[Antihypertensive treatment with metoprolol: haemodynamic reactions in hypertensives with normal left ventricular function (author's transl)].
The haemodynamic effects of a 14-day treatment regimen with 100 mg metoprolol daily were tested on 20 male hypertensives at rest and on exercise. Resting blood pressure had been reduced to comparable normal values with a reserpine combination drug in the control period. With metoprolol the exercise blood pressures were significantly lower than at rest (197/102 mm Hg and 230/109 mm Hg, respectively: P less than 0.001). The product of pressure and heart rate at rest and during exercise was lower (P less than 0.001). On the other hand, in 15 patients the pulmonary wedge pressure rose from 15.6 +/- 4.6 mm Hg to 31.4 +/- 5.4 mm Hg (P less than 0.001). The wedge pressure correlated closely (P less than 0.001) with changes in cardiac index.


Long-term follow-up of canine segmental pancreatic autografts.
The functional and morphologic characteristics of free-draining, pancreatic segmental autografts (FDPS) were studied in 8 beagle dogs that had survived longer than 4 yr. After pancreatectomy, animals received FDPS autografts of the left pancreatic limb, representing approximately one-third of the total pancreas with iliac vessel anastamoses. The grafted recipients were given pancreatic enzyme supplements (Viokase). After transplantation (tx), all 8 animals sustained fasting euglycemia with no evidence of microvascular complications. After 4 yr, IVGTT revealed K-values (%/min) that were not significantly different from age-matched controls (2.9 +/- 0.5 versus 3.7 +/- 0.6, P greater than 0.05). Mean fasting serum insulin levels were significantly greater in the tx animals (49 +/- 5 microU/ml versus 12.2 microU/ml, P less than 0.001), although the incremental response to i.v. glucose (0.5 g/kg) was less than in controls (P less than 0.05). Mean fasting plasma C-peptide levels (0.09 +/- 0.01 pmol/ml versus 0.21 +/- 0.5 pmol/ml) and peak C-peptide responses to i.v. glucose were both significantly less than in controls. Sequential pancreatic biopsies up to 2.5 yr post-tx showed atrophy of the exocrine pancreas with coalescence of islets and mild fibrosis that did not progress with time. Immunoperoxidase stains confirmed the presence of insulin, glucagon, and somatostatin within nests of islet cells. Four years after transplantation of FDPS autografts in pancreatectomized dogs, excellent function is retained. The consequences of peripheral hyperinsulinemia remain to be determined.


Antiretroviral medication adherence and persistence with respect to adherence tool usage.
Adherence to complex drug regimens over an extended period is a key factor in reaping the health benefits of highly active antiretroviral therapy (HAART). Forgetting a dose is the most commonly stated reason for suboptimal adherence, indicating a potential benefit of reminder devices. We examined antiretroviral drug adherence and duration of therapy with respect to adherence tool usage. Adherence was monitored for 12 months in a cohort of patients, using pharmacy refill data. Seventy-eight subjects were administered a questionnaire with regard to tool use at least once at 6 and/or 12 months; patients who replied to the questionnaire were eligible for this study. Persistence of remaining on therapy was obtained from the subjects, charts. The tools included individualized schedules, dosettes and electronic reminder devices, which were offered free of charge to all patients. Of the 64 subjects who entered this study, 60.9% (n = 39) used at least one adherence tool. The median adherence in those using tools was 95%; three quarters showed greater than 91% adherence. Adherence rates with respect to individual tools did not differ significantly for schedules and dosettes, with medians of 95% (n = 31) and 94% (n = 13), respectively. Median adherence with electronic reminders was 76% (n = 5). Seventy-four percent of patients remained on therapy after 12 months of study. Taking into consideration previous antiretroviral treatment, actual persistence at 12 months was 87%. Employing and individualizing strategies, including adherence tools, to enhance patient adherence to complex regimens in addition to counseling and follow-up, has resulted in good adherence rates and persistence.


Biotin decreases retinal apoptosis and induces eye malformations in the early chick embryo.
Proliferation, cell death and differentiation occur simultaneously in developing retina and are precisely orchestrated. We have studied the effects of biotin (vitamin H) on early retinal development. In vivo administration of biotin to early embryonic chick eyes at moderately elevated levels induced malformations, affecting retina and lens structures. The effects were strictly age dependent and were only found in embryos treated between Hamburger and Hamilton stage 14-17. Biocytin, a biotin analogue, mimicked biotin effects, while avidin could block the effects. At the cellular level, biotin did not affect proliferation but reduced apoptosis. These results suggest that an adequate content of biotin and a precise regulation of retinal cell death are required for the correct morphogenesis of the eye.


Monitoring surgical performance using risk-adjusted cumulative sum charts.
The cumulative sum (CUSUM) procedure is a graphical method that is widely used for quality monitoring in industrial settings. More recently it has been used to monitor surgical outcomes whereby it 'signals' if sufficient evidence has accumulated that there has been a change in the surgical failure rate. A limitation of the standard CUSUM procedure in this context is that since it is simply based on the observed surgical outcomes, it may signal as a result of changes in the referral pattern, such as an increased proportion of high-risk patients, rather than due to a change in the actual surgical performance. We describe a new CUSUM procedure that adjusts for each patient's pre-operative risk of surgical failure through the use of a likelihood-based scoring method. The procedure is therefore ideally suited for settings where there is a variable mix of patients over time.


Pilot study of a novel vacuum-assisted method for decellularization of tracheae for clinical tissue engineering applications.
Tissue engineered tracheae have been successfully implanted to treat a small number of patients on compassionate grounds. The treatment has not become mainstream due to the time taken to produce the scaffold and the resultant financial costs. We have developed a method for decellularization (DC) based on vacuum technology, which when combined with an enzyme/detergent protocol significantly reduces the time required to create clinically suitable scaffolds. We have applied this technology to prepare porcine tracheal scaffolds and compared the results to scaffolds produced under normal atmospheric pressures. The principal outcome measures were the reduction in time (9 days to prepare the scaffold) followed by a reduction in residual DNA levels (DC no-vac: 137.8±48.82 ng/mg vs. DC vac 36.83±18.45 ng/mg, p<0.05.). Our approach did not impact on the collagen or glycosaminoglycan content or on the biomechanical properties of the scaffolds. We applied the vacuum technology to human tracheae, which, when implanted in vivo showed no significant adverse immunological response. The addition of a vacuum to a conventional decellularization protocol significantly reduces production time, whilst providing a suitable scaffold. This increases clinical utility and lowers production costs. To our knowledge this is the first time that vacuum assisted decellularization has been explored. Copyright © 2015 John Wiley & Sons, Ltd.


