magnetic resonance (MR) imaging is the method of choice for the diagnosis of stress fractures. In this paper, bilateral stress fracture of the lateral condyle of the third metacarpal bone in a French trotter is described. Results of the radiographic, MR imaging, and histologic examinations are presented, with a focus on the MR signal abnormalities found. Based on this patient, the potential use of MR imaging for the diagnosis of stress fractures in horses is discussed.


Renal hydroxybutyrate and acetoacetate reabsorption and utilization in the rat.
Is the renal conservation of ketones effected through saturable transport systems? Does the renal reabsorption of ketoacids limit their utilization? The reabsorptive transport (T) and metabolic utilization (Q) of D-3-hydroxybutyrate (HB) and acetoacetate (AA) in the kidney were measured in anesthetized rats by use of clearance and arteriovenous extraction determinations. THB and TAA increased in proportion with increasing HB and AA filtered loads. Fractional THB decreases from 0.97 to 0.72 upon increases in the plasma HB. Fractional TAA also decreases from 0.89 to 0.73, at a constant filtered AA load, when the filtered HB load increased. Thus both saturable and nonsaturable components effect the reabsorption of HB and AA. Renal QHB increased from 0.4 to 4 mumol X g-1 X min-1 on increase in the plasma HB. THB always exceeded the simultaneously measured QHB. However, QHB was significantly correlated with THB, suggesting that QHB may be limited by delivery of HB to the renal cells through reabsorptive pathways. There was no net renal conversion of HB and AA. Both HB and AA were utilized by the kidney. Thus, utilized ketoacids must have entered pathways for complete oxidation or for synthesis (lipid?) in the kidney.


Integrated exposure assessment of northern goshawk (Accipiter gentilis) nestlings to legacy and emerging organic pollutants using non-destructive samples.
In the present study, concentrations of legacy and emerging contaminants were determined in three non-destructive matrices (plasma, preen oil and body feathers) of northern goshawk (Accipiter gentilis) nestlings. Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs), together with emerging pollutants, including per- and polyfluorinated alkyl substances (PFASs), novel brominated flame retardants (NBFRs), phosphorus flame retardants (PFRs) and Dechlorane Plus isomers (DPs) were targeted. Plasma, preen oil and feather samples were collected from 61 goshawk nestlings in Norway (Trøndelag and Troms) in 2015 and 2016, and pollutant concentrations were compared between the three matrices. In plasma, PFASs were detected in the highest concentrations, ranging between 1.37 and 36.0 ng/mL, which suggests that the nestlings were recently and continuously exposed to these emerging contaminants, likely through dietary input. In preen oil, OCPs (169-3560 ng/g) showed the highest concentrations among the investigated compounds, consistent with their high lipophilicity. PFRs (2.60-314 ng/g) were the dominant compounds in feathers and are thought to originate mainly from external deposition, as they were not detected in the other two matrices. NBFRs and DPs were generally not detected in the nestlings, suggesting low presence of these emerging contaminants in their environment and/or low absorption. Strong and significant correlations between matrices were found for all POPs (rs = 0.46-0.95, p < 0.001), except for hexachlorobenzene (HCB, rs = 0.20, p = 0.13). Correlations for PFASs were less conclusive: linear perfluorooctane sulfonate (PFOS), perfluoroundecanoate (PFUnA), perfluorododecanoate (PFDoA) and perfluorotetradecanoate (PFTeA) showed strong and significant correlations between plasma and feathers (rs = 0.42-0.72, p < 0.02), however no correlation was found for perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA) and perfluorotridecanoate (PFTriA) (rs = 0.05-0.33, p = 0.09-0.85). A lack of consistency between the PFAS compounds (contrary to POPs), and between studies, prevents concluding on the suitability of the investigated matrices for PFAS biomonitoring.


Identifying Cardiomegaly in ChestX-ray8 Using Transfer Learning.
Recently, the National Institutes of Health (NIH) published a chest X-ray image database named "ChestX-ray8", which contains 108,948 X-ray images that are labeled with eight types of diseases. Identifying the pathologies from the clinical images is a challenging task even for human experts, and to develop computer-aided diagnosis systems to help humans identify the pathologies from images is an urgent need. In this study, we applied the deep learning methods to identify the cardiomegaly from the X-ray images. We tested our algorithms on a dataset containing 600 images, and obtained the best performance with an area under the curve (AUC) of 0.87 using the transfer learning method. This result indicates the feasibility of developing computer-aided diagnosis systems for different pathologies from X-rays using deep learning techniques.


Ultrasonographic Assessment of Deltoid Ligament Integrity in Ankle Fractures.
Regardless of fibular status, the presence of a superficial deltoid ligament disruption or a combination of deep and superficial deltoid ligament disruption is central to the decision-making process in treating ankle fractures. The aims of the present study were to test whether ultrasonography can assess deltoid ligament integrity and to determine its validity and reliability by comparing it with gravity stress radiography. A consecutive series of 81 eligible patients with a nondisplaced or minimally displaced fibula fracture identified on a standard radiograph were prospectively enrolled. All patients underwent gravity stress radiography and ultrasonography. Image analysis included the layer type, integrity, and tear site of the deltoid ligament. Ultrasound validity and intra- and interobserver reliability were assessed by the interpretations of the first author and an independent observer who were blinded to the results. Of all patients, 64 (79.0%) had a deltoid ligament disruption; most of the tears were of both the superficial and deep layers, partial and proximal attachment tears, and only 8 (12.5%) were complete tears. Patients with an intact deltoid ligament had a mean medial clear space (MCS) value of 2.7 ± 0.5 mm, and those with deltoid ligament tears had a mean MCS value of 5.9 ± 3.4 mm (P < .001). In a comparison between ultrasonography and gravity radiography, we found a sensitivity of 100% versus 97%, a specificity of 90% versus 100%, a positive predictive value of 97% versus 100%, and a negative predictive value of 100% versus 90%, respectively. The intra- and interobserver reliability was evaluated as almost perfect in all conditions. In a comparison between ultrasonography and gravity radiography, we found a sensitivity of 100% versus 97%, a specificity of 90% versus 100%, a positive predictive value of 97% versus 100%, and a negative predictive value of 100% versus 90%, respectively. Ultrasonography proved to be an accurate tool, allowing the identification of deltoid ligament disruption and the involved components in a more dynamic fashion. Its relative ease of use and lack of ionizing radiation make it a useful and confident technique that can be performed by an orthopedist. Level II, prospective comparative study.


Non-steroidal anti-inflammatory drugs and perforated diverticular disease: a case-control study.
Non-steroidal anti-inflammatory drugs (NSAIDs) have a wide range of side-effects in the gastrointestinal tract and the large intestine. This study examines the hypothesis that the use of NSAIDs is associated with colonic perforation in diverticular disease. Histological evidence was used to confirm perforation. A retrospective review of case records and pathology reports identified 20 patients admitted over 3 consecutive years. A total of 125 age- and sex-matched patients diagnosed with diverticular disease not complicated by perforation formed the control group. The incidences of NSAID use in the two groups were compared. A second control group consisted of 600 age- and sex-matched randomly selected patients with no known diverticular disease admitted as emergencies in the same period. Of the 20 patients with perforation, 9 were taking NSAIDs for 4 weeks or longer, compared with 19 (15%) of the 125 patients who did not have perforation (relative risk 2.961, 95% confidence interval 1.507-5.348, P < 0.01). 19% of all patients with diverticular disease were taking NSAIDs compared with 10% of the second control group (relative risk 1.869, 95% confidence interval 1.237-2.781, P < 0.01). The findings indicate a strong association between the use of NSAIDs and the perforation of colonic diverticula. The majority of the indications for the use of NSAIDs were cardiovascular and musculoskeletal conditions. Prescribing NSAIDs to patients with diverticular disease carries an increased risk of colonic perforation.


Sequencing improves our ability to study threatened migratory species: Genetic population assignment in California's Central Valley Chinook salmon.
Effective conservation and management of migratory species requires accurate identification of unique populations, even as they mix along their migratory corridors. While telemetry has historically been used to study migratory animal movement and habitat use patterns, genomic tools are emerging as a superior alternative in many ways, allowing large-scale application at reduced costs. Here, we demonstrate the usefulness of genomic resources for identifying single-nucleotide polymorphisms (SNPs) that allow fast and accurate identification of the imperiled Chinook salmon in the Great Central Valley of California. We show that 80 well-chosen loci, drawn from a pool of over 11,500 SNPs developed from restriction site-associated DNA sequencing, can accurately identify Chinook salmon runs and select populations within run. No other SNP panel for Central Valley Chinook salmon has been able to achieve the high accuracy of assignment we show here. This panel will greatly improve our ability to study and manage this ecologically, economically, and socially important species and demonstrates the great utility of using genomics to study migratory species.


