Mitigating climate change: the role of domestic livestock.
Livestock contribute directly (i.e. as methane and nitrous oxide (N2O)) to about 9% of global anthropogenic greenhouse gas (GHG) emissions and around 3% of UK emissions. If all parts of the livestock production lifecycle are included (fossil fuels used to produce mineral fertilizers used in feed production and N2O emissions from fertilizer use; methane release from the breakdown of fertilizers and from animal manure; land-use changes for feed production and for grazing; land degradation; fossil fuel use during feed and animal production; fossil fuel use in production and transport of processed and refrigerated animal products), livestock are estimated to account for 18% of global anthropogenic emissions, but less than 8% in the UK. In terms of GHG emissions per unit of livestock product, monogastric livestock are more efficient than ruminants; thus in the UK, while sheep and cattle accounted for 32% of meat production in 2006, they accounted for 48% of GHG emissions associated with meat production. More efficient management of grazing lands and of manure can have a direct impact in decreasing emissions. Improving efficiency of livestock production through better breeding, health interventions or improving fertility can also decrease GHG emissions through decreasing the number of livestock required per unit product. Increasing the energy density of the diet has a dual effect, decreasing both direct emissions and the numbers of livestock per unit product, but, as the demands for food increase in response to increasing human population and a better diet in some developing countries, there is increasing competition for land for food v. energy-dense feed crops. Recalculating efficiencies of energy and protein production on the basis of human-edible food produced per unit of human-edible feed consumed gave higher efficiencies for ruminants than for monogastric animals. The policy community thus have difficult decisions to make in balancing the negative contribution of livestock to the environment against the positive benefit in terms of food security. The animal science community have a responsibility to provide an evidence base which is objective and holistic with respect to these two competing challenges.


Targeting antimalarial metabolites from the actinomycetes associated with the Red Sea sponge Callyspongia siphonella using a metabolomic method.
Malaria is a persistent illness that is still a public health issue. On the other hand, marine organisms are considered a rich source of anti‑infective drugs and other medically significant compounds. Herein, we reported the isolation of the actinomycete associated with the Red Sea sponge Callyspongia siphonella. Using "one strain many compounds" (OSMAC) approach, a suitable strain was identified and then sub-cultured in three different media (M1, ISP2 and OLIGO). The extracts were evaluated for their in-vitro antimalarial activity against Plasmodium falciparum strain and subsequently analyzed by Liquid chromatography coupled with high-resolution mass spectrometry (LC-HR-MS). In addition, MetaboAnalyst 5.0 was used to statistically analyze the LC-MS data. Finally, Molecular docking was carried out for the dereplicated metabolites against lysyl-tRNA synthetase (PfKRS1). The phylogenetic study of the 16S rRNA sequence of the actinomycete isolate revealed its affiliation to Streptomyces genus. Antimalarial screening revealed that ISP2 media is the most active against Plasmodium falciparum strain. Based on LC-HR-MS based metabolomics and multivariate analyses, the static cultures of the media, ISP2 (ISP2-S) and M1 (M1-S), are the optimal media for metabolites production. OPLS-DA suggested that quinone derivatives are abundant in the extracts with the highest antimalarial activity. Fifteen compounds were identified where eight of these metabolites were correlated to the observed antimalarial activity of the active extracts. According to molecular docking experiments, saframycin Y3 and juglomycin E showed the greatest binding energy scores (-6.2 and -5.13) to lysyl-tRNA synthetase (PfKRS1), respectively. Using metabolomics and molecular docking investigation, the quinones, saframycin Y3 (5) and juglomycin E (1) were identified as promising antimalarial therapeutic candidates. Our approach can be used as a first evaluation stage in natural product drug development, facilitating the separation of chosen metabolites, particularly biologically active ones.


gamma-Glutamyltransferase is a promising biomarker for cardiovascular risk.
Oxidative stress plays a crucial role in a variety of clinical settings of atherogenesis, and mediates many pathways linked to atherosclerosis and inflammation. gamma-Glutamyltransferase (GGT), an enzyme responsible for the extracellular catabolism of antioxidant glutathione, may directly take part in atherogenesis and evolve as a potential biochemical risk indicator of cardiovascular morbidity and mortality. Classically, GGT has been thought of as a diagnostic tool for hepatobiliary disorders and alcohol abuse. More recently, growing body of data points out that serum GGT levels can aid detection of individuals at high risk for subsequent cardiovascular events, and thus have an application in primary and secondary prevention of cardiovascular disease. Although several investigations have shown that some drugs are effective in decreasing both serum lipids and GGT, and concomitantly the incidence of subsequent cardiovascular events; large-scale randomized trials are required to explore this impact directly. Based on current experimental and epidemiological studies, we postulate here that GGT present in the serum, even within its laboratory reference intervals regarded as physiologically normal, is a promising biomarker for cardiovascular risk.


One-pot regiospecific synthesis of imidazo[1,2-a]pyridines: a novel, metal-free, three-component reaction for the formation of C-N, C-O, and C-S bonds.
A novel transition-metal-free three-component reaction for the construction of imidazo[1,2-a]pyridines has been developed. It represents a facile approach for the formation of C-N, C-O, and C-S bonds from ynals, pyridin-2-amines, and alcohols or thiols.


A review of measures of quality of life for children with chronic illness.
To identify currently available generic and disease specific measures of quality of life (QoL) for work with children; and make recommendations about the future development and application of QoL measures. Systematic searches were conducted to identify measures of QoL. Primary research papers were coded by the authors on the basis of predefined inclusion and exclusion criteria. Of the 137 papers included in the review, 43 involved the development of a new measure. These included 19 generic and 24 disease specific measures. Almost half the measures were developed in the USA. Measures were identified which were appropriate for children across a broad age range, and included provision for completion by different respondents (child only, parent only, or both). There were no clear distinctions between measures of QoL, health, or functional status. We have identified a small number of measures which fulfil basic requirements and could be used to assess QoL in clinical trials or following interventions. However, there remain a number of problems in measuring QoL in children. These include limited availability of disease specific measures; discrepancies between child and parent ratings; limited availability of measures for self completion by children; lack of precision regarding the content of domains of QoL; and the cultural appropriateness of measures developed elsewhere for children in the UK.


Simultaneous estimation of andrographolide and wedelolactone in herbal formulations.
Andrographolide and wedelolactone are active components of Andrographis paniculata and Eclipta alba, respectively. The extracts of these plants are used in many traditional hepatoprotective formulations. An attempt has been made to develop an accurate, precise and specific HPTLC method to quantify simultaneously both these chemical markers of diversified chemical structures in different dosage forms like tablet and syrup. Precoated silica 60F(254) plates with toluene:acetone:formic acid (9:6:1) as mobile phase and detection wavelength of 254 nm were used. The method was validated in terms of linearity, accuracy, precision and specificity. The calibration curve was found to be linear between 200 to 400 ng/spot for andrographolide and 100 to 200 ng/spot for wedelolactone. The limit of detection and the limit of quantification for andrographolide were 26.16 and 79.28 ng/spot, respectively and for wedelolactone 5.06 and 15.32 ng/spot, respectively.


Smac mimetic and glucocorticoids synergize to induce apoptosis in childhood ALL by promoting ripoptosome assembly.
Apoptosis resistance contributes to poor outcome in pediatric acute lymphoblastic leukemia (ALL). Here, we identify a novel synergistic combination of Smac mimetic BV6 and glucocorticoids (GCs) (ie, dexamethasone, prednisolone) to trigger apoptosis in ALL cells. BV6 and GCs similarly cooperate to induce apoptosis in patient-derived leukemia samples, underlining the clinical relevance. Importantly, BV6/dexamethasone cotreatment is significantly more effective than monotherapy to delay leukemia growth in a patient-derived xenograft model of pediatric ALL without causing additional side effects. In contrast, BV6 does not increase cytotoxicity of dexamethasone against nonmalignant peripheral blood lymphocytes, mesenchymal stromal cells, and CD34-positive hematopoietic cells. We identify a novel mechanism by showing that BV6 and dexamethasone cooperate to deplete cIAP1, cIAP2, and XIAP, thereby promoting assembly of the ripoptosome, a RIP1/FADD/caspase-8-containing complex. This complex is critical and is required for BV6/dexamethasone-induced cell death, because RIP1 knockdown reduces caspase activation, reactive oxygen species production, and cell death. Ripoptosome formation occurs independently of autocrine/paracrine loops of death receptor ligands, because blocking antibodies for TNFα, tumor necrosis factor-related apoptosis-inducing ligand, or CD95 ligand or knockdown of death receptors fail to rescue BV6/dexamethasone-induced cell death. This is the first report showing that BV6 sensitizes for GC-triggered cell death by promoting ripoptosome formation with important implications for apoptosis-targeted therapies of ALL.


Hypocholesteremic derivatives of styrylacetic acid. 1. gem-Dimethyl analogs of benzalbutyric acid.
The preparation of alpha, alpha-dimethyl analogs of the hypocholesteremic and hypolipemic agent 3-methyl-4-phenyl-3-butenoic acid (beta-benzalbutyric acid, BBA) is described. These compounds were prepared as part of a continuing program directed toward a study of the structure-activity interrelationships of styryl- and phenoxyacetic acid antilipemic agents and the preparation of metabolically resistant analogs of BBA. Preliminary results on the in vitro ability of the compounds to inhibit cholesterol biosynthesis indicate that alpha, alpha-dimethyl substitution reduces activity although the potency of the p-chloro analog 6b was comparable to that of BBA.