Associations of dietary patterns with kidney cancer risk, kidney cancer-specific mortality and all-cause mortality among postmenopausal women.
The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) are novel measures of dietary quality associated with insulin hypersecretion or chronic inflammation, respectively, whereas the Healthy Eating Index (HEI-2015) measures adherence to the Dietary Guidelines for Americans (DGA). We evaluated associations of EDIH, EDIP and HEI-2015 on the risk of both kidney cancer development and mortality. We calculated the dietary scores from baseline food frequency questionnaires among 115,830 participants aged 50-79 years in the Women's Health Initiative. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for kidney cancer risk, kidney cancer-specific mortality and all-cause mortality, per 1-standard deviation increment in dietary pattern scores. Higher EDIH was associated with greater risk of kidney cancer development [HR, 1.12; 95%CI, (1.01,1.23)], kidney cancer-specific death [1.22(0.99,1.48)], and all-cause mortality, [1.05(1.02,1.08)]. Higher HEI-2015 was associated with lower risk of kidney cancer development, [0.85(0.77, 0.94)], kidney cancer-specific death, [0.84(0.69,1.03)] and all-cause mortality, [0.97(0.95,1.00)]. However, EDIP was not significantly associated with outcomes. Associations did not differ by BMI categories. Low-insulinemic dietary patterns and higher quality diets, are worthy of testing in dietary pattern intervention trials for kidney cancer prevention and improved survivorship.


One-step preparation of carboxyl-functionalized porous organic polymer as sorbent for enrichment of phenols in bottled water, juice and honey samples.
Herein, a novel carboxyl-functionalized porous organic polymer (COOH-POP) was prepared as sorbent. Due to multiple hydrogen bonds and π-π interactions between COOH-POP and phenols, COOH-POP shows good enrichment ability and very fast adsorption rate for phenols. Then, an analytical method was developed for determination of five phenols (2-chlorophenol, bisphenol A, 2,6-dichlorophenol, 2,4-dichlorophenol and p-tert-butylphenol) in bottled water, lemon juice, peach juice and honey samples using COOH-POP as solid phase extraction sorbent in combination with high performance liquid chromatography. Under optimal conditions, the COOH-POP based method gave the detection limits (S/N = 3) of 0.02-0.10 ng mL-1 for bottled water, 0.03-0.12 ng mL-1 for lemon juice, 0.03-0.25 ng mL-1 for peach juice and 0.7-1.5 ng g-1 for honey samples. The recoveries for spiked samples ranged from 84.0 % to 119.0 % with relative standard deviation less than 7.6 %. This study provides a new yet effective method for enrichment of phenols by designing carboxyl-functionalized porous organic polymer as sorbent.


[The oxygen diffusion coefficient in isolated skeletal muscle fibers].
The oxygen diffusion coefficients in isolated skeletal muscle fibres of Baikal seal and grayling, white rat, chicken were calculated on the basis of experimentally determined curve of dependence of the O2 consumption on pO2 and the radius of the fibres. In all the cases, the diffusion coefficient was smaller in the fibres than in water. The oxygen diffusion coefficient was increased during embryogenesis and postnatal period in chicken. The influence of different parameters of the oxygen transport and of properties of different fibres on the values of the oxygen diffusion coefficients, are discussed.


Does the Number of Comorbidities Predict Pain and Disability in Older Adults With Chronic Low Back Pain? A Longitudinal Study With 6- and 12-Month Follow-ups.
People who live longer often live with multimorbidity. Nevertheless, whether the presence of multimorbidity affects pain and disability in older adults with chronic low back pain (LBP) remains unclear. The aim of this study was to investigate whether multimorbidity predicts pain intensity and disability at 6- and 12-month follow-ups in older adults with chronic LBP. This was a prospective, longitudinal study with 6- and 12-month follow-ups. Participants with chronic LBP (age ≥ 60 years) were recruited and interviewed at baseline, 6 months, and 12 months. Self-reported measures included the number of comorbidities, assessed through the Self-Administered Comorbidity Questionnaire, pain intensity, assessed with the 11-point Numerical Rating Scale, and disability, assessed with the Roland-Morris Disability Questionnaire. Data were analyzed using univariate and multivariate regression models. A total of 220 participants were included. The number of comorbidities predicted pain intensity at 6-month (β= 0.31 [95% CI: 0.12 to 0.50]) and 12-month (β= 0.29 [95% CI: 0.08 to 0.50]) follow-ups. The number of comorbidities predicted disability at 6-month (β= 0.55 [95% CI: 0.20 to 0.90]) and 12-month (β= 0.40 [95% CI: 0.03 to 0.77]) follow-ups. The number of comorbidities at baseline predicted pain and disability at 6-month and 12-month follow-ups in older adults with chronic LBP. These results highlight the role of comorbidities as a predictive factor of pain and disability in patients with chronic LBP, emphasizing the need for timely and continuous interventions in older adults with multimorbidity to mitigate LBP-related pain and disability.


Biological nutrient removal from meat processing wastewater using a sequencing batch reactor.
Meat processing effluents are rich in nutrients (nitrogen: 75-200 mg L(-1) and phosphorus: 20-40 mg L(-1)) and COD (800-2,000 mg L(-1)) after primary treatment. A laboratory scale sequencing batch reactor (SBR) was operated for the treatment of a beef processing effluent from slaughtering and boning operations. An effective SBR cycle was found for removal of COD, nitrogen and phosphorus at 22 degrees C. The solid retention time was 15 days while the hydraulic retention time (HRT) was 2.5 days. The total nitrogen in the wastewater was reduced to less than 10 mg L(-1), while the total phosphorus decreased to less than 1.0 mg L(-1). The residual effluent soluble COD was found to be non-biodegradable as reflected by no further soluble COD removal following prolonged aeration. Removal of biodegradable soluble COD, ammonia nitrogen and soluble phosphate phosphorus of greater than 99% was achieved in the SBR. Good prediction of ammonia and nitrate nitrogen removal was obtained using IWA Activated Sludge Model. The operating cycle is shown to be appropriate to achieve simultaneous removal of COD and nutrients from the meat processing wastewater. Alkalinity and pH have an inverse relationship during the initial anaerobic and aerobic stages due to production and stripping of CO2. Use of a low level of DO in the final aerobic stage ensured complete ammonia removal and enhanced denitrification.


[School museums, collections, and elementary teaching of the natural sciences in late XIX century Argentina].
In this study we analyze the organization of natural science teaching within the Argentinian school context starting with teaching practices and material support in the late XIX century. By that time, school staff and teachers fostered modernization and nationalization of teaching by using collections with national issues and the foundation of museums within the schools. In particular, we examine the official debates over the mineralogical collections offered for sale by the naturalist Enrique de Carlés, and the "school museums" by professors Pedro Scalabrini and Guillermo Navarro. These account for the tension between searching for modern didactic materials associated with foreign models, and the importance of counting on elements that represented the country nature and industry.