A mathematical model for the computation of carboxyhaemoglobin in human blood as a function of exposure time.
A mathematical model is developed for the carbon monoxide (CO) uptake by the blood by taking into account the molecular diffusion, convection, facilitated diffusion and the non-equilibrium kinetics of CO with haemoglobin. The overall rate for the combination of CO with haemoglobin is derived by including the dissociation of CO from carboxyhaemoglobin (COHb). The resulting coupled system of nonlinear partial differential equation with physiologically relevant initial, entrance and boundary conditions is solved numerically. A fixed point iterative technique is used to deal with nonlinearities. The concentration of COHb in the blood is computed as a function of exposure time and ambient CO concentration. The COHb levels computed from our model are in good agreement with those measured experimentally. Also, results computed from our model give better approximation to the experimental values compared with the results from other models. The time taken by the blood COHb to attain 95% of its equilibrium value is computed. The COHb concentration in the blood increases with the increase in ventilation rate, association rate coefficient of CO with haemoglobin and total haemoglobin content in the blood, and with the decrease in dissociation rate coefficient of CO with haemoglobin and mean capillary blood PO2. It is found that the COHb level in the blood is not affected significantly because of endogenous production of CO in the body under normal condition. However, the effect may be significant in the patients with haemolytic anaemia.


Impact of a customised dietary intervention on antioxidant status, dietary intakes and periodontal indices in patients with adult periodontitis.
Dietary modification may be important in the prevention and control of chronic adult periodontitis. The role of promoting an adequate consumption of fruits, vegetables and whole grains in chronic periodontitis has not been thoroughly investigated. The main aim of this dietary intervention study was to assess the influence of a customised dietary intervention (aiming to increase the consumption of fruits, vegetables and whole grains) on antioxidant status in adults with chronic periodontitis. Fifty-one participants, aged 30-65 years, were recruited from a U.K. Dental Hospital and randomly allocated to an intervention or control group. Both groups received normal clinical treatment but customised dietary advice was delivered to the intervention group by a community nutrition assistant. Dietary intakes, anthropometric parameters and biochemical indices with respect to blood and saliva and periodontal indices were evaluated at baseline, as well as at 3 and 6 months post-dietary intervention. At 3 and 6 months post-intervention, the intervention group showed a significant (P < 0.05) increase in plasma total antioxidant capacity measured by Trolox equivalent antioxidant capacity assay compared to the control group. At 3 and 6 months after dietary intervention, the intervention group had significantly higher intakes of fruits and vegetables compared to the control group. The intake of whole grain was significantly higher in the intervention group than in the control group, 6 months post-intervention. No significant differences were observed with respect to periodontal indices between groups. It is suggested that dietary advice may help to improve dietary habits and, consequently, the antioxidant status of patients with chronic periodontitis. However, the impact of such intervention on periodontal indices needs further investigation.


Local Recurrence Outcomes of Colorectal Cancer Oligometastases Treated With Stereotactic Ablative Radiotherapy.
The aim of this study was to report local failure (LF) outcomes and associated predictors in patients with oligometastatic colorectal cancer (CRC) treated with stereotactic ablative radiotherapy (SABR). We retrospectively reviewed patients with CRC metastases to the brain, liver, spine, or lung treated with SABR between 2001 and 2016. Time to LF was summarized using cumulative incidence of LF curves with death as a competing risk. The analysis included a total of 130 patients and 256 lesions. Of the metastases treated, 129 (50%) were brain, 50 (20%) liver, 49 (19%) spine, and 28 (11%) lung. Median gross tumor volume was 24 mL for liver metastases, 2 mL for brain metastases, 4 mL for spine metastases, and 1 mL for lung metastases. The overall 1, 2, and 3-year cumulative incidence of LF rates were 21.6% (16.5, 27.1), 28.2% (22.3, 34.4), and 31.5% (25.2, 38.0), respectively. LF was highest among the liver metastases (1 y: 26.0%, 2 y: 38.5%), followed by spine (1 y: 25.1%, 2 y: 31.1%), brain (1 y: 20%, 2 y: 25.2%), and lung (1 y: 13.7%, 2 y: insufficient data). Metastases from right-sided primary CRC were significantly more likely to have LF (P=0.0146, HR=2.23). Biologically effective dose>70 Gy, defined using a standard linear quadratic model using α/β ratio of 10 on the individual lesion level, and pre-SABR chemotherapy were also significant predictors of LF (P= 0.0009 and 0.018, respectively). CRC metastases treated with SABR had significantly higher rates of LF if they originated from right-sided primary CRC, compared with left-sided. Liver metastases had the highest rates of LF compared with other metastatic sites. Thus, CRC liver metastases and metastases from right-sided CRC may benefit from more aggressive radiotherapy.


Phase I study of a chloroquine-gemcitabine combination in patients with metastatic or unresectable pancreatic cancer.
Following a previously published pre-clinical validation, this phase I study evaluated the safety, maximum tolerated dose, anti-tumour activity and immune status of a gemcitabine-chloroquine combination as a first- or late-line treatment in patients with metastatic or unresectable pancreatic cancer. In this 3 + 3 dose escalation study, patients received a single weekly standard dose of intravenous gemcitabine, followed by single weekly oral intake of 100, 200 or 300 mg of chloroquine. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Immune status was evaluated by RT-PCR to measure the relative expression of immune-related genes in peripheral blood mononuclear cells (PBMCs). Overall, nine patients [median age 72 years; interquartile range (IQR), 68-78 years] were treated. No dose-limiting toxicities as defined in the protocol were observed. Three patients experienced partial response, and two patients had stable disease. The median time to progression was 4 months (95% CI 0.8-7.2), and the median overall survival was 7.6 months (95% CI 5.3-9.9). Among 86 assayed immune genes, three were significantly differentially expressed in PBMCs from responding versus non-responding patients: interferon-gamma receptor-1, toll-like receptor 2, and beta-2 microglobulin. The addition of chloroquine to gemcitabine was well tolerated and showed promising effects on the clinical response to the anti-cancer chemotherapy. Based on these initial results, the efficacy of the gemcitabine-chloroquine combination should be further assessed.


Genotypic and functional properties of early infant HIV-1 envelopes.
Understanding the properties of HIV-1 variants that are transmitted from women to their infants is crucial to improving strategies to prevent transmission. In this study, 162 full-length envelope (env) clones were generated from plasma RNA obtained from 5 HIV-1 Clade B infected mother-infant pairs. Following extensive genotypic and phylogenetic analyses, 35 representative clones were selected for functional studies. Infant quasispecies were highly homogeneous and generally represented minor maternal variants, consistent with transmission across a selective bottleneck. Infant clones did not differ from the maternal in env length, or glycosylation. All infant variants utilized the CCR5 co-receptor, but were not macrophage tropic. Relatively high levels (IC₅₀ ≥ 100 μg/ml) of autologous maternal plasma IgG were required to neutralize maternal and infant viruses; however, all infant viruses were neutralized by pooled sera from HIV-1 infected individuals, implying that they were not inherently neutralization-resistant. All infant viruses were sensitive to the HIV-1 entry inhibitors Enfuvirtide and soluble CD4; none were resistant to Maraviroc. Sensitivity to human monoclonal antibodies 4E10, 2F5, b12 and 2G12 varied. This study provides extensive characterization of the genotypic and functional properties of HIV-1 env shortly after transmission. We present the first detailed comparisons of the macrophage tropism of infant and maternal env variants and their sensitivity to Maraviroc, the only CCR5 antagonist approved for therapeutic use. These findings may have implications for improving approaches to prevent mother-to-child HIV-1 transmission.


Temporal Relations Between Pain Catastrophizing and Adverse Health and Mental Health Outcomes After Whiplash Injury.
Pain catastrophizing has been shown to be a prognostic indicator for pain severity and the co-occurrence of mental health conditions such as depression and post-traumatic stress disorder after whiplash injury. However, the pattern of available findings is limited in its implications for the possible "antecedent" or "causal" role of pain catastrophizing. The purpose of the present study was to examine the temporal relations between pain catastrophizing, pain severity, depressive symptoms, and post-traumatic stress symptoms (PTSS) in individuals receiving treatment for whiplash injury. The sample consisted of 388 individuals enrolled in a multidisciplinary program for whiplash injury. Participants completed self-report measures of pain catastrophizing, pain severity, depressive symptoms, and PTSS at the time of admission, mid-treatment (4 week), and treatment completion (7 week). A cross-lagged panel analysis was used to examine the temporal relations between pain catastrophizing, pain severity, depressive symptoms, and PTSS across all 3 timepoints. Model fit was acceptable after the inclusion of modification indices. Pain catastrophizing at the time of admission predicted all other variables at 4 weeks. Pain catastrophizing at 4 weeks also predicted all other variables at 7 weeks. In addition, some bidirectional relations were present, particularly for variables assessed at week 4 and week 7. Findings support the view that pain catastrophizing might play a transdiagnostic role in the onset and maintenance of health and mental health conditions. The findings call for greater emphasis on the development of treatment techniques that target pain catastrophizing in intervention programs for whiplash injury.