Laparoscopic versus open splenectomy in the management of hematologic diseases.
Splenectomy is the best available treatment for severe forms of hereditary spherocytosis, idiopathic thrombocytopenic purpura, and other hematologic conditions when these prove refractory to conservative management. It has been employed for many decades with low mortality and favorable remission rates. The use of laparoscopic splenectomy in recent years has been rapidly and even enthusiastically adopted in this field. However, the exact role of laparoscopic versus open surgery for hematologic diseases is still debated. In this study of 58 adult patients, laparoscopic procedures were compared with conventional splenectomies for similar indications. All patients were operated on within an 8-year period. Subjects underwent similar procedures under the supervision of the same surgical school and were compared regarding age, gender, body mass index, and diagnosis. Laparoscopically managed cases (Group I, n = 30) were prospectively followed according to a written protocol, whereas the same investigation was retrospectively done with regard to traditional laparotomy (Group II, n = 28). Methods included general and demographic findings, duration and technical steps of operation, blood loss, weight of spleen, need for conversion (in minimally invasive subjects), intraoperative and postoperative complications, time until realimentation, postoperative hospitalization, mortality, and late follow-up including recurrence rate. Idiopathic thrombocytopenic purpura was the surgical indication in over 50% of the patients in both groups, but familial spherocytosis, thalassemia, myelodysplasia, and lymphomas were also represented in this series. Laparoscopic procedures took more time to perform (P = 0.004), and postoperative hospitalization was 2 days shorter, but this difference was not statistically significant. Postoperative hematocrit and volume of blood transfusions was equivalent, although the laparoscopic cases had a somewhat lower preoperative hematocrit (NS) and displayed better recovery for this measurement (P = 0.03). More patients in Group I were able to accept oral food on the first day than subjects undergoing conventional operations (P < 0.05). Relatively few conversions were necessary during the minimally invasive surgeries (13.3%), and postoperative early and late complications as well as recurrences occurred in similar proportions. Also, the mean weight of the spleen was not statistically different between the groups, although there was a marked numerical tendency toward larger masses in conventional procedures. No spleen in Group I exceeded 2.0 kg, whereas in Group II values up to 4.0 kg occurred, and the mean weight was 50% higher in the latter group. 1) Minimally invasive splenectomy was essentially comparable to open surgery with regard to safety, efficacy, and late results; 2) Advantages concerning shorter postoperative hospitalization could not be shown, despite earlier food intake and a non-significant tendency toward earlier discharge; 3) This new modality should be considered an option in cases of hematologic conditions whenever the spleen is not hugely enlarged.


Multiple potential clinical benefits for 1alpha,25-dihydroxyvitamin D3 analogs in kidney transplant recipients.
Therapeutic trials of 1alpha,25(OH)(2)D(3) and related synthetic analogs are merited in diverse clinical fields, including treatment or prevention of bone disease, cancer, immune-mediated diseases, cardiovascular diseases, and prostatic hypertrophy. Potential difficulties of carrying out such trials successfully, include experimental data suggesting relatively modest therapeutic effects of 1alpha,25(OH)(2)D(3) analogs as stand-alone intervention and the likely requirement for large study group size and lengthy follow-up periods, if individual prophylactic effects are to be proven. Thus, it may be wise to identify patient groups with multiple potential benefits, accelerated disease risks, and the possibility for exploring synergistic pharmacological effects, in whom to carry out clinical trials of 1alpha,25(OH)(2)D(3) analogs. With this consideration in mind, the suitability of kidney transplant recipients for such studies is discussed. Although, highly effective in reversing end-stage renal disease, kidney transplantation continues to be limited by heightened risk of osteoporosis, persistent hyperparathyroidism, acute and chronic immunological injury, new cancer diagnosis, and cardiovascular events. In addition, kidney transplant recipients generally receive multiple immunosuppressants with a high prevalence of medication-related toxicities. Finally, it is pointed out that clinical trials carried out in organ transplant recipients provide a unique opportunity for longitudinal comparison of target tissue structural and gene expression profiles among treated and control patient groups. It is proposed that addition of a 1alpha,25(OH)(2)D(3) analog to conventional post-kidney transplant medication regimens is likely to be associated with measurable effects to prevent or retard multiple important complications and that this patient group is especially suitable for carrying out clinical trials of these compounds.


Inflammatory myositis in systemic lupus erythematosus.
The coexistence of inflammatory myositis in systemic lupus erythematosus (SLE) has not been extensively studied. In this study, we describe the incidence, distinct types of inflammatory myositis, and risk factors for this finding in a cohort of pediatric and adult SLE patients. We identified SLE patients with coexisting myositis followed between 2010 and 2019 at two pediatric hospitals and one adult hospital. Demographic, clinical, laboratory, and pathological features of myositis were collected, and descriptive statistics were applied. A total of 1718 individuals were identified as having SLE (451 pediatric and 1267 adult patients). Of these, 108 were also diagnosed with inflammatory myositis (6.3%). People of black race had a significantly higher prevalence of inflammatory myositis, as did those with childhood-onset SLE compared to adult-onset disease. In the majority of patients (68%), SLE and inflammatory myositis presented concurrently. Overlapping features of systemic sclerosis occurred in 48%, while dermatomyositis-specific rashes were present in a third. Arthralgias and inflammatory arthritis were seen in >90%. Thrombotic events and significant pregnancy-related morbidity were present in more than a third of patients. Lymphopenia, hypocomplementemia, and a positive RNP were the most common laboratory features noted. Myositis-specific antibodies (MSA) and myositis-associated antibodies (MAA) were present in >40% of patients. A review of 28 muscle biopsy reports revealed a wide array of pathological features, including nonspecific changes, dermatomyositis, polymyositis, and necrotizing auto-immune myopathy. In our SLE patient population, 6.3% presented with concurrent inflammatory myositis. Dermatomyositis-specific rashes, clinical features of systemic sclerosis, arthralgias and arthritis, and cytopenias were common coexisting clinical manifestations. A high frequency of RNP, MSA, and MAA were found. People of black race and with childhood-onset disease had a higher prevalence of myositis. Our findings suggest that SLE patients of black race, with childhood-onset SLE, and who possess MSA or MAA should be routinely screened for myositis.


Early-onset drusen in a girl with bloom syndrome: probable clinical importance of an ocular manifestation.
Ophthalmic examination of a girl admitted with the complaint of growth failure revealed retinal hard drusen. It was surprising to observe drusen in a child because they represent an age-related degenerative change in normal individuals. After further evaluation, she was diagnosed to have Bloom syndrome, a premature aging syndrome. To the authors' knowledge, this is the first case of Bloom syndrome associated with drusen. It is probable that not only aging but also other fundamental cell processes, especially uncontrolled cell proliferation, might be similarly affected and might follow a more rapid course in this inherited condition presenting with drusen. The authors suggest paying extra attention to drusen during the ophthalmic assessment in the diagnosis of all Bloom syndrome patients; it may be prudent to watch more carefully for the development of cancer in patients with drusen than those without drusen.


Use of porous membranes in tissue barrier and co-culture models.
Porous membranes enable the partitioning of cellular microenvironments in vitro, while still allowing physical and biochemical crosstalk between cells, a feature that is often necessary for recapitulating physiological functions. This article provides an overview of the different membranes used in tissue barrier and cellular co-culture models with a focus on experimental design and control of these systems. Specifically, we discuss how the structural, mechanical, chemical, and even the optical and transport properties of different membranes bestow specific advantages and disadvantages through the context of physiological relevance. This review also explores how membrane pore properties affect perfusion and solute permeability by developing an analytical framework to guide the design and use of tissue barrier or co-culture models. Ultimately, this review offers insight into the important aspects one must consider when using porous membranes in tissue barrier and lab-on-a-chip applications.


Porcine Urinary Bladder Matrix for Management of Infected Radiation Mastectomy Wound.
We present a case report on the successful healing of a Pseudomonas infection wound in a 52-year-old female with morbid obesity, noninsulin dependent diabetes mellitus and a history of tobacco use, who presented with Stage IIIA (T3, N2, Mo) infiltrating ductal carcinoma. The patient received neoadjuvant chemotherapy prior to her bilateral skin-sparing total mastectomies with right axillary sentinel lymphadenectomy. She also had staged reconstruction with temporary breast implants and plans for deep inferior epigastric perforator flaps. Two months after chest wall and regional nodal radiation therapy, she developed a marked soft tissue reaction to radiation. She underwent over 10 right chest wall open wound radical debridements resulting in a tissue defect of 25 cm in length, by 20 cm in width, by 10 cm in depth. Despite surgical debridement, intravenous antibiotics, hyperbaric oxygen therapy, colistin spray therapy, and heat lamp therapy, the infection failed to resolve and the wound failed to heal. She was left with an open wound that was extremely painful and required chronic pain management with opioids. The patient later was found to have developed a multidrug-resistant Pseudomonas infection in her wound. However, the experimental placement of a porcine bladder matrix (ACell©, Inc., Columbia, MD) on the wound resulted in the complete relief of pain just three days after the application of the product. After two weekly applications of ACell


Immunological evidence for two physiological forms of protein kinase C.
Our recently described purification scheme for rat brain protein kinase C yields an enzyme consisting of a 78/80-kilodalton (kDa) doublet upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis (submitted for publication). Antisera against this preparation were raised in two rabbits. One of the antisera detected only the 80-kDa component by immunoblotting of purified protein kinase C and immunoprecipitated an 80-kDa [35S]methionine-labeled protein from a variety of human, rodent, and bovine cells, which was shown to represent protein kinase C by comparative one-dimensional peptide mapping. In contrast, the second antiserum detected both 78- and 80-kDa enzyme forms by immunoblotting and immunoprecipitated a [35S]methionine-labeled 78/80-kDa doublet from mammalian cells. One-dimensional peptide maps of these 78- and 80-kDa proteins were similar to those derived from the 78- and 80-kDa forms of purified protein kinase C, respectively. The two forms were not related by either partial proteolysis or differential phosphorylation, showing that two distinct forms of this enzyme exist in mammalian cells. Treatment of mouse B82 L cells with 2.5 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) per ml for 18 h resulted in complete loss of immunoprecipitable protein kinase C with a half time of disappearance of 48 min. Since the normal half-life of protein kinase C was greater than 24 h and the biosynthetic rate of the protein was not decreased after 18 h by TPA treatment, TPA induces down-regulation by increasing the degradation rate of the enzyme. Treatment of cells with 50 ng of TPA per ml followed by resolution of the membrane and cytosol in the presence of ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA) promoted an apparent translocation of both 78- and 80-kDa proteins from the cytosol to the membrane fraction. A similar translocation was effected by cell lysis in the presence of Ca2+, indicating the subcellular localization of protein kinase C to be sensitive to the presence of both activators and micromolar amounts of Ca2+.


Variability in drug susceptibility amongst clones and isolates of Plasmodium falciparum.
Heterogeneity within isolates of Plasmodium falciparum in regard to drug susceptibility is described from studies with three Thai isolates and some clones derived from them. One isolate (T9), which before cloning was resistant in vitro to chloroquine and pyrimethamine, contained a diverse assortment of clones, some of which were sensitive to one or other, or both, of these drugs. Another isolate (CH150) was initially sensitive to mefloquine in vitro, but, on recrudescence of infection in the patient, developed a number of clones all of which had diminished susceptibility to mefloquine. Drug pressure in a laboratory culture of CH150 resulted in a similar change in susceptibility. Hence resistant clones are thought to have been present as a minority component of the original isolate CH150. On testing uncloned isolates at different times after growth in culture, drug susceptibility showed considerable variability, but clones remained stable. Reaction in vitro of these isolates to some other drugs (amodiaquine, Fansidar, quinine) is also described, and the results are discussed in relation to changes in drug resistance of malaria parasites which may occur in laboratory cultures and under field conditions.