[Potential therapeutic usefulness of cannabis and cannabinoids].
Diseases in which Cannabis and cannabinoids have demonstrated some medicinal putative properties are: nausea and vomiting associated with cancer chemotherapy, muscle spasticity (multiple sclerosis, movement disorders), pain, anorexia, epilepsy, glaucoma, bronchial asthma, neuroegenerative diseases, cancer, etc. Although some of the current data comes from clinical controlled essays, the majority are based on anecdotic reports. Basic pharmacokinetic and pharmacodynamic studies and more extensive controlled clinical essays with higher number of patients and long term studies are necessary to consider these compounds useful since a therapeutical point of view.


The management of chronic non-gonococcal urethritis.
Non-gonococcal urethritis (NGU) is one of the most common sexually transmitted diseases today. Oral tetracyclines and erythromycin are well established choices of treatment. Despite adequate treatment, about 30-35% of NGU persist or recur. The cause of persistence or recurrence remains unknown. Prostate gland involvement has to be ruled out where indicated. A 4 to 6 week course of tetracyclines or erythromycin is suggested for persistent or recurrent NGU. Counselling to emphasize that chronic NGU is probably a self limited disorder would be of help.


A comparison of basal and insulin-stimulated glucose transport in rat adipocyte plasma membranes.
Specific D-glucose transport in plasma membranes prepared from control and insulin-treated rat adipocytes was measured using a recently developed dual isotope ([3H]-D-glucose and [14C]-L-glucose), rapid filtration assay which allowed measurements of initial rates at 1 s and 37 degrees. Plasma membranes from insulin-treated adipocytes showed an increase in glucose transport compared with control cells. Saturation kinetic data revealed that the plasma membranes from insulin-treated and control cells had the same Km (26 mM) for glucose transport, whereas insulin treatment increased the Vmax from 4433 pmol/mg protein/s to 9465 pmol/mg proteins/s. Arrhenius plots showed no difference in the energy of activation between control and insulin-stimulated glucose transport states. The optimum pH of both control and insulin-stimulated glucose transport was 7.4. Lower or higher pHs progressively decreased both control and insulin-stimulated glucose transport proportionately. Calcium in the transport assay media did not affect basal or insulin-stimulated glucose transport. However, omission of calcium from the adipocyte incubation media significantly lowered the insulin stimulation by 24% while basal levels were not significantly affected. Insulin specifically bound to the plasma membrane was carried through the fractionation procedure, but removal of this insulin did not alter the stimulated glucose transport. Glucose transport by plasma membranes from control or insulin-treated adipocytes was equally (percentage) inhibited by N-ethylmaleimide, dithiothreitol, reduced glutathione, or cytochalasin B. No inhibition of control or insulin-stimulated transport was seen with cytochalasin D or oxidized glutathione. The data presented are consistent with insulin causing the formation of new transport sites similar to the existing basal sites.


The reduced genome of the parasitic microsporidian Enterocytozoon bieneusi lacks genes for core carbon metabolism.
Reduction of various biological processes is a hallmark of the parasitic lifestyle. Generally, the more intimate the association between parasites and hosts the stronger the parasite relies on its host's physiology for survival and reproduction. However, some systems have been held to be indispensable, for example, the core pathways of carbon metabolism that produce energy from sugars. Even the most hardened anaerobes that lack oxidative phosphorylation and the tricarboxylic acid cycle have retained glycolysis and some downstream means to generate ATP. Here we describe the deep-coverage genome resequencing of the pathogenic microsporidiian, Enterocytozoon bieneusi, which shows that this parasite has crossed this line and abandoned complete pathways for the most basic carbon metabolism. Comparing two genome sequence surveys of E. bieneusi to genomic data from four other microsporidia reveals a normal complement of 353 genes representing 30 functional pathways in E. bieneusi, except that only 2 out of 21 genes collectively involved in glycolysis, pentose phosphate, and trehalose metabolism are present. Similarly, no genes encoding proteins involved in the processing of spliceosomal introns were found. Altogether, E. bieneusi appears to have no fully functional pathway to generate ATP from glucose. Therefore, this intracellular parasite relies on transporters to import ATP from its host.


Selected neonatal outcomes in dizygotic twins after IVF versus non-IVF pregnancies.
To compare neonatal outcome among twins conceived after in vitro fertilisation (IVF) with that of spontaneously conceived twins. Comparison of different-sex (dizygotic) twins born after IVF with non-IVF dizygotic twins. National health registers in Sweden. All births in Sweden during the period 1982-2007. We studied gestational duration, lowest birthweight and birthweight difference in the twin pair, presence of one or two twins with a respiratory complication, and with jaundice in one or both twins. Risk estimates were calculated as odds ratios with adjustments for year of birth, maternal age, parity and smoking in pregnancy. Gestational duration, birth weight, respiratory complications, jaundice. We studied 1545 pairs of dizygotic twins born after IVF, and 8675 pairs of dizygotic twins where IVF was not known to have occurred. The risk for preterm delivery before 32 weeks of gestation was significantly increased among dizygotic twin pairs born after IVF compared with non-IVF dizygotic twin pairs. No significant difference in low birthweight or birthweight difference within twin pairs was seen. There was an increased occurrence of twin pairs with respiratory problems or jaundice, but only the latter diagnosis occurred in a statistically significant excess. The study confirms recent findings that IVF is associated with an increased risk for some neonatal complications, not only among singletons but also among twins.


HSC70 expression is reduced in lymphomonocytes of sporadic ALS patients and contributes to TDP-43 accumulation.
Aim: The demonstration that chaperone-mediated autophagy (CMA) contributes to the degradation of TDP-43, the main constituent of cytoplasmic inclusions typically found in motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS), has pointed out a possible involvement of CMA in aggregate formation. To explore this possibility, in this study, we verified the presence of a possible systemic CMA alteration in sALS patients and its effect on TDP-43 expression. Materials and methods: Gene and protein expression of the cytosolic chaperone HSC70 and the lysosome receptor LAMP2A, the two pivotal mediators of CMA, was assessed in peripheral blood mononuclear cells (PBMCs) derived from 30 sALS patients and 30 healthy controls. The expression of TDP-43 and co-chaperones BAG1 and BAG3 was also analyzed. Results: We found reduced HSC70 expression in patient cells, with no change in LAMP2A, and increased insoluble TDP-43 protein levels, with an aberrant intracellular localization. We also observed an unbalanced expression of co-chaperones BAG1 and BAG3. HSC70 down-regulation was confirmed in immortalized lymphoblastoid cell lines derived from sporadic and TARDBP mutant ALS patients. Lastly, we demonstrated that HSC70 silencing directly increases TDP-43 protein levels in human neuroblastoma cells. Discussion: Our results do not support the existence of a systemic CMA alteration in sALS patients but indicate a direct involvement of HSC70 alterations in ALS pathogenesis.