[Primary care physicians in Israel--compared with European countries].
This study compares Israeli primary care physicians with those of European countries. In Israel a larger proportion of those in primary care are women. The Israeli physicians see many patients a day, but almost never make home visits. They also report for work the fewest hours a day, but spend 21 hours a month in continuous medical education. (more than Europeans?) The Israeli primary care physician scores high in screening for breast cancer and blood cholesterol level, but very low in the fields of minor surgery and alcohol and smoking prevention, contraception, nutrition counseling and normal pregnancy follow-up. Residency training and education may be inadequate, and more emphasis has to be put on the health system and recognizing environmental influences.


A Standardized Approach to Evaluating Lower Extremity Chronic Wounds Using a Checklist.
As the population ages and more people live with diabetes, obesity, and vascular disease, chronic wounds have become more prevalent. Increasingly, wound care falls into the hands of clinicians who may be new to the specialty. To facilitate a better understanding of wounds and to ensure all integral items for best outcomes are considered, an interprofessional panel of wound care experts developed a checklist to aid in lower extremity wound identification, assessment, evaluation, and potential complication recognition. This checklist focuses on an evidence-based approach to obtaining a medical history, evaluating the wound, determining the etiology, and assessing perfusion, edema, infection, and neurologic status. The goal of this fundamental evaluation tool is to help the clinician move towards the next steps in optimizing patient care. Evidence-based support for each item on the checklist is reviewed and detailed for clinician reference.


Preperitoneal repair of acute incarcerated and strangulated hernias of the groin.
The preperitoneal approach to groin hernia is applicable particularly for the operative management of incarcerated and strangulated inguinal or femoral hernias. This technique allows excellent exposure to reduce and, when necessary, to resect the hernia contents through a single incision. Both inguinal and femoral hernial defects can be repaired easily using this method.


Perinatal management of preterm premature ruptured membranes affects neonatal prognosis.
To determine the factors affecting neonatal prognosis in preterm premature rupture of membranes (PPROM). We conducted a case-control study involving 92 women between the years 2000 and 2010 diagnosed with PPROM between 25 and 31 weeks' gestation, who received antenatal steroids, and delivered between 26 and 31 weeks' gestation; a retrospective cohort study was conducted based on the results. We used data from four tertiary centers and compared the frequencies of neonatal neurologic deficits and neonatal deaths. There was a difference between the two groups; specifically, the ND group (n=18) consisted of patients whose infants had neurologic deficits and/or neonatal deaths and the neurologically normal (NN) group (n=74) included NN neonates amongst the patients who had expectant management (94% vs. 73%, respectively). Multivariable analysis revealed that expectant management was independently associated with an increased risk for neonatal neurologic deficits and neonatal deaths (odds ratio, 16.14). All neonates with poor prognosis in the expectant-management group delivered within 14 days after PPROM. Expectant management within 14 days after PPROM is associated with poor neonatal outcomes. Decisions regarding an expectant strategy should be made carefully. An immediate, planned delivery after steroid administration should be considered to improve neonatal prognosis in patients who have PPROM after 26 weeks' gestation.


Nonparametric estimation of stochastic differential equations with sparse Gaussian processes.
The application of stochastic differential equations (SDEs) to the analysis of temporal data has attracted increasing attention, due to their ability to describe complex dynamics with physically interpretable equations. In this paper, we introduce a nonparametric method for estimating the drift and diffusion terms of SDEs from a densely observed discrete time series. The use of Gaussian processes as priors permits working directly in a function-space view and thus the inference takes place directly in this space. To cope with the computational complexity that requires the use of Gaussian processes, a sparse Gaussian process approximation is provided. This approximation permits the efficient computation of predictions for the drift and diffusion terms by using a distribution over a small subset of pseudosamples. The proposed method has been validated using both simulated data and real data from economy and paleoclimatology. The application of the method to real data demonstrates its ability to capture the behavior of complex systems.


Analysis of trends and opportunities of anti-allergy patents in China from 1998 to 2008.
The prevalence of allergic diseases has increased dramatically in recent decades. Holding patents is one of the means to protect good anti-allergy products. However, little is known of anti-allergy patent situation in China. The paper summarized and analyzed anti-allergy patents issued in China from January 1988 to September 2008. A total of 789 anti-allergy patents have been granted in China during the 20 years. China, European countries, USA, Japan and other countries possesses 44%, 21%, 19%, 12% and 4% of all of these anti-allergy patents respectively. Interestingly, 88% anti-allergy patents issued to Chinese are held by civilians, whereas vast majority of the patents issued to foreigners were held by pharmaceutical companies. All anti-allergy patents are focused on synthetic compounds, Traditional Chinese Medicines (TCM),combinations of synthetic compounds and TCM (CST), biological products and medical apparatus. The anti-allergy patents in China mainly focus on well-known targets, such as histamine receptor and leukotrienes, which consist of 93% of patents for validated targets. Approximately 93% targeting diseases are bronchial asthma, allergic rhinitis and atopic dermatitis. Our analyzing results indicate that there are great opportunities for application of patents on development of novel anti-allergic compounds and modernization of TCM in China.


[The quantitative testing of V617F mutation in gen JAK2 using pyrosequencing technique].
The somatic mutation V617F in gen JAK2 is a frequent cause of chronic myeloprolific diseases not conditioned by BCR/ABL mutation. The quantitative testing of relative percentage of mutant allele can be used in establishing severity of disease and its prognosis and in prescription of remedy inhibiting activity of JAK2. To quantitatively test mutation the pyrosequencing technique was applied. The developed technique permits detecting and quantitatively, testing percentage of mutation fraction since 7%. The "gray zone" is presented by samples with percentage of mutant allele from 4% to 7%. The dependence of expected percentage of mutant fraction in analyzed sample from observed value of signal is described by equation of line with regression coefficients y = - 0.97, x = -1.32 and at that measurement uncertainty consists ± 0.7. The developed technique is approved officially on clinical material from 192 patients with main forms of myeloprolific diseases not conditioned by BCR/ABL mutation. It was detected 64 samples with mautant fraction percentage from 13% to 91%. The developed technique permits implementing monitoring of therapy of myeloprolific diseases and facilitates to optimize tactics of treatment.


Ontogeny, understorey light interception and simulated carbon gain of juvenile rainforest evergreens differing in shade tolerance.
A long-running debate centres on whether shade tolerance of tree seedlings is mainly a function of traits maximizing net carbon gain in low light, or of traits minimizing carbon loss. To test these alternatives, leaf display, light-interception efficiency, and simulated net daily carbon gain of juvenile temperate evergreens of differing shade tolerance were measured, and how these variables are influenced by ontogeny was queried. The biomass distribution of juveniles (17-740 mm tall) of seven temperate rainforest evergreens growing in low (approx. 4 %) light in the understorey of a second-growth stand was quantified. Daytime and night-time gas exchange rates of leaves were also determined, and crown architecture was recorded digitally. YPLANT was used to model light interception and carbon gain. An index of species shade tolerance correlated closely with photosynthetic capacities and respiration rates per unit mass of leaves, but only weakly with respiration per unit area. Accumulation of many leaf cohorts by shade-tolerant species meant that their ratios of foliage area to biomass (LAR) decreased more gradually with ontogeny than those of light-demanders, but also increased self-shading; this depressed the foliage silhouette-to-area ratio (STAR), which was used as an index of light-interception efficiency. As a result, displayed leaf area ratio (LAR(d) = LAR × STAR) of large seedlings was not related to species shade tolerance. Self-shading also caused simulated net daily carbon assimilation rates of shade-tolerant species to decrease with ontogeny, leading to a negative correlation of shade tolerance with net daily carbon gain of large (500 mm tall) seedlings in the understorey. The results suggest that efficiency of energy capture is not an important correlate of shade tolerance in temperate rainforest evergreens. Ontogenetic increases in self-shading largely nullify the potential carbon gain advantages expected to result from low respiration rates and long leaf lifespans in shade-tolerant evergreens. The main advantage of their long-lived leaves is probably in reducing the costs of crown maintenance.


[Nonalcoholic fatty liver disease: clinical and histological characteristics in obese who underwent bariatric surgery].
Obesity is an important risk factor of Nonalcoholic Fatty Liver Disease (NAFLD) and it has been considered a predictor of severity of this condition. However, in severe obese patients the spectrum of NAFLD is in discussion. To describe the clinical and histological characteristics of NAFLD in obese patients submitted to bariatric surgery. The study included 141 severe obese (BMI > or = 35kg/m2) who underwent bariatric surgery from October 2004 to May 2005 had clinical and histological diagnosis of NAFLD. alcoholic intake more than 140 g/week, positive markers for other liver diseases. All patients were submitted to hepatic biopsy, as first procedure during the surgery. The mean age of the patients was of 37.3 +/- 11.1 years and 76.4% were female. BMI was greater than 40 kg/m2 in 77.7% of the cases. The frequency of metabolic syndrome was 51.9% (104). Elevated aminotransferases and hepatic steatosis on ultrasound were present in 29.5% (105) and 59.0% (105) respectively. Normal liver biopsy or unspecfic findings were found in 11.3% of the cases and NAFLD in 88.7%: isolated steatosis in 2.8%, steatohepatitis (NASH) in 85.1% (NASH and fibrosis in 76.6%) and cirrhosis in 0.7%. NAFLD in severe obese patients, in general, was asymptomatic and presented normal enzymes, liver function and ultrasound. However, it has a large histological spectrum and cases of steatohepatitis with fibrosis were more frequent. These results suggest that liver biopsy may be considered during the bariatric surgery to better diagnosis and prognosis of severe obese patients.