Preliminary OSL studies on beige sepiolites.
Radiation-induced luminescence signals in beige sepiolite samples were investigated using optically stimulated luminescence. A thermally stable, light-sensitive radiation-induced signal was detected, and radiation dose response and thermal properties of this signal were studied. The thermal stability and dose sensitivity of the signal implies the potential of the material for dating and retrospective radiation dosimetry.


Recovery of Antimicrobials and Bioaccessible Isoflavones and Phenolics from Soybean (Glycine max) Meal by Aqueous Extraction.
Soybeans display strategic potential in food security as a source of protein and functional bioactives for human consumption. Polyphenols and other bioactive compounds can be recovered after an aqueous extraction from soybean meal, a byproduct of soy oil refining. The objective of the present study was to compile and quantify compounds from soybean oil refinery by-products, providing information about valuable bioactive phytochemicals, their bioaccessibility and potential bioactivities. Genistin, daidzin, glycitin and malonylgenistin were the predominant isoflavones, and the overall bioaccessibility of their glycosidic forms was of nearly 75%. Sixteen phenolics were identified and caffeic acid, 5-caffeoylquinic chlorogenic acid and hesperidin were the most predominant. Approximately 30% of gallic acid, syringic acid, vanillic acid and myricetin were released and the antioxidant capacity of aqueous extract was enhanced after simulated in vitro gastro intestinal digestion. The ability of aqueous soybean meal extract to inhibit lipid peroxidation was higher than natural and synthetic food antioxidants. Antimicrobial activity against several foodborne pathogens and antitumoral activity towards human glioblastoma cell line were also observed, but the aqueous extract showed no cytotoxicity to healthy murine cells. Compounds derived from the aqueous soybean meal extract have the potential to be used as health promoting agents.


Enhanced skeletal muscle insulin sensitivity in year-old rats adapted to hypergravity.
Rats adapted to hypergravity by continuous centrifugation at 4.15 g for 7 mo exhibit increased glucose uptake at lower plasma insulin levels than weight-matched control animals following oral glucose administration. To assess insulin sensitivity of specific tissues, glucose uptake by perfused skeletal muscle and liver from year-old hypergravic rats was compared with perfused tissue from weight-matched control rats (2.5-mo-old). The results show that metabolic clearance of glucose by skeletal muscle from hypergravic rats ws not significantly greater than control muscle when perfused in the absence of insulin (10.6 vs. 8.1 microliter.min-1.g muscle-1) but was twofold faster (23.0 vs. 9.5) at perfusate insulin levels of 35 microunits/ml. Conversely, glucose uptake by hypergravic livers was significantly decreased (P less than 0.001) compared with control livers (10.3 vs. 27.8) at perfusate insulin levels of 40 microunits/ml. These findings suggest that skeletal muscle rather than liver is the tissue primarily responsible for enhanced sensitivity to insulin observed in older rats adapted to hypergravity.


Obesity and shift work: chronobiological aspects.
The present review has the objective of summarising chronobiological aspects of shift work and obesity. There was a systematic search in PubMed databases, using the following descriptors: shift work; obesity; biological clock. Shift work is extremely frequent in several services and industries, in order to systematise the needs for flexibility of the workforce, necessary to optimise productivity and business competitiveness. In developing countries, this population represents a considerable contingent workforce. Recently, studies showed that overweight and obesity are more prevalent in shift workers than day workers. In addition, the literature shows that shift workers seem to gain weight more often than those workers submitted to a usual work day. In conclusion, there is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes and CVD, perhaps as a result of physiological maladaptation to chronically sleeping and eating at abnormal circadian times. The impact of shift work on metabolism supports a possible pathway to the development of obesity and its co-morbities. The present review demonstrated the adverse cardiometabolic implications of circadian misalignment, as occurs chronically with shift workers.


Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges.
At the time of writing, there are seven marketed kinase inhibitor drugs. The first kinase inhibitor, imatinib mesilate (Gleevec, Novartis), came to market in 2001, an inhibitor of the breakpoint cluster region (BCR)/Abelson murine leukemia oncogene homolog (ABL) fusion, platelet-derived growth factor (PDGF) receptor, and c-kit kinases. The most recent kinase inhibitor to come to market, disatinib (Sprycel, Bristol-Myers Squibb), acts on c-SRC, ABL and Bruton's tyrosine kinase. To date, kinase inhibitor drugs are approved for oncology and demonstrate that it is possible to develop compounds with relative selectivity for the target kinase against the broader kinome. However, the use of kinase inhibitors in chronic inflammatory and immunologic diseases may require greater selectivity for the target kinase. This review addresses the opportunities and challenges of kinase inhibition as a therapeutic approach in chronic immune and inflammatory disease.


Classification of Heat-Related Illness Symptoms Among Florida Farmworkers.
Farmworkers working in hot and humid environments have an increased risk for heat-related illness (HRI) if their thermoregulatory capabilities are overwhelmed. The manifestation of heat-related symptoms can escalate into life-threatening events. Increasing ambient air temperatures resulting from climate change will only exacerbate HRI in vulnerable populations. We characterize HRI symptoms experienced by farmworkers in three Florida communities. A total of 198 farmworkers enrolled in 2015-2016 were asked to recall if they experienced seven HRI symptoms during the previous work week. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between selected sociodemographic characteristics and reporting three or more symptoms. Latent class analysis was used to identify classes of symptoms representing the HRI severity range. We examined sociodemographic characteristics of the farmworkers across the latent classes. The mean age (±SD) of farmworkers was 38.0 (±8) years; the majority were female (60%) and Hispanic (86%). Most frequently reported symptoms were heavy sweating (66%), headache (58%), dizziness (32%), and muscle cramps (30%). Females had three times the odds of experiencing three or more symptoms (OR = 2.86, 95% CI 1.18-6.89). Symptoms fell into three latent classes, which included mild (heavy sweating; class probability = 54%), moderate (heavy sweating, headache, nausea, and dizziness; class probability = 24%), and severe (heavy sweating, headache, nausea, dizziness, muscle cramps; class probability = 22%). Farmworkers reported a high burden of HRI symptoms that appear to cluster in physiologic patterns. Unrecognized accumulation of symptoms can escalate into life-threatening situations if untreated. Our research can inform interventions to promote early recognition of HRI, on-site care, and appropriate occupational health policy. Administrative or engineering workplace controls may also reduce the manifestation of HRI. This study advances the current knowledge of HRI symptoms in farmworkers and moves beyond reporting individual symptoms by utilizing latent class analysis to identify how symptoms tend to co-occur together in this population. It acknowledges multiple symptoms occurring as a result of occupational heat exposure and highlights the importance of symptom recognition.


Characteristics of secondary electrons produced by 6, 10 and 24 MV x-ray beams.
Megavoltage x-ray beams generated by linear accelerators (linacs) deliver their maximum dose a few centimetres below the treatment or phantom surface. This skin-sparing effect is degraded by the generation of secondary electrons as the x-ray beam passes to the patient or phantom. This work measures the characteristics of these electrons. A light-weight electromagnet was constructed that could be mounted in the block-tray position, 58 cm from the x-ray source of a Varian Clinac 2100C or 2500 linac. A field strength as high as 0.1500 T was generated, which was strong enough to sweep secondary electrons out of a 10 cm x 10 cm field. For 6, 10 and 24 MV x-ray beams, secondary contamination electrons produced 18, 38 and 65% of the surface dose, corresponding to 3, 5 and 12% of the maximum dose, respectively. A parameterized depth-dose curve for the contamination electrons was produced and was valid for all the x-ray energies studied.


Exercise Science and Child Health: A Tale of Many Journeys.
Children are the most naturally physically active human beings; reduced physical activity is a cardinal sign of childhood disease, and exercise testing provides mechanistic insights into health and disease that are often hidden when the child is at rest. The physical inactivity epidemic is leading to increased disease risk in children and, eventually, in adults in unprecedented ways. Cardiopulmonary exercise testing (CPET) biomarkers are used to assess disease severity, progress, and response to therapy across an expanding range of childhood diseases and conditions. There is mounting data that fitness in children tracks across the life span and may prove to be an early, modifiable indicator of cardiovascular disease risk later in life. Despite these factors, CPET has failed to fulfill its promise in child health research and clinical practice. A major barrier to more accurate and effective clinical use of CPET in children is that data analytics and testing protocols have failed to keep pace with enabling technologies and computing capacity. As a consequence, biomarkers of fitness and physical activity have yet to be widely incorporated into translational research and clinical practice in child health. In this review, the author re-examines some of the long-held assumptions that mold CPET in children. In particular, the author suggests that current testing strategies that rely predominantly on maximal exercise may, inadvertently, obfuscate novel and clinically useful insights that can be gleaned from more comprehensive data analytics. New pathways to discovery may emanate from the simple recognition that the physiological journey that human beings undertake in response to the challenge of exercise may be far more important than the elusive destination of maximal or peak effort.


Gene regulation by H-NS as a function of growth conditions depends on chromosomal position in Escherichia coli.
Cellular adaptation to changing environmental conditions requires the coordinated regulation of expression of large sets of genes by global regulatory factors such as nucleoid associated proteins. Although in eukaryotic cells genomic position is known to play an important role in regulation of gene expression, it remains to be established whether in bacterial cells there is an influence of chromosomal position on the efficiency of these global regulators. Here we show for the first time that genome position can affect transcription activity of a promoter regulated by the histone-like nucleoid-structuring protein (H-NS), a global regulator of bacterial transcription and genome organization. We have used as a local reporter of H-NS activity the level of expression of a fluorescent reporter protein under control of an H-NS-regulated promoter (Phns) at different sites along the genome. Our results show that the activity of the Phns promoter depends on whether it is placed within the AT-rich regions of the genome that are known to be bound preferentially by H-NS. This modulation of gene expression moreover depends on the growth phase and the growth rate of the cells, reflecting the changes taking place in the relative abundance of different nucleoid proteins and the inherent heterogeneous organization of the nucleoid. Genomic position can thus play a significant role in the adaptation of the cells to environmental changes, providing a fitness advantage that can explain the selection of a gene's position during evolution.