Comparative analysis of plasmids and some metabolic characteristics of Escherichia coli K1 from diseased and healthy individuals.
All 62 Escherichia coli strains possessing the K1 capsular polysaccharide contained plasmid deoxyribonucleic acid, and most (51 of 62) had multiple plasmid species. The incidence of hemolysins, colicins, hemagglutinins for human erythrocytes, and plasmids did not differ among K1 strains isolated from the cerebrospinal fluids of neonates with meningitis or among those strains isolated from the stools of healthy individuals of all ages. There was an association between E. coli serotype and the distribution of plasmids, hemolysins, and colicins among the K1 strains. A common plasmid of about 65 megadaltons was found in all of the O18 serotypes; the similarity of these plasmids was confirmed by analysis with the restriction endonuclease EcoRI. Plasmids of similar molecular weight were also present in E. coli strains of the O7:K1 and O75:K100 serogroups. These data are consistent with the hypothesis that E. coli strains of the same serotype may be descendents of a single bacterial clone.


Remote preconditioning provides potent cardioprotection via PI3K/Akt activation and is associated with nuclear accumulation of β-catenin.
rIPC [remote IPC (ischaemic preconditioning)] has been shown to invoke potent myocardial protection in animal studies and recent clinical trials. Although the important role of PI3K (phosphoinositide 3-kinase)/Akt activation in the cardioprotection afforded by local IPC is well described, our understanding of the intracellular signalling of rIPC remains incomplete. We therefore examined the hypothesis that the myocardial protection afforded by rIPC is mediated via the PI3K/Akt/GSK3β (glycogen synthase kinase 3β) signalling pathway, activation of which is associated with nuclear accumulation of β-catenin. rIPC was induced in mice using four cycles of 5 min of ischaemia and 5 min of reperfusion of the hindlimb using a torniquet. This led to reduced infarct size (19 ± 4% in rIPC compared with 39 ± 7% in sham; P<0.05), improved functional recovery and reduced apoptosis after global I/R (ischaemia/reperfusion) injury using a Langendorff-perfused mouse heart model. These effects were reversed by pre-treatment with an inhibitor of PI3K activity. Furthermore, Western blot analysis demonstrated that, compared with control, rIPC was associated with activation of the PI3K/Akt signalling pathway, resulting in phosphorylation and inactivation of GSK3β, accumulation of β-catenin in the cytosol and its translocation to the nucleus. Finally, rIPC increased the expression of β-catenin target genes involved in cell-survival signalling, including E-cadherin and PPARδ (peroxisome-proliferator-activated receptor δ). In conclusion, we show for the first time that the myocardial protection afforded by rIPC is mediated via the PI3K/Akt/GSK3β signalling pathway, activation of which is associated with nuclear accumulation of β-catenin and the up-regulation of its downstream targets E-cadherin and PPARδ involved in cell survival.


[MINERAL WATER AS AN IMPORTANT FACTOR IN THE NUTRITIONAL SUPPORT OF HOMEOSTASIS].
The article presents the significance of mineral water (MV) eating as the important factor of water homeostasis and the hole digestive system nutritional support. The impact of MV was studied on the processes of transport and absorption of nutrients, lipid peroxidation.


Dietary selenium protect against redox-mediated immune suppression induced by methylmercury exposure.
The antagonism between selenium (Se) and mercury (Hg) has been widely recognized, however, the protective role of Se against methylmercury (MeHg) induced immunotoxicity and the underlying mechanism is still unclear. In the current study, MeHg exposure (0.01 mM via drinking water) significantly inhibited the lymphoproliferation and NK cells functions of the female Balb/c mice, while dietary Se supplementation (as Se-rich yeast) partly or fully recovered the observed immunotoxicity, indicating the protective role of Se against MeHg-induced immune suppression in mice. Besides, MeHg exposure promoted the generation of the reactive oxygen species (ROS), reduced the levels of nonenzymic and enzymic antioxidants in target organs, while dietary Se administration significantly diminished the MeHg-induced oxidative stress and subsequent cellular dysfunctions (lipid peroxidation and protein oxidation). Two possible mechanisms of Se's protective effects were further revealed. Firstly, the reduction of mercury concentrations (less than 25%, modulated by Se supplementation) in the target organs might contribute, but not fully explain the alleviated immune suppression. Secondly and more importantly, Se could help to maintain/or elevate the activities of several key antioxidants, therefore protect the immune cells against MeHg-induced oxidative damage.


PTSD, mental illness, and care among survivors of sexual violence in Northern Uganda: Findings from the WAYS study.
Previous studies have mainly considered war-affected youth as a homogenous group yet several subpopulations of war-affected youth, such as survivors of sexual violence, exist with unique mental health problems and treatment needs. This study aimed to assess posttraumatic stress disorder (PTSD), perceptions and meaning of mental illness, and access and barriers to mental health care among survivors of sexual violence. Data were collected from survivors of sexual violence during war (N = 181) who are participants in the longitudinal War-Affected Youth Survey (WAYS) study in Northern Uganda. Chi-square tests of independence and binary logistic regression were used to compute participants' characteristics and assess relations between exposure to sexual violence and PTSD. Sixty-six (n = 119, 66%) reported sexual abuse: 35% (n = 63) of whom returned from captivity with at least 1 child, and 43% (n = 78) met the criteria for PTSD (Impact of Events Scale-Revised score [IES-R] ≥33). Those who reported sexual abuse scored significantly higher on PTSD (OR = 3.23; 95% CI [2.09, 6.93]), perceived more stigma, reported more barriers to seeking care, and viewed mental illness as futile and fatal compared with their peers without a history of sexual abuse. Survivors of sexual violence are at risk of PTSD and report major obstacles to treatment and care. More resources should be allocated for interventions to improve access to care for survivors of sexual violence. Psychoeducation to create awareness, demystify myths and public stigma about mental illness, and trauma-focused cognitive-behavioral therapies to reduce PTSD among survivors are recommended. (PsycINFO Database Record