Age- and sex-related differences in corneal epithelial thickness measured with spectral domain anterior segment optical coherence tomography among Egyptians.
Is to measure the corneal epithelial thickness (CET) in a group of healthy Egyptian population and to investigate its variation with age and sex using spectral domain-anterior segment optical coherence tomography (SD-AS-OCT).This cross-sectional observational study includes 240 eyes of 120 healthy individuals (60 men, 60 women). Each gender was divided into 4 equal groups according to age as follows (18-29 years), (30-44 years), (45-59 years), and (60-80 years). The CET in 17 points over a corneal diameter of 6.0 mm was measured in each subject by SD-AS-OCT. The regional thickness changes were compared in different age groups of each gender separately and the correlations between the CET, age, and gender were analyzed.The CET of the central cornea (2 mm), the paracentral and the midperipheral zones (2-5 and 5-6 mm, respectively) of all males and females groups demonstrates highly significant changes with age (P < .001) with no significant difference between males and females. The measured parameters in the 2 age groups below 45 and above 45 years old revealed statistically significant difference with lower values in the elderly group (P < .001).The CET became thinner with age in the central, paracentral, and midperipheral zones in both genders and there is no difference between males and females. These findings could be valuable in refractive surgeries especially in age over 45.


Visual disorders after traumatic brain injury in developmental age.
Visual disorders secondary to TBI are common, often multiple, associated with complex clinical pictures; in developmental age they may particularly interfere with the development process, and compromise the rehabilitation and outcome processes. The aim of this study is to identify visual disorders in 56 post-traumatic children admitted to the Traumatic Brain Injury Unit. All patients underwent a complete clinical, neurological and neuroophthalmological assessment. Correlations were studied between visual disorders and clinical parameters of acute phase, age at trauma, neuroimaging data and outcome, in order to identify possible risk factors for their occurrence. A high incidence was found of complex visual disorders following head trauma: decreased visual acuity, together with a convergence oculo-motor deficit, is the most frequently detected deficit. Trauma severity, indicated by duration of coma, is associated with most of the visual disorders and appears to be the main risk factor conducive to their appearance.


Determination of neutrophil Fcgamma receptor IIIb antigens (HNA-1a, HNA-1b and HNA-1c) by fluorescence-primed allele-specific polymerase chain reaction.
We evaluate a technique for genotyping HNA-1a, -1b and -1c antigens, resorting to fluorescence-primed allele-specific polymerase chain reaction (FPAS-PCR), and determine the frequency of the different genotypes in a normal Portuguese population. Our results indicate that the FPAS-PCR system is a reliable and simple tool for genotyping the neutrophil Fcgamma receptor IIIB antigens. The HNA-1a, -1b and -1c gene frequencies of 42.98, 84.21 and 6.14%, respectively, found in this study are similar to those reported for other white populations.


What to choose and why to use - a critical review on the clinical relevance of rASRM, EFI and Enzian classifications of endometriosis.
Endometriosis is a common benign gynaecological disease that affects pelvic structures and causes adhesions. Endometriosis outside the pelvis exists but is rarer. Deep endometriosis may affect organs such as the urinary bladder, ureters, bowel and sacral roots. Adenomyosis (growth of endometrium in the myometrium, sometimes explained by disruption of the uterine junctional zone) frequently co-exists with deep endometriosis. Over the past decades, multiple attempts have been made to describe the anatomical extent of endometriosis. Out of approximately 20 classification systems suggested and published so far, three have gained widespread acceptance. These are the rASRM (American Society of Reproductive Medicine) classification, the Endometriosis Fertility Index (EFI) and the Enzian classification. Ideally, a classification system should be useful both for describing disease extent based on surgical findings and results of imaging methods (ultrasound, magnetic resonance imaging). To highlight the advantages and disadvantages of the three classification systems. This is a narrative review based on selected publications and experience of the authors. We discuss the current literature on the use of the rASRM, EFI and Enzian classification systems for describing disease extent with imaging methods and for prediction of fertility, surgical complexity, and risk of surgical complications. We underline the need for one universally acceptable terminology to describe the extent of endometriosis. A useful classification system for endometriosis should describe the sites and extent of the disease, be related to surgical complexity and to disease-associated symptoms, including subfertility and should satisfy needs of both, imaging specialists for pre-operative classification and surgeons. The need for such a system is obvious and is provided by the #Enzian classification. Future research is necessary to test its validity.


[Incidence of antinuclear antibodies during treatment with acebutolol. A 1-year prospective study in 45 hypertensive patients treated by monotherapy].
Determinations of antinuclear antibodies (ANA) were performed before treatment, then every 3 months for one year, in 45 hypertensive patients treated with acebutolol alone in daily doses equal or superior to 800 mg. Non significant ANA titers (1/10 to 1/40) were detected before treatment in 8.8% of the patients. After one year of treatment, 15.5% of the patients were found to have antinuclear antibodies. In 4 (8.8%) female patients (3 of whom were ANA-negative before treatment) the ANA titers were above 1/40. Treatment was discontinued in one of these due to the occurrence of bronchospasm. No lupus-like syndrome was observed during the course of the study. Prolonged prospective studies with acebutolol alone would be required to determine whether in the long term the incidence of significant ANA titers remains at the 8.8% level or increases.


The DNA damage checkpoint protein RAD9A is essential for male meiosis in the mouse.
In mitotic cells, RAD9A functions in repairing DNA double-strand breaks (DSBs) by homologous recombination and facilitates the process by cell cycle checkpoint control in response to DNA damage. DSBs occur naturally in the germline during meiosis but whether RAD9A participates in repairing such breaks is not known. In this study, we determined that RAD9A is indeed expressed in the male germ line with a peak of expression in late pachytene and diplotene stages, and the protein was found associated with the XY body. As complete loss of RAD9A is embryonic lethal, we constructed and characterized a mouse strain with Stra8-Cre driven germ cell-specific ablation of Rad9a beginning in undifferentiated spermatogonia in order to assess its role in spermatogenesis. Adult mutant male mice were infertile or sub-fertile due to massive loss of spermatogenic cells. The onset of this loss occurs during meiotic prophase, and there was an increase in the numbers of apoptotic spermatocytes as determined by TUNEL. Spermatocytes lacking RAD9A usually arrested in meiotic prophase, specifically in pachytene. The incidence of unrepaired DNA breaks increased, as detected by accumulation of γH2AX and DMC1 foci on the axes of autosomal chromosomes in pachytene spermatocytes. The DNA topoisomerase IIβ-binding protein 1 (TOPBP1) was still localized to the sex body, albeit with lower intensity, suggesting that RAD9A may be dispensable for sex body formation. We therefore show for the first time that RAD9A is essential for male fertility and for repair of DNA DSBs during meiotic prophase I.


Follicular Lymphoma in China: Systematic Evaluation of Follicular Lymphoma Prognostic Models.
To systematically evaluate the baseline characteristics, tumour microenvironment indicators such as the lymphocyte/monocyte ratio (LMR) and treatment response (POD24) as prognostic predictors of follicular lymphoma (FL) among Chinese patients. We retrospectively analysed 112 FL patients from 2000 to 2017, whose pathology grading included 1-3a. Absolute lymphocyte and monocyte counts were determined by cell blood counting. The Kaplan-Meier method was used to analyse the influence of prognostic predictors on progression-free survival (PFS) and overall survival (OS). Multivariate analysis was conducted using the Cox proportional risk model. The long-term survival of Chinese FL patients (median PFS, 74.8 months) was slightly better than that of patients in foreign countries. Among several prognostic models, the Follicular Lymphoma International Prognostic Index (FLIPI) score had a significant effect on both PFS and OS, while there were no independent prognostic predictors. Patients with LMR ≤3.6, ALC ≤0.6*109/L and AMC >0.6*109/L had worse OS, among which LMR was an independent indicator of OS. The POD24 subgroup had a higher frequency of high-risk patients according to FLIPI and FLIPI2 scores (63.0% vs 35.1%, P = 0.013 and 18.5% vs 3.9%, P = 0.003) and had an markedly shorter OS (P < 0.0001). This study is a systematic prognostic evaluation based on Chinese clinical data. We found a new factor, the LMR, that could independently predict prognosis compared with FLIPI or FLIPI2.