Effects of protein separation conditions on the functional and thermal properties of canola protein isolates.
Canola meal protein isolates were prepared from defatted canola meal flour using alkaline solubilization and acid precipitation. A central composite design was used to model 2nd-order response surfaces for the protein yield and the functional properties of protein isolates. The solubilization pH and precipitation pH were used as design factors. The models showed that the protein yield and functional properties of isolates, such as water absorption and fat absorption, were sensitive to both solubilization pH and precipitation pH, whereas the emulsification was sensitive to only solubilization pH. Gel electrophoresis analysis of protein fractions gave evidence to the compositional changes between proteins isolated under different conditions. Differences in glass transition temperatures suggest that proteins tend to be more denatured when solubilized at highly alkaline conditions. These conformational and compositional changes due to different protein separation conditions have contributed to the changes in functional properties of protein isolates. Protein isolation conditions may be determined primarily through optimization of total protein yield. Improvements in protein functional properties may be achieved with a relatively small sacrifice in yield by altering isolation conditions.


Expression of IDO1 in Tumor Microenvironment Significantly Predicts the Risk of Recurrence/Distant Metastasis for Patients With Esophageal Squamous Cell Carcinoma.
In this study, we aimed to explore immune markers predicting locoregional recurrence/distant metastasis (R/M) for patients with esophageal squamous cell carcinoma (ESCC) post-surgical intervention by using a novel high-throughput spatial tool to quantify multiple immune proteins expressed in ESCC and lymphocytes in tumor microenvironment (TME-L). First, formalin-fixed paraffin-embedded tissues from surgical patients with ESCC (n = 94) were constructed on a microarray, which was then divided into discovery (n = 36) and validation cohorts (n = 58). Using a newly developed GeoMx digital spatial profiling tool, 31 immune proteins in paired ESCC and TME-L, morphologically segmented by PANCK and CD45, respectively, from the discovery cohort were quantified, releasing 2,232 variables. Next, the correlation matrix was analyzed using the Corrplot package in R Studio, resulting in 6 closely correlated clusters. The Least Absolute Shrinkage and Selection Operator regression scoring model predictive of R/M risk with superior specificity was successfully established based on the 3 following hierarchically clustered immune proteins: ARG1 in ESCC/PANCK+, STING, and IDO1 in TME-L/CD45+. Moreover, the expression of IDO1 in TME-L, rather than in ESCC, significantly predicted the R/M risk score with an area under curve of 0.9598. In addition, its correlation with R/M status was further validated by dual immunohistochemistry staining of IDO1 and CD45 in discovery and validation cohorts. Above all, our findings not only provide a more accurate scoring approach based on quantitative immune proteins for the prediction of R/M risk, but also propose that IDO1 in TME-L potentially plays a driving role in mediating R/M in ESCC.


Development and characterization of transdermal drug delivery systems for diltiazem hydrochloride.
Transdermal drug delivery system of diltiazem hydrochloride was developed to obtain a prolonged controlled drug delivery. Both the matrix diffusion controlled (MDC) and membrane permeation controlled (MPC) systems were developed. The matrix diffusion controlled systems used various combinations of hydrophilic and lipophillic polymers, whereas membrane permeation controlled systems were developed using the natural polymer chitosan. The MDC systems were prepared using the cast film method and the MPC systems by an adhesive sealing technique. Both the systems were characterized for in vitro and in vivo performance. The MDC systems were characterized for physicochemical properties such as tensile strength, moisture content, and water vapor transmission. The in vitro release studies showed that the release from the matrix diffusion controlled transdermal drug delivery systems follows a nonfickian pattern and that from the membrane permeation controlled transdermal drug delivery systems follow zero-order kinetics. The release from the matrix systems increased on increasing the hydrophilic polymer concentration, but the release from the membrane systems decrease on cross-linking of the rate controlling membrane and also on addition of citric acid to the chitosan drug reservoir gel. The in vivo studies of the selected systems showed that both systems are capable of achieving the effective plasma concentration for a prolonged period of time. The MPC system achieved effective plasma concentration a little more slowly than the MDC system, but it exhibited a more steady state plasma level for 24 hr.


Aggressive surgical treatment of multiple primary lung cancers.
A case of triple primary lung cancers--squamous cell carcinoma, adenocarcinoma and large-cell carcinoma--is presented. Surgical treatment comprised, respectively, left pneumonectomy, partial resection of the right upper lobe and completion right upper lobectomy. The postoperative courses were uneventful and the patient remains well, with no sign of recurrence, 20 months after the third operation.


Flow cytometry in primary breast cancer: improving the prognostic value of the fraction of cells in the S-phase by optimal categorisation of cut-off levels.
The use of continuous prognostic variables is clinically impractical, and arbitrarily chosen cut-off points can result in a loss of prognostic information. Here we report findings from a study of primary breast cancer, showing how the prognostic value of the fraction of cells in the S-phase of the cell cycle (SPF), as measured by flow cytometry, can be affected by the SPF cut-off level(s) adopted. It was possible to evaluate the SPF in 566 (94%) of 603 consecutive cases where fresh frozen specimens were available in a tumour bank at our department. Clinically, all patients were without distant spread at the time of diagnosis, and the median duration of follow-up was 4 years. Using different survival end-points and chi 2 values for each cut-off level, two optimal cut-off points, at the 7% and 12% levels, were consistently obtained for the SPF. Furthermore, both disease-free survival and the relative risk of recurrence exhibited a non-linear relationship with SPF values; the curves implied that the prognosis was better among patients with SPF values about 2-5% than in patients with lower SPF values (parabolic shape), though the relationship with higher SPF values approached linearity. The non-linearity of the curves is incompatible with the general use of the median SPF as a prognostic cut-off value. An alternative procedure might be to use two cut-off levels, one to distinguish patients with the lowest SPF values (i.e. within the parabolic survival curve) from those with higher values (i.e. with a survival curve approaching linearity), the other to distinguish between patients with intermediate SPF values and those with high values (i.e. within the almost linear part of the survival curve). The 7% and 12% obtained here would be suitable for this purpose. We conclude that prognostic information can be gained by dividing the SPF into three prognostic categories (less than 7.0%, 7.0-11.9% and greater than or equal to 12%), instead of using the median SPF level.


Pathways to quality inpatient management of hyperglycemia and diabetes: a call to action.
Currently patients with diabetes comprise up to 25-30% of the census of adult wards and critical care units in our hospitals. Although evidence suggests that avoidance of hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) is beneficial for positive outcomes in the hospitalized patient, much of this evidence remains controversial and at times somewhat contradictory. We have recently formed a consortium for Planning Research in Inpatient Diabetes (PRIDE) with the goal of promoting clinical research in the area of management of hyperglycemia and diabetes in the hospital. In this article, we outline eight aspects of inpatient glucose management in which randomized clinical trials are needed. We refer to four as system-based issues and four as patient-based issues. We urge further progress in the science of inpatient diabetes management. We hope this call to action is supported by the American Diabetes Association, The Endocrine Society, the American Association of Clinical Endocrinologists, the American Heart Association, the European Association for the Study of Diabetes, the International Diabetes Federation, and the Society of Hospital Medicine. Appropriate federal research funding in this area will help ensure high-quality investigations, the results of which will advance the field. Future clinical trials will allow practitioners to develop optimal approaches for the management of hyperglycemia in the hospitalized patient and lessen the economic and human burden of poor glycemic control and its associated complications and comorbidities in the inpatient setting.


Risk factors for radiological changes after bipolar hemiarthroplasty for osteonecrosis of the femoral head.
This study aimed to report the mid-term radiological outcomes of patients with bipolar hemiarthroplasty (BHA) for stage 3 osteonecrosis of the femoral head (ONFH), and to identify the risk factors for postoperative radiological changes. We retrospectively investigated 62 patients (38 men and 24 women; mean age, 50.1 years) aged <70 years who underwent primary BHA for Association Research Circulation Osseous stage 3 ONFH between 1998 and 2010. The mean follow-up period after BHA was 12.8 years. The following changes were assessed on follow-up radiographs: outer head migration, polyethylene wear, and femoral osteolysis. The association between demographic data and the development of postoperative radiological changes was evaluated. Radiological changes were found in 20 hips (32.3%) at a mean of 8.1 years after BHA; of these, three hips (4.8%) underwent total hip arthroplasty conversion at a mean of 10.9 years after BHA. Both univariate and multivariate analysis revealed that younger age and female sex were independent risk factors for the development of postoperative radiological changes. The current results suggest that the indication of BHA should be carefully determined in young or female patients with ONFH, even when the disease is in the early stage.