Effects of the COVID-19 pandemic and nationwide lockdown on trust, attitudes toward government, and well-being.
The contagiousness and deadliness of COVID-19 have necessitated drastic social management to halt transmission. The immediate effects of a nationwide lockdown were investigated by comparing matched samples of New Zealanders assessed before (Nprelockdown = 1,003) and during the first 18 days of lockdown (Nlockdown = 1,003). Two categories of outcomes were examined: (a) institutional trust and attitudes toward the nation and government and (b) health and well-being. Applying propensity score matching to approximate the conditions of a randomized controlled experiment, the study found that people in the pandemic/lockdown group reported higher trust in science, politicians, and police, higher levels of patriotism, and higher rates of mental distress compared to people in the prelockdown prepandemic group. Results were confirmed in within-subjects analyses. The study highlights social connectedness, resilience, and vulnerability in the face of adversity and has applied implications for how countries face this global challenge. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


UV photoreceptors and UV-yellow wing pigments in Heliconius butterflies allow a color signal to serve both mimicry and intraspecific communication.
Mimetic wing coloration evolves in butterflies in the context of predator confusion. Unless butterfly eyes have adaptations for discriminating mimetic color variation, mimicry also carries a risk of confusion for the butterflies themselves. Heliconius butterfly eyes, which express recently duplicated ultraviolet (UV) opsins, have such an adaptation. To examine bird and butterfly color vision as sources of selection on butterfly coloration, we studied yellow wing pigmentation in the tribe Heliconiini. We confirmed, using reflectance and mass spectrometry, that only Heliconius use 3-hydroxy-DL-kynurenine (3-OHK), which looks yellow to humans but reflects both UV- and long-wavelength light, whereas butterflies in related genera have chemically unknown yellow pigments mostly lacking UV reflectance. Modeling of these color signals reveals that the two UV photoreceptors of Heliconius are better suited to separating 3-OHK from non-3-OHK spectra compared with the photoreceptors of related genera or birds. The co-occurrence of potentially enhanced UV vision and a UV-reflecting yellow wing pigment could allow unpalatable Heliconius private intraspecific communication in the presence of mimics. Our results are the best available evidence for the correlated evolution of a color signal and color vision. They also suggest that predator visual systems are error prone in the context of mimicry.


Use of lomustine to treat cutaneous nonepitheliotropic lymphoma in a cat.
A 17-year-old spayed female domestic shorthair cat was referred for evaluation of severe skin lesions, including ulceration, nodule formation, erythema, and alopecia. Cutaneous nonepitheliotropic lymphoma was diagnosed histologically. There was no evidence of visceral organ involvement, but renal function was decreased. The cat was treated with lomustine (45.5 mg/m2, PO, q 21 d), and skin lesions resolved after administration of the third dose. No severe toxicoses were identified. Results suggest that lomustine may be useful for treatment of cutaneous nonepitheliotropic lymphoma in cats; however, optimal dosage, efficacy, and potential adverse effects must be determined.


An Advanced One-Step RT-LAMP for Rapid Detection of Little cherry virus 2 Combined with High-Throughput Sequence-Based Phylogenomics Reveal Divergent Flowering Cherry Isolates.
Little cherry virus 2 (LChV-2, genus Ampelovirus) is considered to be the main causal agent of the economically damaging little cherry disease, which can only be controlled by removal of infected trees. The widespread viral disease of sweet cherry (Prunus avium L.) is affecting the survival of long-standing orchards in North America and Europe, hence the dire need for an early and accurate diagnosis to establish a sound disease control strategy. The endemic presence of LChV-2 is mainly confirmed using laborious time-consuming reverse-transcription (RT-PCR). A rapid reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay targeting a conserved region of the coat protein was developed and compared with conventional RT-PCR for the specific detection of LChV-2. This affordable assay, combined with a simple RNA extraction, deploys desirable characteristics such as higher ability for faster (<15 min), more analytically sensitive (100-fold), and robust broad-range diagnosis of LChV-2 isolates from sweet cherry, ornamental flowering cherry displaying heterogenous viral etiology and, for the first time, newly identified potential insect vectors. Moreover, use of Sanger and total RNA high-throughput sequencing as complementary metaviromics approaches confirmed the LChV-2 RT-LAMP detection of divergent LChV-2 isolates in new hosts and the relationship of their whole-genome was exhaustively inferred using maximum-likelihood phylogenomics. This entails unprecedented critical understanding of a novel evolutionary clade further expanding LChV-2 viral diversity. In conclusion, this highly effective diagnostic platform facilitates strategical support for early in-field testing to reliably prevent dissemination of new LChV-2 outbreaks from propagative plant stocks or newly postulated insect vectors. Validated results and major advantages are herein thoroughly discussed, in light of the knowledge required to increase the potential accuracy of future diagnostics and the essential epidemiological considerations to proactively safeguard cherries and Prunus horticultural crop systems from little cherry disease.


The molecular nature of multiple tumour-associated antigens expressed by a Rauscher-MuLV induced leukaemia.
The identification of the molecules that bear the antigenic determinants recognized during an anti-tumour immune response is an important goal of tumour biology. It is now well established that most murine tumours express multiple tumour-associated antigens and in many cases it has been possible to show that these multiple antigens are expressed on completely different molecules. In the case of tumours induced by DNA and RNA viruses, certain virally encoded proteins may be tumour antigens. However, these tumours, like tumours of nonviral origin, also express other antigen-bearing molecules that are encoded by cellular genes. Frequently, the same tumour-associated antigen-bearing molecules are shared by all independently induced tumours of similar aetiology leading to the prediction that the expression of these antigenic molecules is linked to the molecular events necessary for tumour induction. Many of the nonviral tumour-associated antigen-bearing molecules purified to date are also found on normal tissues, but the normal metabolic function of these molecules and the alterations that render them antigenic are not yet understood.


Degree of vinyl conversion, polymerization shrinkage and stress development in experimental endodontic composite.
This study explores degree of vinyl conversion (DVC), polymerization shrinkage (PS) and shrinkage stress (PSS) of the experimental amorphous calcium phosphate (ACP) composites intended for use as an endodontic sealer. Light-cure (LC), chemical cure (CC) or dual-cure (DC; combined light and chemical cure) resins comprised urethane dimethacrylate (UDMA), 2-hydroxyethyl methacrylate (HEMA), methacryloyloxyethyl phthalate (MEP) and a high molecular mass oligomeric co-monomer, poly(ethyleneglycol)-extended UDMA (PEG-U) (designated UPHM resin). To fabricate composites, a mass fraction of 60 % UPHM resin was blended with a mass fraction of 40 % as-made (am-ACP) or ground ACP (g-ACP). DVC values of copolymer (unfilled UPHM resin) and composite specimens were determined by infrared spectroscopy. Glass-filled composites were used as controls. PS and PSS of composites were determined by dilatometry and tensometry, respectively. LC copolymers attained extraordinary high DVC values at 24 h post-cure (95.7 %), compared to CC (52 %) and DC (79.3 %) copolymer specimens. While the DVC values of LC and DC am-ACP composites were reduced between 5 and 10 %, DVC values of DC g-ACP composites increased almost 8 % compared to the corresponding copolymers. High DVC attained in LC composites was, expectedly, accompanied with high PS values (on average 7 vol%). However, PSS developed in LC and especially DC composites did not exceed PSS values seen in other UDMA-based composites. Based on this initial evaluation, it is concluded that, DC, g-ACP filled UPHM composite shows promise as an endodontic sealer. However, further physicochemical evaluations, including water sorption, mechanical stability and ion release as well as a leachability studies need to be performed before this experimental material is tested for cellular responses and, eventually recommended for clinical utility.