Concerns with oral health care services for adults with cognitive and intellectual disabilities.
It is of interest to document data on oral health care services for adults with cognitive and intellectual disabilities. Hence, a study protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO) with registration number: CRD42020150759. We used PubMed, Science Direct, LILACS and SCIELO to collect data from known literature using keywords containing MESH (Medical Subject Headings) terms. The risk of bias rating for the collected data was calculated using the Newcastle-Ottawa assessment Scale. The AHRQ (Agency for Healthcare, Research and Quality) was used for classifying the level of evidence in the collected data. Analysis of available data shows that there is a lack of dentists with adequate skills to treat people with disabilities resulting in high cost for dental treatment. Thus, we conclude that inconvenient location of dental clinic, lack of dentists willing to treat people with disabilities and attitude of dental staff towards people with learning disabilities were considered as barriers and challenges faced for dental health service utilization in this context.


"Unless you went in with your head under your arm": patient perceptions of emergency room visits.
There is increasing concern in Canada regarding growing pressures on emergency room care. Frequent media reports call attention to overcrowding, lengthy waiting times and the re-routing of ambulances due to the closure of emergency rooms during periods of overcrowding. Much of this information, however, is anecdotal. As such, little is known about patients' experiences in emergency rooms in Canada. The purpose of this study is to explore patients' perceptions of their most recent emergency room visit. Semi-structured, in-depth interviews were conducted with 41 men and women from two socially distinct neighbourhoods in Hamilton, Ontario, Canada. Much of the previous work on experiences in emergency room care is international in scope and uses quantitative methods to examine patient satisfaction with emergency care. This study considers patient experiences more broadly and looks beyond satisfaction to examine reasons for seeking emergency room care and the factors that shape experiences. The findings show that most patients describe their experiences in negative terms. The aspects of emergency room care that were most often linked with negative experiences were waiting times, patient perceptions of the quality of care received and staff-patient interactions. The findings are discussed in the context of recent health care reforms in Canada, which we argue have not addressed adequately the 'crisis' in emergency rooms.


Social representation of Hansen's disease thirty years after the term "leprosy" was replaced in Brazil.
Based on the theories of social representation (SC) and Central Core (CC), a structural study was undertaken regarding the neologism hanseniase (Hansen's disease), the term adopted by Brazil's Ministry of Health in the 1970s. Carried out during 2001, this study interviewed eight hundred housewives residing in the Rio de Janeiro and Duque de Caxias municipalities. It found that Hansen's disease is part of a process of modernization of common thinking, anchored in the additional representation of leprosy. This finding is understandable from the perspective that the central structure of a social representation has a historical determination, so short -and middle-term changes are not to be expected. Furthermore, there has been no ongoing investment in social marketing to make the new terminology more widely known. The authors discuss the relation between social representation and the concept of the history of mentalities.


A new one-dimensional clarifier model--verification using full-scale experimental data.
A new one-dimensional clarifier model was developed, including components of existing models, and extended with a height-dependent cross-sectional area and two flowrate-dependent dispersion coefficients. This model is evaluated using data from a detailed one-month measuring campaign on a full-scale wastewater treatment plant. The data included hourly sludge concentration profile, sludge heights at 10 minute intervals, sludge concentrations in inlet, effluent and recycle flows and regular settling properties characterised by batch setting tests. Due to the poor quality concentration measurements at the surface of the clarifier, the model was not calibrated to perform well in concentration predictions at this surface. However, excellent descriptive capabilities were obtained for sludge profiles and blanket level. The Cho et al. setting velocity function was found to be significantly better in terms of description capability than the more traditional Vesilind function.


EPR investigation of clomipramine interaction with phosphatidylcholine membranes in presence and absence of cholesterol.
The effects of tricylic antidepressant clomipramine (CLO) on the membrane properties of saturated dimyristoyl phosphatidylcholine and dipalmitoyl phosphatidylcholine as well as on unsaturated egg yolk phosphatidylcholine liposomes were investigated by the electron paramagnetic resonance spin-labeling technique, in combination with the simulation of the spectra, taking into account that the membrane is heterogeneous and composed of the regions with different fluidity characteristics. Different spin labels, monitoring membrane properties in the upper and inner parts of the membrane, were used. In general, two spectral components, having different motional characteristics, were detected in all liposomes investigated. In liposomes with saturated chains, CLO decreased the phase-transition temperature, disordered the membrane, and increased polarity in the upper part of the membrane. However, less impact was observed in liposomes with unsaturated chains. In dipalmitoyl phosphatidylcholine liposomes, it also induced molecular rearrangements near the pretransition temperature. The presence of 30 mol% cholesterol increased the fluidizing effect of CLO and modified the lateral diffusion of nitroxide in the inner part of the membrane. A unique anomalous increase in diffusion of nitroxide, dependent on CLO concentration, was detected in the temperature region where the phosphatidylcholine membrane without cholesterol experiences the phase transitions. Since the changes in the central part of the membrane were even more pronounced than in the upper part of the membrane, it could be concluded that CLO incorporates into the membrane with its hydrophobic ring parallel to the phospholipid chains.


[Autoradiographic studies of the distribution of 14C-endralazine in the mouse].
In a macroautoradiographic study in pregnant and nonpregnant mice the distribution pattern of 14C-Endralazine (6-Benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido(4,3-c)-pyridazine- mesilate), a new direct vasodilator drug, was investigated, since earlier studies with minoxidil and hydralazine had shown apparent discrepancies between the relatively short elimination-half-life and the long pharmacological effect of the drugs. After a single oral administration of 5 mg/kg 14C-endralazine the initial high amounts of radioactivity in the gastro-intestinal tract, the kidneys and the liver continuously decreased in the course of the 2nd to the 8th hour after application. 24 h after administration the drug was nearly completely eliminated from these organs except the liver. A remarkably high and persistent affinity of 14C-radioactivity to the blood vessel walls was found even 48 h after application which could explain the long acting pharmacological response to the drug. Only low levels of radioactivity were registrated in the fetus of pregnant mice.


Vitamin D and insulin resistance.
Vitamin D is a steroid hormone, which in active form binds to the vitamin D receptor. Expression of the vitamin D receptor in diverse cell types (pancreatic islet cells, myocytes, hepatocytes and adipocytes) raises the suspicion that vitamin D may be involved in multiple cellular processes, including the response to insulin. Insulin resistance is a characteristic feature of type 2 DM, and its attenuation may reduce the incidence of type 2 DM and cardiovascular disease. In observational studies, low serum 25-hydroxyvitamin D (25-OHD) concentrations are associated with an increased risk of type 2 DM. It has been suggested that increasing serum 25-OHD concentrations may have beneficial effects on glucose and insulin homeostasis. However, cross-sectional and interventional studies of vitamin D supplementation provide conflicting results and demonstrate no clear beneficial effect of vitamin D on insulin resistance. These studies are complicated by inclusion of different patient cohorts, different 25-OHD assays and different doses and preparations of vitamin D. Any possible association may be confounded by alterations in PTH, 1,25-dihydroxyvitamin D or tissue vitamin D concentrations. We identified 39 studies via MEDLINE and PUBMED. We review the evidence from 10 studies (seven observational and three interventional) examining vitamin D and type 2 DM incidence, and 29 studies (one prospective observational, 12 cross-sectional and 16 interventional trials) examining vitamin D and insulin resistance. Based on this data, it is not possible to state that vitamin D supplementation has any effect on type 2 DM incidence or on insulin resistance. Data from the multiple ongoing randomized controlled trials of vitamin D supplementation due to report over the next few years should help to clarify this area.


Serum levels of progesterone, estradiol, and hydrocortisone in ewes after abortion due to Listeria monocytogenes type 5.
Estradiol, progesterone, and hydrocortisone were measured by radioimmunoassay in peripheral serum of pregnant ewes infected with Listeria monocytogenes type 5 and in normal pregnant controls. Progesterone had decreased in both groups at abortion or parturition. Estradiol and hydrocortisone of control ewes had increased at parturition. In infected ewes, the serum hydrocortisone value was high for 3 days after inoculation, but it returned to preinoculation levels for the remainder of gestation. Serum concentrations of hydrocortisone did not change, and estradiol values increased slightly at abortion by infected ewes.