ImmunoCAP® ISAC and Microtest for multiplex allergen testing in people with difficult to manage allergic disease: a systematic review and cost analysis.
Allergy is a form of immune-mediated exaggerated sensitivity (hypersensitivity) to a substance that is either inhaled, swallowed, injected or comes into contact with the skin. Foreign substances that provoke allergies are called allergens. It has been claimed that multiplex allergen testing may help in diagnosing the cause of symptoms in patients with an unclear cause of allergy or who are allergic to more than one substance. To evaluate multiplex allergen testing [devices that can measure the presence of multiple immunoglobulin E (IgE) antibodies in a patient's blood at the same time], by assessing (1) clinical effectiveness (allergy symptoms, incidence of acute exacerbations, mortality, adverse events of testing and treatment, health-care presentations or admissions, health-related quality of life); (2) effects on treatment (diet, immunotherapy medications, other potential testing); (3) any additional diagnostic information provided by multiplex allergen testing; and (4) cost-effectiveness (cost of different assessment strategies). Fifteen databases were searched from 2005 to April 2015, including MEDLINE (via OvidSp), MEDLINE In-Process Citations, MEDLINE Daily Update, PubMed (National Library of Medicine), EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, Science Citation Index (SCI), Conference Proceedings Citation Index-Science (CPCI-S), BIOSIS Previews, Latin American and Caribbean Health Sciences Literature (LILACS), National Institute for Health Research (NIHR) HTA programme, and the US Food and Drug Administration (FDA); supplementary searches of conference proceedings and trials registries were performed. Review methods followed published guidance from the Cochrane Collaboration and the Centre for Reviews and Dissemination, University of York, UK. The methodological quality of included studies was assessed using appropriate published tools or a review-specific tool designed by the project team. Studies were summarised in a narrative synthesis. Owing to a lack of data on the clinical effectiveness of multiplex allergen testing, no long-term cost-effectiveness model was developed. A conceptual model structure was developed and cost analyses were performed to examine the short-term costs of various possible diagnostic pathways. Fifteen studies were included in the review. The very limited available data indicated that the addition of multiplex allergen testing [ImmunoCAP(®) Immuno Solid-phase Allergen Chip (ISAC), Thermo Fisher Scientific/Phadia AB, Uppsala, Sweden] to standard diagnostic work-up can change the clinicians' views on the diagnosis, management and treatment of patients. There was some indication that the use of ImmunoCAP ISAC testing may be useful to guide decisions on the discontinuation of restrictive diets, the content of allergen-specific immunotherapy (SIT) prescriptions, and whether or not patients should receive SIT. However, none of the studies that we identified reported any information on clinical outcomes subsequent to changes in treatment or management. There was some evidence that ImmunoCAP ISAC may be useful for discriminating allergens that are structurally similar and are recognised by the same IgE antibody (cross-immunoreactive). No data were available for Microtest (Microtest Matrices Ltd, London, UK). Detailed cost analyses suggested that multiplex allergen testing would have to result in a substantial reduction of the proportions of patients receiving single IgE testing and oral food challenge tests in order to be cost-saving in the short term. No recommendations for service provision can be made based on the analyses included in this report. It is suggested that a consensus-based protocol for the use of multiplex allergen testing be developed. The clinical effectiveness and cost-effectiveness of the proposed protocol should then be assessed by comparing long-term clinical and quality of life outcomes and resource use in patients managed using the protocol with those managed using a standard diagnostic pathway. This study is registered as PROSPERO CRD42015019739. This project was a Diagnostic Assessment Report commissioned by the NIHR HTA programme on behalf of the National Institute for Health and Care Excellence.


A Bilingual-Monolingual Comparison of Young Children's Vocabulary Size: Evidence from Comprehension and Production.
It is often assumed that young bilinguals are lexically delayed in comparison to monolinguals. A comprehensive comparison of comprehension and production vocabulary in 31 firstborn bilingual and 30 matched monolingual children fails to find empirical foundation for this assumption. Several raters completed Dutch and French adaptations of the MacArthur Communicative Development Inventories for children aged 13 and 20 months. At 13 months, bilinguals understood more words than monolinguals; at 20 months, monolinguals knew more Dutch words than bilinguals (combining comprehension and production). There were no group differences for word production or for Dutch word comprehension. Both groups understood and produced the same number of lexicalized meanings; ratios of word comprehension to word production did not differ; inter-individual variation was similar. This study underscores the importance of conducting bilingual-monolingual comparisons with matched groups and suggests that if individual bilingual children appear to be slow in early vocabulary development, reasons other than their bilingualism should be investigated.


Deposition of Centromeric Histone H3 Variant CENP-A/Cse4 into Chromatin Is Facilitated by Its C-Terminal Sumoylation.
Centromeric localization of CENP-A (Cse4 in Saccharomyces cerevisiae, CID in flies, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of overexpressed CENP-A contributes to aneuploidy in yeast, flies, and humans, and is proposed to promote tumorigenesis in human cancers. Hence, defining molecular mechanisms that promote or prevent mislocalization of CENP-A is an area of active investigation. In budding yeast, evolutionarily conserved histone chaperones Scm3 and chromatin assembly factor-1 (CAF-1) promote localization of Cse4 to centromeric and noncentromeric regions, respectively. Ubiquitin ligases, such as Psh1 and Slx5, and histone chaperones (HIR complex) regulate proteolysis of overexpressed Cse4 and prevent its mislocalization to noncentromeric regions. In this study, we have identified sumoylation sites lysine (K) 215/216 in the C terminus of Cse4, and shown that sumoylation of Cse4 K215/216 facilitates its genome-wide deposition into chromatin when overexpressed. Our results showed reduced levels of sumoylation of mutant Cse4 K215/216R/A [K changed to arginine (R) or alanine (A)] and reduced interaction of mutant Cse4 K215/216R/A with Scm3 and CAF-1 when compared to wild-type Cse4 Consistent with these results, levels of Cse4 K215/216R/A in the chromatin fraction and localization to centromeric and noncentromeric regions were reduced. Furthermore, in contrast to GAL-CSE4, which exhibits Synthetic Dosage Lethality (SDL) in psh1∆, slx5∆, and hir2∆ strains, GAL-cse4K215/216R does not exhibit SDL in these strains. Taken together, our results show that deposition of Cse4 into chromatin is facilitated by its C-terminal sumoylation.


Step characteristic interaction and asymmetry during the approach phase in long jump.
The aim of this study was to investigate the relative influence of step length (SL) and step frequency (SF) on step velocity (SV) during the approach run of high-level long jumpers and to quantify the asymmetry of these step characteristics. Spatiotemporal data of the approach run were collected during national competition from 10 long jumpers (age 26.2 ± 4.1 years, height 1.84 ± 0.06 m, mass 72.77 ± 3.23 kg, personal best performance 7.96 ± 0.30 m). Analyses were conducted for total approach, early approach and late approach. For the total approach 4/10 athletes were SF reliant and 6/10 athletes favoured neither characteristic. At the early approach, 3/10 athletes were SF reliant and 7/10 athletes favoured neither. During late approach 2/10 athletes demonstrated SL reliance, 7/10 athletes were SF reliant and 1/10 athletes favoured neither. Four athletes displayed significant asymmetry for SL and three for SF. However, no athletes demonstrated significant asymmetry for SV indicating that the asymmetrical demands of take-off do not have a marked influence on step characteristic asymmetry, probably due to the constraints of the event. Consideration should be given to the potentially conflicting demands between limbs for individual athletes.


Predictive Factors of Intraocular Pressure Level Evolution Over Time and Glaucoma Severity in Fuchs' Heterochromic Iridocyclitis.
To investigate the clinical and virologic-associated and predictive factors of intraocular pressure (IOP) evolution over time and its severity in Fuchs' heterochromic iridocyclitis (FHC). Consecutive patients with both clinical FHC and intraocular synthesis of rubella virus (RV)-specific antibodies were included in this study. Specific ocular production of RV antibodies was confirmed using the quotient of serum/aqueous humor ratio of RV IgGs (Crv) and control antiviral IgGs (Cctl), using quantitative serology methods. Epidemiologic, clinical, biological, and virologic data at referral were collected and correlated with IOP values over time, occurrence, and severity of glaucoma. Sixty-eight eyes of 68 patients were included. Mean age at diagnosis was 40.7 ± 11.1 years. Mean follow-up was 4.3 ± 4.3 years. Mean baseline Crv and Cctl values were 12.34 ± 14.67 and 216.70 ± 98.4, respectively. Mean baseline IOP was 17.2 ± 7.2 mm Hg (range, 9-40) and 15.6 ± 5.6 (range, 3-30) 5 years after referral. The predictive factors for pejorative IOP evolution over time and glaucoma severity were male sex (P = 0.03) and decreased Crv (P = 0.04) and presence of iris nodules (P < 0.001) and decreased Cctl (P = 0.02), respectively. Diagnostic delay was associated with increased likelihood of undergoing glaucoma surgery (P = 0.02). Time to diagnosis, male sex, presence of iris nodules at baseline, and decreased Crv and Cctl ratios were associated with increased likelihood of pejorative IOP evolution over time. Given the aggressiveness of glaucoma in FHC, these results provide interesting insight into what category of patients should need the closest screening.


Knowledge and attitudes of allied health professional students regarding the stroke rehabilitation team and the role of the Speech and Language Therapist.
One of the major barriers to effective team working among healthcare professionals is a lack of knowledge of each other's roles. The importance of understanding Irish healthcare students' attitudes towards team working and each other's roles led to the development of this study. The aims were to investigate allied health professional students' perceptions and experiences of the stroke rehabilitation team and the role of the Speech and Language Therapist (SLT). A survey first developed by Felsher and Ross (1994) and further developed by Insalaco et al. (2007) was adapted to the Irish healthcare setting. The survey was administered to final-year Occupational Therapy (n = 23), Speech and Language Therapy (21) students and Physiotherapy (20) students (64 in total) (a 98.5% response rate). Results indicate that students had a good understanding of teamwork in the healthcare setting and the possible benefits and challenges it presents. Students had a strong appreciation for interprofessional collaboration, with the majority (79%) choosing shared leadership as their preferred option for the stroke rehabilitation team. Further to this, the team approaches that students felt were most appropriate for the stroke rehabilitation setting were the more collaborative approaches of interdisciplinary (43.5%) and transdisciplinary (37.1%). The students had clear perceptions of the SLT's role in aphasia, dysphagia, dysarthria, apraxia and auditory agnosia, but were less knowledgeable of the SLT's role in the acquired disorders of alexia and agraphia (p < 0.05). More than half of all students perceived that the SLT is involved in the treatment of hemispatial neglect (55.5%), depression (71.5%) and visual agnosia (59.4%). The results provide valuable information for further developments in interprofessional education at an undergraduate level. Further opportunities should be provided to students to collaborate with each other, particularly in their final year of training as, by then, students have a well-established knowledge of their own roles and would be more capable of sharing this role with other professions. Through this collaboration students would also gain valuable insight into the importance of teamwork, which they could take with them into their professional careers.


Trends in sexually transmitted infections in the Netherlands, combining surveillance data from general practices and sexually transmitted infection centers.
Sexually transmitted infections (STI) care in the Netherlands is primarily provided by general practitioners (GPs) and specialized STI centers. STI surveillance is based on data from STI centers, which show increasing numbers of clients. Data from a GP morbidity surveillance network were used to investigate the distribution in the provision of STI care and the usefulness of GP data in surveillance. Data on STI-related episodes and STI diagnoses based on ICPC codes and, for chlamydia, prescriptions, were obtained from GP electronic medical records (EMRs) of the GP network and compared to data from STI centers from 2002 to 2007. Incidence rates were estimated for the total population in the Netherlands. The incidence of STI-consultations and -diagnoses increased substantially in recent years, both at GPs and STI centers. The increase in consultations was larger than the increase in diagnoses; Chlamydia incidence rose especially at STI centers. GPs were responsible for 70% of STI-related episodes and 80-85% of STI diagnoses. STI centers attract relatively younger and more often male STI-patients than GPs. Symptomatic STIs like Herpes genitalis and genital warts were more frequently diagnosed at GPs and chlamydia, gonorrhea and syphilis at STI centers. GPs fulfill an important role in STI care, complementary to STI centers. Case definitions of STI could be improved, particularly by including laboratory results in EMRs. The contribution of primary care is often overlooked in STI health care. Including estimates from GP EMRs can improve the surveillance of STIs.