Is This a Drug?" Answers From Medical Students in a Tertiary Care Teaching Hospital in Eastern India.
World Health Organization (WHO) defines what is drug and what is not. Second year MBBS students learn the principles of Pharmacology that they use in their later clinical practice life. The aim of the survey was to determine how medical students classify a range of preparations they might encounter in their professional lives and whether a brand name or a commercial preparation of a drug would influence their decision in the categorization of the preparation as a 'drug' or 'not a drug'. To assess the knowledge of medical students, if a substance or product is a drug. We surveyed 2 concurrent years of medical students to classify 60 candidate medicinal preparations into "drug" and "not-drug" from a validated questionnaire. The candidate preparations were named either in generic or in their commercially available forms and they were all essential drugs as per WHO definition. The two groups of students, A and B, included 192 and 215 students respectively. Demographically there was little difference in the two groups. Agents like Aspirin, Paracetamol, Amphetamine, Salbutamol, Atropine, Dextromethorphan, Codeine, Diazepam, Ciprofloxacin ear drops, Levonorgestrol, Neosporin eye ointment, Furosemide, Metronidazole, Penicillin, Sorbitrate, Lignocaine, Methotrexate, Penicillin, Zolpidem and Thalidomide received almost unanimous votes as drugs. Arsenic trioxide, Fentanyl and petroleum jelly were considered to be "non-drugs" by most participants. The two groups did not differ significantly in their responses. Some major lacunae were noted in the knowledge of the participating students despite book teaching on the definition of a drug. Drugs used for prophylaxis and those used in physiological conditions or topically, were often missed. These gaps need to be filled by more emphasis on definition of a drug and its clinical applicability based on example and case based studies.


Anti-proliferation and Apoptosis Induction of Aqueous Leaf Extract of Carica papaya L. on Human Breast Cancer Cells MCF-7.
Breast cancer is the most frequently diagnosed cancer in women. Chemotherapy is the main method of breast cancer treatment but there are side effects. Carica papaya leaves is vegetable foods consumed by most people of Indonesia have potential as anticancer. The aim of this study was to investigate anti-proliferative and apoptotic induced effect of aqueous papaya leaves extracts on human breast cancer cell lines MCF-7. Inhibitory on cell proliferation was measured by MTT assay while apoptosis induction was measured using Annexin V. The results showed that papaya leaf can inhibit the proliferation of human breast cancer cells MCF-7 with IC50 in 1319.25 μg mL-1. The IC50 values of papaya leaf extract was higher than the IC50 value quercetin and doxorubicin. Papaya leaf extract can also induce apoptosis of breast cancer cells MCF-7 about 22.54% for concentration 659.63 μg mL-1 and about 20.73% for concentration 329.81 μg mL-1. The percentage of cell apoptosis of papaya leaf extract lower than doxorubicin but higher than quercetin. This study indicated that papaya leaf extract have potential as anticancer through mechanism anti-proliferation and apoptosis induction.


Novel Monoclonal Antibodies and Recombined Antibodies Against Variant SARS-CoV-2.
The mutants resulted from the ongoing SARS-CoV-2 epidemic have showed resistance to antibody neutralization and vaccine-induced immune response. The present study isolated and identified two novel SARS-CoV-2 neutralizing antibodies (nAbs) from convalescent COVID-19 patients. These two nAbs (XG81 and XG83) were then systemically compared with nine nAbs that were reconstructed by using published data, and revealed that, even though these two nAbs shared targeting epitopes on spike protein, they were different from any of the nine nAbs. Compared with XG81, XG83 exhibited a higher RBD binding affinity and neutralization potency against wild-typed pseudovirus, variant pseudoviruses with mutated spike proteins, such as D614G, E484Q, and A475V, as well as the authentic SARS-CoV-2 virus. To explore potential broadly neutralizing antibodies, heavy and light chains from all 18 nAbs (16 published nAbs, XG81 and XG83) were cross-recombined, and some of the functional antibodies were screened and studied for RBD binding affinity, and neutralizing activity against pseudovirus and the authentic SARS-CoV-2 virus. The results demonstrated that several recombined antibodies had a more potent neutralization activity against variant pseudoviruses compared with the originally paired Abs. Taken together, the novel neutralizing antibodies identified in this study are a likely valuable addition to candidate antibody drugs for the development of clinical therapeutic agents against SARS-CoV-2 to minimize mutational escape.


Optimization in interstitial plasmonic photothermal therapy for treatment planning.
Gold nanorods have the potential to enhance the treatment efficacy of interstitial photothermal therapy. In order to enhance both the potential efficiency and the safety of such procedures, treatment planning on laser power density, nanoparticle concentration, and exposure time has turned out to be useful in predicting the thermal damage and optimizing treatment outcome. To the best of our knowledge, there is no previous report on the optimization of interstitial plasmonic photothermal therapy (PPTT) for all these free parameters simultaneously. The authors propose to develop a suitable optimization algorithm for interstitial PPTT to optimize these parameters and achieve complete damage to spherical tumors of different sizes with a damage margin width of 1 mm from the tumor boundary embedded deep inside a normal tissue model. In a numerical tissue model, the standard Pennes bioheat equation and the first-order thermal-chemical rate equation were used to model the temperature and thermal damage distributions, respectively, in spherical tumors that were embedded deep inside a normal tissue and incubated with nanorods. The concentration of nanorods in the normal tissue was set to be about one quarter of that in the tumor. Thermal damage due to varying concentrations of nanorods, laser power density, and exposure time was computed for a series of tumor radii including 2, 3, 4, and 5 mm. An optimization algorithm was developed to determine the optimum laser power density, nanorod concentration, and exposure time for the treatment of such spherical tumors. In this algorithm, a novel objective function was created to enable the optimization of multiple key parameters, including nanoparticle concentration, power density, and exposure time, simultaneously to achieve not only the complete thermal damage to the entire tumor but also the collateral damage to the surrounding normal tissue with a margin width of 1 mm from the tumor boundary. Different weights were assigned sequentially to each free parameter according to the relative importance of the parameters. A thermal damage value of one calculated by Arrhenius damage law, which is more accurate than a threshold temperature typically used for characterizing thermal damage, was used to indicate effective treatment. The simulation results show that there is a steady increase in the overall temperature as the nanorod concentration increases; however, the uniformity of the temperature distribution changes significantly which in turn affects the thermal damage. Optimization results show that any slight decrease in one free parameter can be compensated by the increase in other free parameters, in which the complete thermal damage of the tumor and the collateral damage to normal tissue with a margin width of 1 mm can be always achieved. This implies the importance of optimization in interstitial PPTT. The proposed method can optimize laser power density, nanoparticle concentration, and exposure time simultaneously with different weights in interstitial PPTT planning for deep seated tumors. It provides flexibility for a clinician to make appropriate planning for individual patients according to their special needs.