Measuring adult mortality using sibling survival: a new analytical method and new results for 44 countries, 1974-2006.
For several decades, global public health efforts have focused on the development and application of disease control programs to improve child survival in developing populations. The need to reliably monitor the impact of such intervention programs in countries has led to significant advances in demographic methods and data sources, particularly with large-scale, cross-national survey programs such as the Demographic and Health Surveys (DHS). Although no comparable effort has been undertaken for adult mortality, the availability of large datasets with information on adult survival from censuses and household surveys offers an important opportunity to dramatically improve our knowledge about levels and trends in adult mortality in countries without good vital registration. To date, attempts to measure adult mortality from questions in censuses and surveys have generally led to implausibly low levels of adult mortality owing to biases inherent in survey data such as survival and recall bias. Recent methodological developments and the increasing availability of large surveys with information on sibling survival suggest that it may well be timely to reassess the pessimism that has prevailed around the use of sibling histories to measure adult mortality. We present the Corrected Sibling Survival (CSS) method, which addresses both the survival and recall biases that have plagued the use of survey data to estimate adult mortality. Using logistic regression, our method directly estimates the probability of dying in a given country, by age, sex, and time period from sibling history data. The logistic regression framework borrows strength across surveys and time periods for the estimation of the age patterns of mortality, and facilitates the implementation of solutions for the underrepresentation of high-mortality families and recall bias. We apply the method to generate estimates of and trends in adult mortality, using the summary measure (45)q(15)-the probability of a 15-y old dying before his or her 60th birthday-for 44 countries with DHS sibling survival data. Our findings suggest that levels of adult mortality prevailing in many developing countries are substantially higher than previously suggested by other analyses of sibling history data. Generally, our estimates show the risk of adult death between ages 15 and 60 y to be about 20%-35% for females and 25%-45% for males in sub-Saharan African populations largely unaffected by HIV. In countries of Southern Africa, where the HIV epidemic has been most pronounced, as many as eight out of ten men alive at age 15 y will be dead by age 60, as will six out of ten women. Adult mortality levels in populations of Asia and Latin America are generally lower than in Africa, particularly for women. The exceptions are Haiti and Cambodia, where mortality risks are comparable to many countries in Africa. In all other countries with data, the probability of dying between ages 15 and 60 y was typically around 10% for women and 20% for men, not much higher than the levels prevailing in several more developed countries. Our results represent an expansion of direct knowledge of levels and trends in adult mortality in the developing world. The CSS method provides grounds for renewed optimism in collecting sibling survival data. We suggest that all nationally representative survey programs with adequate sample size ought to implement this critical module for tracking adult mortality in order to more reliably understand the levels and patterns of adult mortality, and how they are changing. Please see later in the article for the Editors' Summary.


Circulating Tumor Cell Subtypes and T-cell Populations as Prognostic Biomarkers to Combination Immunotherapy in Patients with Metastatic Genitourinary Cancer.
Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy. Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test. From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9-2.3 vs. 28.2 months; P < 0.0001-0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (P = 0.045). PD-L1+ CTCs on-therapy were associated with worse OS (P < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.


Potential Applications of PET/MR Imaging in Cardiology.
Recent advances in hybrid PET/MR imaging have opened new perspectives for cardiovascular applications. Although cardiac MR imaging has gained wider adoption for routine clinical applications, PET images remain the reference in many applications for which objective analysis of metabolic and physiologic parameters is needed. In particular, in cardiovascular diseases-more specifically, coronary artery disease-the use of quantitative and measurable parameters in a reproducible way is essential for the management of therapeutic decisions and patient follow-up. Functional MR images and dynamic assessment of myocardial perfusion from transit of intravascular contrast medium can provide useful criteria for identifying areas of decreased myocardial perfusion or for assessing tissue viability from late contrast enhancement of scar tissue. PET images, however, will provide more quantitative data on true tissue perfusion and metabolism. Quantitative myocardial flow can also lead to accurate assessment of coronary flow reserve. The combination of both modalities will therefore provide complementary data that can be expected to improve the accuracy and reproducibility of diagnostic procedures. But the true potential of hybrid PET/MR imaging may reside in applications beyond the domain of coronary artery disease. The combination of both modalities in assessment of other cardiac diseases such as inflammation and of other systemic diseases can also be envisioned. It is also predicted that the 2 modalities combined could help characterize atherosclerotic plaques and differentiate plaques with a high risk of rupture from stable plaques. In the future, the development of new tracers will also open new perspectives in evaluating myocardial remodeling and in assessing the kinetics of stem cell therapy in myocardial infarction. New tracers will also provide new means for evaluating alterations in cardiac innervation, angiogenesis, and even the assessment of reporter gene technologies. The fusion of 2 potentially competing modalities can certainly offer the best of each modality in a single procedure. The impact of such advanced technology in routine clinical practice will still need to be demonstrated. Beyond the expected improvement in patient management and the potential impact on patient outcome, PET/MR imaging will also need to establish its medicoeconomic justification in an era of health-care economic restrictions.


Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia.
Exposure of rats to hypoxia (7% O2) markedly increased the level of heme oxygenase-1 (HO-1) mRNA in several tissues. Accumulation of HO-1 transcripts was also observed after exposure of rat aortic vascular smooth muscle (VSM) cells to 1% O2, and this induction was dependent on gene transcription. Activation of the mouse HO-1 gene by all agents thus far tested is mediated by two 5'-enhancer sequences, SX2 and AB1, but neither fragment was responsive to hypoxia in VSM cells. Hypoxia-dependent induction of the chloramphenicol acetyltransferase (CAT) reporter gene was mediated by a 163-bp fragment located approximately 9.5 kilobases upstream of the transcription start site. This fragment contains two potential binding sites for hypoxia-inducible factor 1 (HIF-1). A role for HIF-1 in HO-1 gene regulation was established by the following observations: 1) HIF-1 specifically bound to an oligonucleotide spanning these sequences, 2) mutation of these sequences abolished HIF-1 binding and hypoxia-dependent gene activation in VSM cells, 3) hypoxia increased HIF-1alpha and HIF-1beta protein levels in VSM cells, and 4) hypoxia-dependent HO-1 mRNA accumulation was not observed in mutant hepatoma cells lacking HIF-1 DNA-binding activity. Taken together, these data demonstrate that hypoxia induces HO-1 expression in animal tissues and cell cultures and implicate HIF-1 in this response.


The role of the epithelial cell in Escherichia coli induced neutrophil migration into the urinary tract.
Neutrophil influx to mucosal surfaces represents one of the earliest inflammatory responses to mucosal infection. We have been studying external interactions with urinary tract epithelial cells in an attempt to understand the molecular mechanisms behind this process. Uropathogenic Escherichia coli induced urinary tract epithelial cells to secrete the neutrophil chemoattractant interleukin-8 (IL-8). IL-8 secretion was higher in response to isogenic strains expressing type 1 or P fimbriae that adhered to the epithelial surface. Deliberate colonization of the human urinary tract with E. coli induced the local production of IL-8 and levels correlated with urinary neutrophil numbers suggesting a role for IL-8 in neutrophil migration. E. coli induced neutrophil migration across urinary tract epithelial layers in vitro, and this process was blocked with anti-IL-8 antibody. IL-8's activity was localized to the epithelial surface. Furthermore, these cells were shown to constitutively express IL-8 receptor A and B messenger ribonucleic acid (mRNA), suggesting a possible role for IL-8 on epithelial cell function. E. coli enhanced the expression of intercellular adhesion molecule-1 (ICAM-1) on urinary tract epithelial cells, and neutrophil migration across urinary tract epithelial layers in vitro was dependent on epithelial ICAM-1 and neutrophil Mac-1 (CD11b/CD18) expression. These results suggest that bacterial/epithelial cell interactions play a key role in the induction of neutrophil migration during mucosal infection, and show the necessity for host-derived chemotactic factors and cell adhesion events in E. coli induced transuroepithelial migration in vitro.


Anti-inflammatory effects of prostaglandin E1: in vivo modulation of the formyl peptide chemotactic receptor on the rat neutrophil.
The local generation of chemotactic factors at sites of acute inflammation is thought to be responsible for the recruitment of polymorphonuclear leukocytes (PMN) from the intravascular compartment to the site of tissue injury (1). Many of these potent phlogistic mediators have also been shown to activate PMN resulting in degranulation of lysosomal granules with release of hydrolytic enzymes into the extracellular environment and the generation of superoxide anion (O2-) and other toxic metabolites (reviewed in Reference 2). Several in vitro studies have shown that treatment of PMN with specific prostaglandins will inhibit both soluble mediator- and particulate material-induced neutrophil lysosomal enzyme release and chemotaxis (3, 4). In vivo studies have demonstrated potent anti-inflammatory activity of prostaglandins of the E series (5-7). Systemic administration of prostaglandin E1 (PGE1) or its stable analog 15-(S)-15-methyl-PGE1 (15-M-PGE1) will inhibit neutrophil dependent immune complex tissue injury in a dose-dependent manner (8). In addition, i.v. infusion of PGE1 into humans has been shown to inhibit formyl-methionyl-leucyl-phenylalanine- (FMLP) induced lysosomal enzyme release from PMN (9). This study was undertaken to examine the effects of in vivo systemic treatment of rats with 15-M-PGE1 on FMLP-induced neutrophil lysosomal enzyme release and O2- secretion. As we will show, the modulation of FMLP-induced neutrophil function is correlated with a decrease in binding affinity for formyl-methionyl-leucyl-(3H)phenylalanine ((3H)-FMLP) to its specific receptor on the neutrophil plasma membrane. The data suggest a novel mechanism for the anti-inflammatory effects of prostaglandins of the E series.