Isolation and characterization of multipotent human keloid-derived mesenchymal-like stem cells.
In this study, we report the isolation and characterization of a population of multipotent keloid-derived mesenchymal-like stem cells (KMLSCs) from keloid scalp tissues. These KMLSCs expressed the typical mesenchymal stem cell marker proteins CD13, CD29, CD44, CD90, fibronectin, and vimentin when they were cultured in serum-containing medium and when subsequent exposure to various differentiation media resulted in their differentiation into adipocytes, osteoblasts, chondrocytes, smooth muscle cells, and angiogenic endothelial cells. When KMLSCs were cultured in neural stem culture conditions (i.e., in the presence of epidermal growth factor and fibroblast growth factor 2 in substrate-free conditions), they produced large numbers of neurospheres containing nestin-, CD133-, and SOX2-positive cells that expressed neural-crest stem cell markers. Subsequent exposure of these cells to different differentiation conditions resulted in cells that expressed neuronal cell-, astrocyte-, oligodendrocyte-, or Schwann cell-specific markers. Our study suggests that KMLSCs may be an alternative adult stem cell resource for regenerative tissue repair and auto-transplantation.


A new approach to adoptive immunotherapy of cancer using tumorcytotoxic macrophages grown from peripheral blood monocytes.
Clinical trials to evaluate the potential of adoptive immunotherapy in cancer patients have been restricted to the use of lymphoid effector cells. Of the other probably even more important host defense system against tumor growth, the mono-nuclear phagocyte system, only monocytes (mo) have been reinfused which, however, represent immature precursor cells and acquire full functional competence only upon further maturation. This is a report on 7 patients who received autologous macrophages (MO) grown in vitro from blood mo and activated by interferon-gamma (IFN gamma). Mononuclear cells were isolated from whole blood by cytapheresis and cultured for 7 days with 2% autologous serum on hydrophobic Teflon foils. Eighteen house before cell harvest, recombinant human IFN gamma was added at 200 IU/ml. Mo-derived MO were purified by counter-current elutriation. Starting with 10(8) MO cells, therapy was escalated up to the maximal number of MO obtainable from one single preparation cycle. Currently, 26 therapies have been performed with the maximal dose being 1.7 x 10(9) MO per infusion. Except for low grade fever (less than 38 degrees C), MO autografts were well tolerated, with no side effects observed. Biological response was followed by analyzing the serum levels of beta 2-microglobulin, neopterin, interleukin-6, tumor necrosis factor, and lysozyme. While in 3 out of 7 patients serum neopterin increased in response to MO therapy, other biological response parameters remained at pretreatment levels. Radiolabeled MO were shown to first accumulate in the lungs, then to pool into liver and spleen.(ABSTRACT TRUNCATED AT 250 WORDS)


Utilization of brain scans to create realistic phosphene maps for cortical visual prosthesis simulation studies.
It has been shown that we can restore sensations of light by stimulating the visual cortex. Cortical prosthetic vision consists of light perception in the visual field named phosphenes. Phosphenes are like pixels on a monitor which we can control to form the desired perception. However, the locations of phosphenes evoked vary between individuals. One of the biggest challenges is how to utilize phosphenes to present recognizable patterns that represent real-world scenes. Because of the difficulties of recruiting participants, and the risks of neurosurgery, researchers have used computer simulations to investigate the outcome of cortical visual prostheses. Previous simulations used regular phosphene maps, which may overestimate the visual ability cortical visual prosthesis can provide. This study aims to develop a more realistic simulation for cortical visual prostheses. We derived realistic phosphene maps using an existing cortical retinotopy dataset and decided implant placement by considering neurosurgery restrictions. We rendered some visual stimuli to evaluate the usability of those phosphene maps. The results indicate that presenting information on phosphenes maps may be more challenging than previously estimated.


Inflammatory Myofibroblastic Tumor of the Orbit in an 8-Month Old.
Inflammatory myofibroblastic tumor is a mesenchymal neoplasm, commonly seen in the lung and abdominopelvic region of children. The authors present an 8-month-old female with a 2-month history of left-sided proptosis. Examination was significant for left-sided proptosis, a left exotropia and hypotropia, left supraduction and adduction deficits, and left optic disc elevation. MRI imaging revealed an extraconal left superomedial orbital mass with globe displacement and proptosis. Left anterior orbitotomy with excisional biopsy showed a solid mass composed of an infiltrative proliferation of bland spindle cells in a variably myxoid background with associated perivascular lymphoplasmacytic infiltration. Immunohistochemistry was positive for ALK-1 and CD34 and demonstrated focal positivity for S100. Fluorescence in-situ hybridization showed an additional copy of the 3'ALK gene (46%) in interphase cells examined. Next generation targeted sequencing found a DCTN1/ALK fusion. Findings were consistent with inflammatory myofibroblastic tumor. To the authors' knowledge, this is one of the largest primary orbital inflammatory myofibroblastic tumors in the youngest reported patient.


Unmanned aerial vehicles reveal the impact of a total solar eclipse on the atmospheric surface layer.
We use unmanned aerial vehicles to interrogate the surface layer processes during a solar eclipse and gain a comprehensive look at the changes made to the atmospheric surface layer as a result of the rapid change of insolation. Measurements of the atmospheric surface layer structure made by the unmanned systems are connected to surface measurements to provide a holistic view of the impact of the eclipse on the near-surface behaviour, large-scale turbulent structures and small-scale turbulent dynamics. Different regimes of atmospheric surface layer behaviour were identified, with the most significant impact including the formation of a stable layer just after totality and evidence of Kelvin-Helmholtz waves appearing at the interface between this layer and the residual layer forming above it. The decrease in surface heating caused a commensurate decrease in buoyant turbulent production, which resulted in a rapid decay of the turbulence in the atmospheric surface layer both within the stable layer and in the mixed layer forming above it. Significant changes in the wind direction were imposed by the decrease in insolation, with evidence supporting the formation of a nocturnal jet, as well as backing of the wind vector within the stable layer.


NBS1 directly activates ATR independently of MRE11 and TOPBP1.
NBS1 plays unique and essential roles in ATM activation in response to DNA double-strand breaks. We found that CHK1 phosphorylation and FANCD2 ubiquitination induced by various DNA replication-stalling agents were abrogated in Nbs1 knockout DT40 cells but not in conditional Mre11 knockout cells, indicating an MRE11-independent role for NBS1 in ATR activation. The results of in vitro ATR kinase assay indicated that the N-terminal region of NBS1 directly activates ATR independently of TOPBP1, consistent with the findings that this region of NBS1 directly interacts with ATR. This conclusion was furthermore supported by the results of in vivo experiments; the expression of the N-terminal region of NBS1 fused to PCNA induces ATR activation in Rad17 knockout cells, and the expression of the ATR activation domain of TOPBP1 fused to PCNA induces ATR activation in Nbs1 knockout cells. These results therefore indicate that NBS1 and TOPBP1 have the potential to activate ATR independently, although both are required for functional activation of ATR in vivo.


Centrosome overduplication and mitotic instability in PKD2 transgenic lines.
Polycystin-2 (PC-2), a protein encoded by PKD2 and involved in autosomal dominant polycystic kidney disease (ADPKD), is a non-selective cationic channel recently implicated in the function of primary cilia. We recently constructed a new animal model in the form of a transgenic mouse with a BAC-containing human PKD2 inserted in its genome. Two transgenic mouse lines overexpressing human PKD2 showed mitotic instability. Fibroblasts from these transgenic mouse lines have abnormal chromosomal numbers. These lines also have supernumerary centrosomes. PC-2 overexpression is associated with mitotic instability and centrosome overduplication. PC-2 therefore seems to play a role in centrosome duplication, and this hypothesis is being evaluated in other models.


Leprosy in Mexico.
The time of the settlement of leprosy in Mexico is uncertain, however recent studies pointed out that leprosy was probably brought by Asian's migration at about 12,000 years ago and not by the Europeans conquerors during XVI and XVII centuries. Registration of leprosy has been done since the colonial era and the disease was considered as a public health problem until the year 2004 in Mexico when the incidence was achieved to be less than 1 per 10,000 as defined by the world health organization (WHO). Although the national epidemiological parameters like prevalence show the leprosy are controlled well, there are still 49 prefectures with higher prevalence in Mexico. In addition, the incidence in last 10 years has not been stably reduced, in other words the infection cycle has not been interrupted. Therefore, it is necessary to keep the careful epidemiological monitoring, and to increase the search and follow-up of new cases and their contacts in order to eliminate leprosy in this country.


Noninvasive monitoring of gene transfer using a reporter receptor imaged with a high-affinity peptide radiolabeled with 99mTc or 188Re.
Gene therapy protocols require better modalities to monitor the location and level of transferred gene expression. One potential in vivo mechanism to assess gene expression would be to image the binding of a radiolabeled peptide to a reporter receptor that is expressed in targeted tissues. This concept was tested in a tumor model using a replication-incompetent adenoviral vector encoding the human type 2 somatostatin receptor (Ad5-CMVhSSTr2). Expression of the hSSTr2 reporter was imaged using a radiolabeled, somatostatin-avid peptide (P829). Bilateral subcutaneous A427 tumor xenografts were established on the flanks of athymic nude mice. These human-origin, non-small cell lung tumors are normally negative for hSSTr2 expression. One tumor was injected directly with Ad5-CMVhSSTr2, whereas the second tumor was injected directly with a control Ad5 vector. The mice were injected intravenously 48 h later with P829 peptide that was radiolabeled to high specific activity with 99mTc (half-life, 6 h) or 188Re (half-life, 17 h). Tumors were frozen and evaluated for somatostatin receptor expression using fluorescein-labeled somatostatin. The accumulation of radiolabeled P829 in hSSTr2-expressing tumors was easily visualized by gamma camera imaging 3 h after injection. Imaging region of interest analyses and biodistribution studies confirmed a 5- to 10-fold greater accumulation of both radiolabeled P829 peptides in the Ad5-CMVhSSTr2-injected tumors versus control tumors injected with control Ad5 vectors. Ad5-CMVhSSTr2-injected tumors accumulated 2.5-3.8 percentage injected dose per gram 3 h after injection. Only Ad5-CMVhSSTr2-injected tumors expressed somatostatin receptors, as determined by immunohistochemistry. These studies show the feasibility of imaging a 99mTc-labeled peptide's binding to a reporter receptor after in vivo gene transfer to tumor cells. The 188Re-labeled peptide worked equally well for this imaging approach and offers the additional advantage of energetic beta decay with potential therapeutic efficacy. 99mTc and 188Re are generator produced, an advantage for widespread availability and low cost, and both radioisotopes can be imaged with existing, high-resolution modalities. There is great potential for using 99mTc-labeled peptides for imaging gene transfer with the hSSTr2 reporter receptor, especially when the reporter correlates with the expression of therapeutic genes that can be included simultaneously in the gene therapy vector.