Acalculous parotid sialadenopathy.
Acalculous inflammation of the parotid gland has been regarded by some as a specific disorder that can be staged as to the severity of the disease process. A review of the literature, however, indicates a divergence of opinion. It is the purpose of this study to test this hypothesis by a retrospective double-blind analysis of clinical, sialographic and histopathologic findings. Forty-two patients who were seen by the Department of Otolaryngology, Washington University School of Medicine from 1961 to 1970 were evaluated by two separate teams. There were 20 sialograms and 30 pathologic specimens, and all were re-examined. Eleven patients had both sialographic studies and histopathologic examination. The clinical presentations and sialographic findings were reviewed. These findings were then compared to each other. Our results indicate that we could not evaluate the severity of the clinical disease by sialography or histopathology. There was no consistent method of staging the sialographic and pathologic findings. In addition, there was no correlation between these two parameters. They reflect neither the patient's clinical syndrome pattern nor the extent of disease. It appears that the parotid gland responds variable to inflammation. These observations are exemplified by case histories.


Crystal structure of an engineered, HIV-specific recombinase for removal of integrated proviral DNA.
As part of the HIV infection cycle, viral DNA inserts into the genome of host cells such that the integrated DNA encoding the viral proteins is flanked by long terminal repeat (LTR) regions from the retrovirus. In an effort to develop novel genome editing techniques that safely excise HIV provirus from cells, Tre, an engineered version of Cre recombinase, was designed to target a 34-bp sequence within the HIV-1 LTR (loxLTR). The sequence targeted by Tre lacks the symmetry present in loxP, the natural DNA substrate for Cre. We report here the crystal structure of a catalytically inactive (Y324F) mutant of this engineered Tre recombinase in complex with the loxLTR DNA substrate. We also report that 17 of the 19 amino acid changes relative to Cre contribute to the altered specificity, even though many of these residues do not contact the DNA directly. We hypothesize that some mutations increase the flexibility of the Cre tetramer and that this, along with flexibility in the DNA, enable the engineered enzyme and DNA substrate to adopt complementary conformations.


dl-3n-butylphthalide reduces oxygen-glucose deprivation-induced endothelial cell damage by increasing PGC-1α.
Animal experiments verified that dl-3-n-butylphthalide (NBP) can protect vascular endothelial cells from ischemic damage and promote vascular proliferation in ischemic stroke treatment, but the underlying mechanism has not been fully clarified. This study aimed to investigate the effects of NBP on peroxisome proliferators-activated receptor-γ coactivator-1α (PGC-1α) expression in endothelial cells exposed to oxygen-glucose deprivation (OGD) and to clarify the related molecular mechanism. SV40-transformed aortic rat endothelial cell line was cultured and subjected to OGD in the presence or absence of NBP. The cell viability was evaluated by using thiazolyl blue tetrazolium bromide (MTT) method. The cellular endothelial nitric oxide synthase (eNOS) activity was measured by using eNOS activity assay. The nuclear changes were assessed with Hoechst 33342 fluorescent dye. The immunofluorescence analysis and Western blotting assay were conducted to evaluate the protein expression. We found that NBP could significantly prevent endothelial cells from OGD-induced injuries, in terms of cell morphology and cell viability. Both immunofluorescence analysis and Western blot findings confirmed that the NBP treatment further enhanced PGC-1α expression during OGD, which was prevented in the presence of selective endothelial nitric oxide synthetase (eNOS) inhibitor N5-(1-Iminoethyl)-L-ornithine-HCL (L-NIO). Furthermore, we found that NBP could protect the eNOS activity about by 40% during OGD and did not influence the eNOS protein level in the spectrophotometric-based analysis. NBP maintained the endothelial PGC-1α expression via regulating eNOS activity during the exposure to OGD; therefore, it presented its protective function to cell viability and vascular proliferation.


Dementia Screening Accuracy is Robust to Premorbid IQ Variation: Evidence from the Addenbrooke's Cognitive Examination-III and the Test of Premorbid Function.
Scores on cognitive screening tools for dementia are associated with premorbid IQ. It has been suggested that screening scores should be adjusted accordingly. However, no study has examined whether premorbid IQ variation affects screening accuracy. To investigate whether the screening accuracy of a widely used cognitive screening tool for dementia, the Addenbrooke's cognitive examination-III (ACE-III), is improved by adjusting for premorbid IQ. 171 UK based adults (96 memory service attendees diagnosed with dementia and 75 healthy volunteers over the age of 65 without subjective memory impairments) completed the ACE-III and the Test of Premorbid Function (TOPF). The difference in screening performance between the ACE-III alone and the ACE-III adjusted for TOPF was assessed against a reference standard; the presence or absence of a diagnosis of dementia (Alzheimer's disease, vascular dementia, or others). Logistic regression and receiver operating curve analyses indicated that the ACE-III has excellent screening accuracy (93% sensitivity, 94% specificity) in distinguishing those with and without a dementia diagnosis. Although ACE-III scores were associated with TOPF scores, TOPF scores may be affected by having dementia and screening accuracy was not improved by accounting for premorbid IQ, age, or years of education. ACE-III screening accuracy is high and screening performance is robust to variation in premorbid IQ, age, and years of education. Adjustment of ACE-III cut-offs for premorbid IQ is not recommended in clinical practice. The analytic strategy used here may be useful to assess the impact of premorbid IQ on other screening tools.