Observation of Fourier transform near-infrared vibrational circular dichroism to 6150 cm-1.
We report here the first measurement of near-infrared (NIR) vibrational circular dichroism (VCD) with Fourier transform (FT) instrumentation. The measurements were carried out using a commercial rapid-scan FT-IR VCD spectrometer modified for operation in the NIR region between 3750 and 6150 cm-1. Overtone and combination band VCD intensities, first reported by Keiderling and Stephens using dispersive VCD instrumentation in 1976, were reproduced with equivalent signal quality and spectral resolution using collection times of only a few minutes. These results offer substantial promise for the routine use of rapid-scan FT instrumentation for the measurement of overtone and combination band VCD spectra in the NIR region.


Applied machine learning for stroke differentiation by electrical impedance tomography with realistic numerical models.
Electrical impedance tomography (EIT) may have potential to overcome existing limitations in stroke differentiation, enabling low-cost, rapid, and mobile data collection. Combining bioimpedance measurement technologies such as EIT with machine learning classifiers to support decision-making can avoid commonly faced reconstruction challenges due to the nonlinear and ill-posed nature of EIT imaging. Therefore, in this work, we advance this field through a study integrating realistic head models with clinically relevant test scenarios, and a robust architecture consisting of nested cross-validation and principal component analysis. Specifically, realistic head models are designed which incorporate the highly conductive layers of cerebrospinal fluid in the subarachnoid space and ventricles. In total, 135 unique models are created to represent a large patient population, with normal, haemorrhagic, and ischemic brains. Simulated EIT voltage data generated from these models are used to assess the classification performance of support vector machines. Parameters explored include driving frequency, signal-to-noise ratio, kernel function, and composition of binary classes. Classifier accuracy at 60 dB signal-to-noise ratio, reported as mean and standard deviation, are (79.92% ± 10.82%) for lesion differentiation, (74.78% ± 3.79%) for lesion detection, (77.49% ± 15.90%) for bleed detection, and (60.31% ± 3.98%) for ischemia detection (after ruling out bleed). The results for each method were obtained with statistics from 3 independent runs with 17,280 observations, polynomial kernel functions, and feature reduction of 76% by PCA (from 208 to 50 features). While results of this study show promise for stroke differentiation using EIT data, our findings indicate that the achievable accuracy is highly dependent on the classification scenario and application-specific classifiers may be necessary to achieve acceptable accuracy.


Protective effects of metformin in the pro-inflammatory cytokine induced intestinal organoids injury model.
Pathogenesis of inflammatory bowel disease (IBD) accompanies disrupted intestinal tight junctions. However, many approaches of therapeutics for IBD are focused only on anti-inflammatory effects and most cellular experiments are based on two-dimensional cell lines which have insufficient circumstances of intestine. Thus, here, we used three-dimensional structure intestinal organoids to investigate effects of metformin in the in vitro IBD condition. In this study, we focused on both tight junctions and the levels of inflammatory cytokines. Metformin enhances the intestinal barrier in injured intestine via upregulation of AMP-activated protein kinase, dysfunction of which contributes to the pathogenesis of intestinal diseases. We aim to investigate the effects of metformin on cytokine-induced injured intestinal organoids. Tumor necrosis factor-alpha (TNF-α) was used to induce intestinal injury in an organoid model, and the effects of metformin were assessed. Cell viability and levels of inflammatory cytokines were quantified in addition to tight junction markers. Furthermore, 4 kDa FITC-dextran was used to assess intestinal permeability. The upregulation of inflammatory cytokine levels was alleviated by metformin, which also restored the intestinal epithelium permeability in TNF-α-treated injury organoids. We confirmed that claudin-2 and claudin-7, representative tight junction markers, were also protected by metformin treatment. This study confirms the protective effects of metformin, which could be used as a therapeutic strategy for inflammatory intestinal diseases.


Impact of Experience Corps(®) participation on school climate.
We examined the impact of the Experience Corps(®) (EC) program on school climate within Baltimore City public elementary schools. In this program, teams of older adult volunteers were placed in high intensity (>15 h per week), meaningful roles in public elementary schools, to improve the educational outcomes of children as well as the health and well-being of volunteers. During the first year of EC participation, school climate was perceived more favorably among staff and students in EC schools as compared to those in comparison schools. However, with a few notable exceptions, perceived school climate did not differ for staff or students in intervention and comparison schools during the second year of exposure to the EC program. These findings suggest that perceptions of school climate may be altered by introducing a new program into elementary schools; however, research examining how perceptions of school climate are impacted over a longer period is warranted.


Analysis of animal and plant selenometabolites in roots of a selenium accumulator, Brassica rapa var. peruviridis, by speciation.
Many studies have examined the metabolic pathway of selenium (Se) compounds in Se-accumulating plants (hereafter "Se accumulators") when the plants are exposed to inorganic Se, such as selenite and selenate. However, if we were to consider Se circulation in the biosphere, the metabolism of organic Se, in particular, selenometabolites of animals and plants, in plants should be elucidated. In this study, Brassica rapa var. peruviridis, a known Se accumulator, was hydroponically cultivated and then exposed to selenometabolites of animals and plants, such as methyl-2-acetamido-2-deoxy-1-seleno-β-d-galactopyranoside (selenosugar, SeSug), trimethylselenonium (TMSe), selenomethionine (SeMet), and Se-methylselenocysteine (MeSeCys). Then, the metabolic pathway of the organic Se compounds/selenometabolites in B. rapa var. peruviridis was investigated by speciation analysis. Two selenometabolites were detected in the roots when the plant was exposed to SeMet, MeSeCys, and SeSug. They were assigned to S-(methylseleno)-glutathione and MeSeCys using electrospray tandem mass spectrometry (ESI-MS-MS) and HPLC-inductively coupled plasma mass spectrometry (ICP-MS). Contrary to SeMet, MeSeCys, and SeSug, TMSe was not metabolized even if it was more efficiently incorporated into the roots than the other Se compounds. The identified metabolites enabled us to propose a metabolic pathway for the organic Se metabolites except TMSe in the plant roots: a monomethylseleno moiety (CH3Se-) commonly existing in SeMet, MeSeCys, and SeSug was cleaved off and conjugated with GSH, and then the CH3Se group was transferred to O-acetylserine to form MeSeCys.


Zinc deficiency and clinical practice--validity of zinc preparations.
Zinc is an essential trace element and serves as the active center of approximately 300 enzymes. Therefore, zinc deficiency may be associated with a variety of clinical features such as hypogeusia, hyposmia, growth retardation, dermatitis, alopecia, gonadal hypofunction, abnormal pregnancy, susceptibility to infections, delayed wound healing, impaired glucose tolerance, and increased carcinogenesis. Zinc deficiency was reported to be on the increase in the Nagano Study conducted from 2003 to 2005. Zinc therapy is classified into two categories, zinc-supplementary and -specific treatments. Ordinarily, zinc-supplementary therapy is carried out for the symptoms and diseases caused by zinc deficiency. On the other hand, zinc-specific therapy is applied to obtain copper- and iron-chelating, antifibrotic, and antidiabetic effects. The availability of zinc-specific therapy is now confirmed in humans and animals. Hereafter, the safety of zinc therapy needs to be examined further.


Entropy Stabilization Effects and Ion Migration in 3D "Hollow" Halide Perovskites.
A recently discovered new family of 3D halide perovskites with the general formula (A)1-x(en)x(Pb)1-0.7x(X)3-0.4x (A = MA, FA; X = Br, I; MA = methylammonium, FA = formamidinium, en = ethylenediammonium) is referred to as "hollow" perovskites owing to extensive Pb and X vacancies created on incorporation of en cations in the 3D network. The "hollow" motif allows fine tuning of optical, electronic, and transport properties and bestowing good environmental stability proportional to en loading. To shed light on the origin of the apparent stability of these materials, we performed detailed thermochemical studies, using room temperature solution calorimetry combined with density functional theory simulations on three different families of "hollow" perovskites namely en/FAPbI3, en/MAPbI3, and en/FAPbBr3. We found that the bromide perovskites are more energetically stable compared to iodide perovskites in the FA-based hollow compounds, as shown by the measured enthalpies of formation and the calculated formation energies. The least stable FAPbI3 gains stability on incorporation of the en cation, whereas FAPbBr3 becomes less stable with en loading. This behavior is attributed to the difference in the 3D cage size in the bromide and iodide perovskites. Configurational entropy, which arises from randomly distributed cation and anion vacancies, plays a significant role in stabilizing these "hollow" perovskite structures despite small differences in their formation enthalpies. With the increased vacancy defect population, we have also examined halide ion migration in the FA-based "hollow" perovskites and found that the migration energy barriers become smaller with the increasing en content.