Promoting Medication Adherence in Children with Attention Deficit Hyperactivity Disorder: A Mixed-Methods Systematic Review with Meta-analysis and Qualitative Comparative Analysis.
To evaluate the efficacy of ADHD medication adherence interventions and explore the pathways to effectiveness. A systematic review was conducted using multiple databases to identify relevant randomized controlled trials (RCTs). Pooled effect sizes were calculated for medication adherence and ADHD symptom outcomes. Qualitative Comparative Analysis (QCA) was used to identify pathways to effectiveness. Six RCTs were included. The interventions significantly improved medication adherence (OR = 2.39, 95% CI [1.19, 4.79]) and ADHD symptoms (Hedges' g = -0.96, 95% CI [-1.38, -0.54]). Multi-regression analysis showed a positive relationship between medication adherence and ADHD symptom reduction. QCA revealed two paths for effectiveness: (1) Presence of ADHD drug education and absence of reminder and (2) Presence of tracking and absence of reminder. ADHD medication adherence interventions have a positive impact on both medication adherence and ADHD symptoms. Interventions should consider including ADHD drug education or tracking to maximize effectiveness.


Interaction of pH and NaCl on enumeration of heat-stressed Staphylococcus aureus.
The effect of pH level and NaCl concentrations, alone and in combination, on the enumeration of unstressed and heat-stressed cells of three strains of Staphylococcus aureus was determined. A definite narrowing of the optimum pH range for enumeration of both unstressed and heat-stressed cells was observed as the NaCl concentration was increased from 0.0 to 7.5%. Counts of unstressed cells diminished only slightly with increases in NaCl, whereas heat-stressed cells showed a marked sensitivity to NaCl concentrations of 4% and above, regardless of the pH level. Because of this sensitivity to NaCl, recoveries were far poorer than with unstressed cells at NaCl concentrations of 4% and above.


[Cigarette smoke affects sexual function of male rats].
To study the effect of cigarette smoke on the sexual function of male rats. Based on Ozyurt's smoking model, we equally divided 30 male adult Sprague-Dawley rats into a control and a smoking group, and exposed the latter to cigarette smoke for 60 days. A week before the end of the experiment, we added 5 female rats to each group and observed their mating through 24-hour video surveillance. Sixty days later, all the rats were killed for the determination of the level of testosterone (T) in the plasma and the activity of nitric oxide synthase (NOS) in the corpus cavernosum, and Masson-dyeing image analysis of the penile tissue. Compared with the controls, the rats in the smoking group showed a significant reduction in the times of mating, the level of plasma T (P < 0.05) and the activity of NOS in the penile cavernous tissue (P < 0.05), but a slight increase in the collagen fibers and obvious changes in the blood sinuses. Cigarette smoke seriously affected penile erection in the experimental rats. The decrease in plasma T, NOS activity and the area of smooth muscle may be an important mechanism underlying their erectile dysfunction.


Gluten-degrading bacteria are present in the human small intestine of healthy volunteers and celiac patients.
Gluten is the only known environmental factor that triggers celiac disease. Several studies have described an imbalance between the intestinal microbiota of different individuals based on diagnoses. Moreover, recent studies have suggested that human bacteria may play an important role in gluten hydrolysis. However, there has been no research focusing on the small intestine. This study aimed to characterize the adult small intestine microbiota possibly implicated in gluten hydrolysis. Duodenal biopsies from different diagnosed individuals were cultured in a gluten-containing medium, and the grown microbiota was analyzed by culture dependent/independent methods. Results showed that gluten-degrading bacteria can be found in the human small intestine. Indeed, 114 bacterial strains belonging to 32 species were isolated; 85 strains were able to grow in a medium containing gluten as the sole nitrogen source, 31 strains showed extracellular proteolytic activity against gluten protein and 27 strains showed peptidolytic activity towards the 33 mer peptide, an immunogenic peptide for celiac disease patients. We found that there are no differences based on the diagnosis, but each individual has its own population of gluten-hydrolyzing bacteria. These bacteria or their gluten-degrading enzymes could help to improve the quality of life of celiac disease patients'.


Salivary Gland Neoplasms: Does Morphological Diversity Reflect Tumor Heterogeneity.
Salivary gland tumor classification encompasses a vast list of benign and malignant neoplasms. Their morphological diversity is recognized not only between different entities but also within individual tumors. Tumor categories as described by the World Health Organization reflect, in part, a true genetic heterogeneity (e.g., translocations involving CRTC1 and CRTC3-MAML2 genes in mucoepidermoid carcinoma and MYB-NFIB fusion in adenoid cystic carcinoma). Carcinoma ex pleomorphic adenoma shows diversity in its histological appearance, but recurrent rearrangements on PLAG1 and HMGA2 are common to its benign precursor. More recently, new categories have been defined, like secretory carcinoma with the t(12;15) (p13;q25) ETV6-NTRK3 translocation and clear-cell carcinoma with EWSR1-ATF1 fusion. Recent studies on cribriform adenocarcinoma of minor salivary gland origin and epithelial-myoepithelial carcinoma point to a correlation with their morphological features. All of these advances show that the search of a histogenetic and genetic basis for salivary gland tumors is helping to clarify morphological categories and unraveling new ones. Nevertheless, currently morphology is still the hallmark of tumor classification and the gold standard. The therapeutic options for advanced tumors remain very limited but the discovery of translocation-generated gene fusions and increased knowledge of the genomic information of salivary gland tumors is creating opportunities for the development of specific targeted therapies.


Degradation of decabromodiphenyl ether (BDE-209) in microcosms mimicking sediment environment subjected to comparative bioremediation strategies.
The aim of this study was to examine bioremediation strategies for BDE-209 contaminated sediments. Sediment microcosms were established to observe anaerobic debromination of BDE-209 under conditions representing three bioremediation strategies: biostimulation, bioaugmentation and natural attenuation. To simulate biostimulation, a defined mineral medium containing both a carbon source (sodium formate) and electron donor (ethanol) was added into sediments. Bioaugmentation was established by enrichment of the sediments using a culture of Dehalobium chlorocoercia strain DF-1, previously shown to dechlorinate polychlorinated biphenyls, to sediments. No amendments were made to the third set in order to represent natural attenuation. The biostimulation, bioaugmentation and natural attenuation strategies resulted in 55.3%, 40.2% and 30.9% reductions in BDE-209, respectively, after 180 days. Nona- through tri-BDEs were observed as products, with 17 PBDE congeners detected in 25 different proposed debromination pathways. At the end of the 180 day incubation period, the products for bioaugmentation, biostimulation and natural attenuation were tri-BDEs, tetra-BDEs and penta-BDEs, respectively. The proposed pathways revealed that meta- and ortho-Br removal were favored in sediments, and that debromination regiospecificity varied with each bioremediation strategy applied. Lastly, pseudo-first-order rate constants for BDE-209 reduction were calculated as 0.0049 d-1, 0.0028 d-1, 0.0025 d-1 for biostimulation, bioaugmentation and natural attenuation, respectively.


Modulation of eating by central catecholamine systems.
The focus of the present review is the modulation of eating by the endogenous catecholamines (CA) dopamine (DA) and norepinephrine (NE). Topics addressed include pharmacological and genomic manipulations of brain CA systems and subsequent changes in ingestive behavior. DA in particular is a key component of brain reinforcement systems and feeding-associated changes in DA may play a role in the reinforcing aspects of feeding. NE has been linked to both stimulation and suppression of eating and recent evidence has linked these effects to activation of distinct adrenoceptor subtypes. Recent evidence suggests that NE systems may interact with DA systems to augment the activational effects of psychostimulant drugs, such as cocaine or amphetamine, and DA/NE interactions may play a key role in the capacity of psychostimulants to suppress eating.


The human ortholog of archaeal Pus10 produces pseudouridine 54 in select tRNAs where its recognition sequence contains a modified residue.
The nearly conserved U54 of tRNA is mostly converted to a version of ribothymidine (T) in Bacteria and eukaryotes and to a version of pseudouridine (Ψ) in Archaea. Conserved U55 is nearly always modified to Ψ55 in all organisms. Orthologs of TrmA and TruB that produce T54 and Ψ55, respectively, in Bacteria and eukaryotes are absent in Archaea. Pus10 produces both Ψ54 and Ψ55 in Archaea. Pus10 orthologs are found in nearly all sequenced archaeal and most eukaryal genomes, but not in yeast and bacteria. This coincides with the presence of Ψ54 in most archaeal tRNAs and some animal tRNAs, but its absence from yeast and bacteria. Moreover, Ψ54 is found in several tRNAs that function as primers for retroviral DNA synthesis. Previously, no eukaryotic tRNA Ψ54 synthase had been identified. We show here that human Pus10 can produce Ψ54 in select tRNAs, including tRNALys3, the primer for HIV reverse transcriptase. This synthase activity of Pus10 is restricted to the cytoplasm and is distinct from nuclear Pus10, which is known to be involved in apoptosis. The sequence GUUCAm1AAUC (m1A is 1-methyladenosine) at position 53-61 of tRNA along with a stable acceptor stem results in maximum Ψ54 synthase activity. This recognition sequence is unique for a Ψ synthase in that it contains another modification. In addition to Ψ54, SF9 cells-derived recombinant human Pus10 can also generate Ψ55, even in tRNAs that do not contain the Ψ54 synthase recognition sequence. This activity may be redundant with that of TruB.