Effectiveness of Er:YAG laser in cavity preparation for retrograde filling--in vitro study.
The purpose of this study was to determine the sealing quality of Super EBA cement in laser prepared root-end cavities in comparison with root-end cavities classically prepared with steel burrs. Two groups of three millimeter root sections were prepared. The first group was prepared with the Er:YAG laser and the second group with a steel burr mounted on a surgical handpiece. The sections were filled with Super EBA cement and tested for leakage with fluid transport techniques. The sealing quality of Super EBA cement in the classically prepared root-end cavities was better, but there was no statistically significant difference between the two preparation techniques. The possible reason for greater leakage in the laser prepared root-end cavities was probably the irregular shape of the root-end cavity.


Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.
Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2-compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70-kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70-kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration-dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.


Internal ophthalmoplegia following chickenpox.
A six year old girl with a six day history of varicella presented with a fixed dilated pupil, paralysis of accomodation and an anterior uveitis in the left eye. The anterior uveitis rapidly resolved but the internal ophthalmoplegia has persisted for fifteen months. Four similar cases are reviewed.


Mobile genomics: tools and techniques for tackling transposons.
Next-generation sequencing approaches have fundamentally changed the types of questions that can be asked about gene function and regulation. With the goal of approaching truly genome-wide quantifications of all the interaction partners and downstream effects of particular genes, these quantitative assays have allowed for an unprecedented level of detail in exploring biological interactions. However, many challenges remain in our ability to accurately describe and quantify the interactions that take place in those hard to reach and extremely repetitive regions of our genome comprised mostly of transposable elements (TEs). Tools dedicated to TE-derived sequences have lagged behind, making the inclusion of these sequences in genome-wide analyses difficult. Recent improvements, both computational and experimental, allow for the better inclusion of TE sequences in genomic assays and a renewed appreciation for the importance of TE biology. This review will discuss the recent improvements that have been made in the computational analysis of TE-derived sequences as well as the areas where such analysis still proves difficult. This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'.


History repeats itself: Role of characterizing flavors on nicotine use and abuse.
The popularity of e-cigarettes has skyrocketed in recent years, and most vapers use flavored e-cigarette products. Consumption of flavored e-cigarettes exceeds that of combustible cigarettes and other tobacco products among adolescents, who are particularly vulnerable to becoming nicotine dependent. Flavorings have been used by the tobacco industry since the 17th century, but the use of flavors by the e-cigarette industry to create products with "characterizing" flavors (i.e. flavors other than tobacco or menthol) has sparked a public health debate. This review addresses the possibility that characterizing flavors make nicotine more appealing, rewarding and addictive. It also discusses ways in which preclinical and clinical studies could improve our understanding of the mechanisms by which flavors may alter nicotine reward and reinforcement. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.


Accelerated gene evolution and subfunctionalization in the pseudotetraploid frog Xenopus laevis.
Ancient whole genome duplications have been implicated in the vertebrate and teleost radiations, and in the emergence of diverse angiosperm lineages, but the evolutionary response to such a perturbation is still poorly understood. The African clawed frog Xenopus laevis experienced a relatively recent tetraploidization ~40 million years ago. Analysis of the considerable amount of EST sequence available for this species together with the genome sequence of the related diploid Xenopus tropicalis provides a unique opportunity to study the genomic response to whole genome duplication. We identified 2218 gene triplets in which a single gene in X. tropicalis corresponds to precisely two co-orthologous genes in X. laevis--the largest such collection published from any duplication event in animals. Analysis of these triplets reveals accelerated evolution or relaxation of constraint in the peptides of the X. laevis pairs compared with the orthologous sequences in X. tropicalis and other vertebrates. In contrast, single-copy X. laevis genes do not show this acceleration. Duplicated genes can differ substantially in expression levels and patterns. We find no significant difference in gene content in the duplicated set, versus the single-copy set based on molecular and biological function ontologies. These results support a scenario in which duplicate genes are retained through a process of subfunctionalization and/or relaxation of constraint on both copies of an ancestral gene.


Automated Aortic Anatomy Analysis: from Image to Clinical Indicators.
Most cerebrovascular diseases (including strokes and aneurysms) are treated endovascularly with catheters that are navigated from the groin through the vessels to the brain. Many patients have complex anatomy of the aortic arch and supra-aortic vessels, which can make it difficult to select the best catheters for navigation, resulting in longer procedures and more complications or failures. To this end, we propose a framework dedicated to the analysis of the aortic arch and supra-aortic trunks. This framework can automatically compute anatomical and geometrical features from meshes segmented beforehand via CNN-based pipeline. These features such as arch type, tortuosity and angulations describe the navigational difficulties encountered during catheterization. Quantitative and qualitative validation was performed by experienced neuroradiologists, leading to reliable vessel characterization.Clinical relevance- This method allows clinicians to determine the type and the anatomy of the aortic arch and its supra-aortic trunks before endovascular procedures. This is essential in interventional neuroradiology, such as navigation with catheters in this complex area.


Preferential release of bioactive luteinizing hormone in response to endogenous and low dose exogenous gonadotropin-releasing hormone pulses in man.
We used the rat interstitial cell testosterone (RICT) bioassay to assess biological LH activity secreted in response to endogenous and low dose exogenous GnRH pulses in normal men. The absence of nonspecific plasma effects in the LH bioassay was demonstrated by the finding of undetectable levels of LH bioactivity despite low but measurable immunoactivity in 10 hypogonadotropic men. Moreover, bolus injections of human LH in 6 hypogonadotropic men defined a curvilinear relationship between plasma bioactive and immunoactive LH concentrations, in which the extrapolated concentration of plasma bioactive LH at a zero dose of immunoactive LH was indistinguishable from zero. Zero bioactive LH intercepts were also found when physiological bio- and immunoactive LH concentrations derived from 7 intensively sampled normal men were subjected to linear regression using 2-dimensional error fitting. In these men, exogenous low dose (10 micrograms) iv GnRH administration resulted in preferential release of bioactive LH, with a consequent significant increase in the median plasma bio- to immunoactive (bioimmuno) LH ratio. This pattern mimicked that of endogenous LH pulsatility, in which median intrapulse bio:immuno LH ratios were significantly higher than median interpulse ratios in the same individuals (P = 0.006). Increases in spontaneous plasma bio:immuno LH ratios were not attributable to spurious rises in bioactive LH concentrations associated with decreases in serum immunoactive LH levels. Rather, sample cross-correlation analyses demonstrated positive correlations between bio- and immunoactive LH at lags of 0-40 min, indicating that both hormones increased or decreased concomitantly. These results demonstrate that LH is secreted physiologically in pulses of increased biological activity, presumably reflecting the release of a functionally compartmentalized LH pool relatively enriched in biologically active hormone. Accordingly, evaluation of the plasma bio:immuno LH ratio can provide a useful and sensitive index of qualitative changes in the LH molecule in response to endogenous (spontaneous) and exogenous GnRH stimulation.


A research on the microfungal flora of some greenhouse soils in the vicinity of Lapseki Canakkale, Turkey.
Qualitative and quantitative distributions of microfungal flora of the some greenhouse soils in the vicinity of Lapseki, Canakkale were studied. A total of 25 soil samples were collected from 10 cm depth in five greenhouses. Using soil dilution technique, 128 different microfungal isolates were obtained Isolates collected belonged to Oomycetes (1), Zygomycetes (7), Ascomycetes (9) and 96 belonging to the Deuteromycetes Fifteen isolates were classified as Mycelia Sterilia. The genera of microfungi most abundant in the greenhouse soils were Aspergillus, Penicillium, Geomyces, Exophiala and Fusarium. Qualitative and quantitative distributions of the Aspergillus were higher than those of the other genera. It was found that the maximum value was in greenhouse 5 and the minimum value was in greenhouse 4. The solarization method was the most effective in reducing fungal numbers.


Early continence after radical prostatectomy: A systematic review.
Urinary incontinence is the adverse effect with more impact on patients' quality of life after undergoing radical prostatectomy. The objective of this study is to review the present evidence that describes the variations on surgical techniques which aim to preserve urinary continence after radical prostatectomy. We searched the literature on PubMed, Cochrane, and ScienceDirect according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement, using the PICO review protocol. The search terms were urinary continence, urinary incontinence, urinary leakage, radical prostatectomy, open radical prostatectomy, laparoscopic prostatectomy, robot-assisted laparoscopic prostatectomy, robotic prostatectomy. We identified 1,603 registers, and 27 articles were reviewed for meeting the inclusion criteria. Six of them are randomized clinical trials and 4 of them, meta-analysis. The surgical techniques more frequently used to achieve early urinary continence are bladder neck and neurovascular bundles preservation, as well as the reconstruction of the rhabdosphincter. The latter has been presented in three randomized clinical trials. Even though some approaches have obtained improved functional outcomes, the lack of consensus on the definition of urinary incontinence and its measurement methods have not advocated for the creation of technical recommendations based on scientific evidence. The reconstruction of the rhabdosphincter is the only technique that has shown improved functional results through randomized trials. The current evidence is limited and heterogenous, and more studies with consistent criteria are needed in order to establish a standard surgical technique.