The broad bean gene VfNOD32 encodes a nodulin with sequence similarities to chitinases that is homologous to (alpha/beta)8-barrel-type seed proteins.
Nodulin gene transcripts isolated from a broad bean (Vicia faba L.) root nodule cDNA library and designated VfNOD32 are detectable in the nitrogen-fixing zone III of nodules and in much smaller amounts in flowers. In nodules, these transcripts are detectable for the first time 7 d after inoculation, at least 1 d before leghemoglobin gene transcription starts. Two putative full-length cDNAs representing different transcript sequences of 92.5% identity were sequenced. The corresponding broad bean genes were termed VfNOD32-A1 and VfNOD32-A2, and the encoded proteins were termed Nvf32-A1 and Nvf32-A2. The derived amino acid sequences of the Nvf32 proteins are highly homologous to the Vicia narbonensis (alpha/beta)8-barrel seed protein narbonin. Considering this homology, Nvf32 is assumed to have a similar structure consisting of beta-sheets forming a central barrel surrounded by alpha-helices. The two Nvf32 sequences also contain two conserved amino acid motifs that are characteristic of class-III chitinases. Several amino acids demonstrated to be essential for chitinase activity are conserved in both regions, whereas one essential glutamic acid was changed to glycine in the Nvf32-A1 isoform but not in the Nvf32-A2 isoform.


Tackling Missing Heritability by Use of an Optimum Curve: A Systematic Review and Meta-Analysis.
Missing heritability is a common problem in psychiatry that impedes precision medicine approaches to autism and other heritable complex disorders. This proof-of-concept study uses a systematic review and meta-analysis of the association between variants of the serotonin transporter promoter (5-HTTLPR) and autism to explore the hypothesis that some missing heritability can be explained using an optimum curve. A systematic literature search was performed to identify transmission disequilibrium tests on the short/long (S/L) 5-HTTLPR polymorphism in relation to autism. We analysed five American, seven European, four Asian and two American/European samples. We found no transmission preference in the joint samples and in Europe, preferential transmission of S in America and preferential transmission of L in Asia. Heritability will be underestimated or missed in genetic association studies if two alternative genetic variants are associated with the same disorder in different subsets of a sample. An optimum curve, relating a multifactorial biological variable that incorporates genes and environment to a score for a human trait, such as social competence, can explain this. We suggest that variants of functionally related genes will sometimes appear in fixed combinations at both sides of an optimum curve and propose that future association studies should account for such combinations.


Post-Eccentric Flywheel Underwater Undulatory Swimming Potentiation in Competitive Swimmers.
Underwater undulatory swimming (UUS) influences overall swimming performance, therefore swimmers should try to maximize it. This research aimed to: 1) assess the effects of an activation protocol based on post-activation performance enhancements upon UUS; and 2) evaluate the differences between males and females. Seventeen competitive swimmers (male = 10; female = 7) participated in a cross-sectional study designed to test performance in UUS at 10 m after a traditional swimming warm-up (TRA) and after adding to the TRA 4 maximal half-squat repetitions on an inertial flywheel device (PAPE). A speedometer and an electronic timing system were used to obtain kinematic variables such as time, frequency and velocity at 10-m, which were processed with MATLAB®. A paired sample t test was applied to determine the differences of the kinematic variables between the TRA and PAPE. An independent sample t test was used to determine the effects of the PAPE in males and females. Participants reduced the time to cover 10 m after PAPE compared to the TRA (males: 5.77 ± 0.44 to 5.64 ± 0.46; females 6.34 ± 0.80 to 6.09 ± 0.66; p < 0.05). In addition, trends towards improvements in UUS velocity were obtained for males and females. However, push-off velocity and frequency showed a different tendency between genders (p < 0.05). In conclusion, the warm-up including repetitions on the flywheel device improved UUS performance. Some differences were obtained between genders after PAPE. Further research should confirm if the benefits obtained after the eccentric overload would depend either on gender or on other components such as fiber type composition.


Copper leaching of MSWI bottom ash co-disposed with refuse: effect of short-term accelerated weathering.
Co-disposal of refuse with municipal solid waste incinerator (MSWI) bottom ash (IBA) either multi-layered as landfill cover or mixed with refuse could pose additional risk to the environment because of enhanced leaching of heavy metals, especially Cu. This study applied short-term accelerated weathering to IBA, and monitored the mineralogical and chemical properties of IBA during the weathering process. Cu extractability of the weathered IBA was then evaluated using standard leaching protocols (i.e. SPLP and TCLP) and co-disposal leaching procedure. The results showed that weathering had little or no beneficial effect on Cu leaching in SPLP and TCLP, which can be explained by the adsorption and complexation of Cu with DOM. However, the Cu leaching of weathered IBA was reduced significantly when situated in fresh simulated landfill leachate. This was attributed to weakening Cu complexation with fulvic acid or hydrophilic fractions and/or intensifying Cu absorption to neoformed hydr(oxide) minerals in weathered IBA. The amount of total leaching Cu and Cu in free or labile complex fraction (the fraction with the highest mobility and bio-toxicity) of the 408-h weathered IBA were remarkably decreased by 86.3% and 97.6% in the 15-day co-disposal leaching test. Accelerated weathering of IBA may be an effective pretreatment method to decrease Cu leaching prior to its co-disposal with refuse.


Lipopolysaccharide induces the expression of interleukin-1alpha distinctly in different compartments of term and preterm human placentae.
The aim of the study was to investigate the stimulatory effect of lipopolysaccharide (LPS) on IL-lalpha production in different compartments of term and preterm placental tissues. Homogenates from amnion, chorion, and from fetal (subchorionic placental tissues, maternal decidua, and mid-placental tissue before and after perfusion of isolated placental cotyledons of 5 term placentas and 4 placentas obtained after preterm birth (28-34 W of gestation) were examined. Isolated placental cotyledons were dually perfused LPS (100 ng/kg perfused placental tissue) was perfused into the maternal side during 10 hours. Homogenates of the samples were examined by ELISA for IL-1alpha levels, and paraffin sections of the samples were stained by immunohistochemical staining, to characterize the cellular origin of placental IL-1alpha. Paired t test and ANOVA determined statistical significance. In the homogenates, there was a tendency towards higher IL-lalpha levels in all preterm placental compartments as compared to the term compartments before perfusion. A significant increase was observed only in the chorion compartment (p = 0.035). LPS had significantly increased IL-la levels only in the decidua compartment of term placentas as compared to other placental compartments (p = 0.0004), and had decreased IL-1alpha levels in the mid-placenta (p = 0.034). In preterm placentas, addition of LPS did not affect the expression levels of IL-1alpha in either fetal or maternal compartments as determined by ELISA and immunohistochemical staining. IL-la levels in the chorion compartment of preterm placenta were significantly higher as compared to term placenta. LPS affects placental tissues of term and preterm placentas differently. Also, in the term placentas, LPS affected the different compartments differently. Thus, IL-1alpha may have a key role (as a autocrine/paracrine factor) in the regulation of normal and pathological pregnancy and parturition.


Internet-Based HIV Self-Testing Among Men Who Have Sex With Men Through Pre-exposure Prophylaxis: 3-Month Prospective Cohort Analysis From China.
Routine HIV testing accompanied with pre-exposure prophylaxis (PrEP) requires innovative support in a real-world setting. This study aimed to determine the usage of HIV self-testing (HIVST) kits and their secondary distribution to partners among men who have sex with men (MSM) in China, who use PrEP, in an observational study between 2018 and 2019. In 4 major cities in China, we prospectively followed-up MSM from the China Real-world oral PrEP demonstration study, which provides daily or on-demand PrEP for 12 months, to assess the usage and secondary distribution of HIVST on quarterly follow-ups. Half of the PrEP users were randomized to receive 2 HIVSTs per month in addition to quarterly facility-based HIV testing. We evaluated the feasibility of providing HIVST to PrEP users. We recruited 939 MSM and randomized 471 to receive HIVST, among whom 235 (49.9%) were daily and 236 (50.1%) were on-demand PrEP users. At baseline, the median age was 29 years, 390 (82.0%) men had at least college-level education, and 119 (25.3%) had never undergone facility-based HIV testing before. Three months after PrEP initiation, 341 (74.5%) men had used the HIVST provided to them and found it very easy to use. Among them, 180 of 341 (52.8%) men had distributed the HIVST kits it to other MSM, and 132 (51.6%) among the 256 men who returned HIVST results reported that used it with their sexual partners at the onset of intercourse. Participants on daily PrEP were more likely to use HIVST (adjusted hazard ratio=1.3, 95% CI 1.0-1.6) and distribute HIVST kits (adjusted hazard ratio=1.3, 95% CI 1.1-1.7) than those using on-demand PrEP. MSM who used PrEP had a high rate of usage and secondary distribution of HIVST kits, especially among those on daily PrEP, which suggested high feasibility and necessity for HIVST after PrEP initiation. Assuming that fourth-generation HIVST kits are available, HIVST may be able to replace facility-based HIV testing to a certain extent. Chinese Clinical Trial Registry ChiCTR1800020374; https://www.chictr.org.cn/showprojen.aspx?proj=32481. RR2-10.1136/bmjopen-2019-036231.


[Medical informatics in the training of students, dentists and teachers in dental schools].
Philosophy of training students, physicians, and tutors of dentistry schools in medical informatics and the relevant curricula are discussed. Specialized software for differential diagnosis and treatment of the major stomatological diseases (dental caries, pulpitis, periodontitis, mucosal, periodontal, oral diseases, tumors, rapid methods for AIDS screening, etc.) are presented.


Large-area, transparent, and flexible infrared photodetector fabricated using P-N junctions formed by N-doping chemical vapor deposition grown graphene.
Graphene is a highly promising material for high speed, broadband, and multicolor photodetection. Because of its lack of bandgap, individually gated P- and N-regions are needed to fabricate photodetectors. Here we report a technique for making a large-area photodetector on the basis of controllable fabrication of graphene P-N junctions. Our selectively doped chemical vapor deposition (CVD) graphene photodetector showed a ∼5% modulation of conductance under global IR irradiation. By comparing devices of various geometries, we identify that both the homogeneous and the P-N junction regions contribute competitively to the photoresponse. Furthermore, we demonstrate that our two-terminal graphene photodetector can be fabricated on both transparent and flexible substrates without the need for complex fabrication processes used in electrically gated three-terminal devices. This represents the first demonstration of a fully transparent and flexible graphene-based IR photodetector that exhibits both good photoresponsivity and high bending capability. This simple approach should facilitate the development of next generation high-performance IR photodetectors.