[Pharmacovigilance of calcineurin inhibitor in peidatric kidney and liver transplantation].
To develop a pharmacovigilance program of calcineurin inhibitors used in pediatric renal and liver transplant patients at Hospital de Pediatría JP Garrahan, Argentina. Adverse drug reactions (ADRs) of pediatric patients with kidney and liver transplantation treated with calcineurin inhibitors (cyclosporine and tacrolimus) were evaluated by retrospective review of medical records of patients transplanted between 2010 and 2011. In addition, we carried out active pharmacovigilance since March, 2011. ADRs were reported to the National Health Authority. A total of 59 patients, 28 kidney transplant and 31 liver tarnsplant patients were analyzed. In both transplants, 60 ADRs to cyclosporine were reported including (number of cases), hypertension (19) and nephrotoxicity (6). In addition, 46 ADRs to tacrolimus were registered as hypomagnesemia (25), hypertension (7) and nephrotoxicity (5). A total of 95% and 96% of the adverse events to cyclosporine and tacrolimus, respectively, were defined as probable or definitive. Lastly, 70% and 98% of the events to cyclosporine and tacrolimus respectively, have been moderately severe or severe. This is the first study in Latin America that developed an intensive qualitative and quantitative analysis of the ADRs to calcineruin inhibitors in pediatric kidney and liver transplant patients. Spontaneous reporting should be motivated as well as monitoring ADRs should continue in the medium and long term for improving patient's quality of life.


Acute cocaine toxicity: the effect of agents in non-seizure-induced death.
Death from cocaine intoxication results from one or more of the multiple mechanisms including seizures, cardiovascular collapse, or apnea. In the free-moving rat model, continuous seizures are a major cause of death. To study other mechanisms of death unrelated to seizures in this model, we suppressed lethal seizures with diazepam (DZP) and investigated the effect of several pharmacological agents. Rats were pretreated with vehicle alone, diazepam 5 mg/kg alone, or a combination of DZP plus either nifedipine (NIFD) 2 mg/kg, propranolol (PROP) 10 mg/kg, or prazosin (PRAZ) 5 mg/kg. Five minutes after pretreatment, all animals received cocaine 100 mg/kg. Each test group consisted of 15 animals and all agents were given IP. Two animals in each group had cortical electrodes implanted. Animals that received vehicle followed by cocaine had 100% incidence of seizures and death. Those rats that received DZP alone followed by cocaine had no seizures and 53% death. Rats that received DZP plus NIFD or DZP plus PROP had suppression of seizures but no significant change in the incidence of death. The group that received DZP and PRAZ followed by cocaine had no seizures and 13% incidence of death (p < 0.001). Electroencephalogram recordings showed cortical electrical spike activity or spike-and-wave afterdischarges in all animals clinically observed to have seizures. In the absence of clinical seizure activity, no significant cortical spike activity was noted. It is concluded that animals protected from seizures with diazepam can still have nonseizure deaths after high-dose cocaine. The incidence of death in these animals is not reduced with nifedipine or propranolol pretreatment but is reduced with prazosin pretreatment.


Suppression of NK and CD8+ T cells reduces astrogliosis but accelerates cerebellar dysfunction and shortens life span in a mouse model of Sandhoff disease.
Sandhoff disease is an inherited lysosomal storage disease, resulting from the deficiency of lysosomal β-hexosaminidase A and B enzyme activity. The Hexb-/- mouse model recapitulates human disease and leads to fatal neurodegeneration and neuroinflammation. IL-15 is important for the proliferation of NK, NK T, and CD8+ cytotoxic/memory T cells. In order to determine how changes to IL-15-dependent immune cell populations would alter the course of Sandhoff disease in mice, we generated a Hexb-/-Il-15-/- double knockout mouse and used motor behaviour tests, analyzed peripheral blood and brain leukocyte immunophenotypes, cytokine secretion, as well as examined markers of microgliosis, astrogliosis and apoptosis. Hexb-/-Il-15-/- mice had an accelerated neurodegenerative phenotype, and reached the humane endpoint at 118±3.5d, compared to Hexb-/- mice (127±2.2d). The performance of Hexb-/-Il-15-/- mice declined earlier than Hexb-/- mice on the rotarod and righting reflex motor behaviour tests. Hexb-/- mice had a significantly higher prevalence of pro-inflammatory monocytes in the blood relative to C57BL/6 mice, but this was unaltered by IL-15 deficiency. The prevalence of NK cells and CD8+ T cells in Il-15-/- and Hexb-/-Il-15-/- mice was decreased compared to wild type and Hexb-/- mice. While Hexb-/- mice displayed an increase in the prevalence of CD4+ and CD8+ T cells in brain leukocytes compared to C57BL/6 mice, there was a decrease in CD8+ T cells in Hexb-/-Il-15-/- compared to Hexb-/- mice. In addition, circulating IL-17 and IL-10 levels were significantly higher in Hexb-/-Il-15-/- mice, suggesting heightened inflammation compared to Hexb-/- mice. Interestingly, astrogliosis levels were significantly reduced in the cerebellum of Hexb-/-Il-15-/- mice compared to Hexb-/- mice while microgliosis was not affected in brains of Hexb-/-Il-15-/- mice. Our study demonstrated that IL-15 depletion dramatically reduced numbers of NK and CD8+ T cells as well as astrocytes but accelerated disease progression in Sandhoff mice. These results pointed to interactions between NK/CD8+ T cells and astrogliosis and potentially a protective role for NK/CD8+ T cells and/or astrocytes during disease progression. This observation supports the notion that expanding the IL-15-dependent NK and CD8+ T cells populations with IL-15 therapy may have therapeutic benefits for Sandhoff disease.


Greener neighbourhoods, slimmer children? Evidence from 4423 participants aged 6 to 13 years in the Longitudinal Study of Australian children.
There is a growing belief that green space (for example, parks) help prevent obesity. There is evidence of an inverse association between green space and childhood body mass index (BMI); however, the majority of these studies are cross-sectional. Longitudinal studies that track change in BMI across childhood in relation to levels of green space proximity would improve the quality of evidence available for decision making. Objectively measured BMI was obtained every 2 years between 2006 and 2012 for 4423 participants initially aged 6-7 years in the Longitudinal Study of Australian Children (LSAC). The LSAC is a nationally representative study on a range of health and socio-demographic measures. Using Australian Bureau of Statistics mesh block data, which classify small scale land areas based on the main usage, each participant was assigned an objective measure of green space availability within their Statistical Area (level 2) of residence. Gender-stratified multilevel linear regression was used to estimate BMI growth curves across childhood in relation to green space availability. Family income, Australian Indigenous status, mothers' education and language spoken were used to adjust for socio-economic confounding. Age was found to be an effect modifier of associations between green space and BMI for boys (P=0.005) and girls (P=0.048). As children grew older, an inverse patterning of BMI by green space availability emerged. These findings held after adjustment for socio-economic circumstances for boys (P=0.009), though were less robust for girls after this adjustment (P=0.056). A beneficial effect of green space on BMI emerges as children grow older. However, there was little additional benefit after a modest amount of green space was met. Further research is needed to understand whether the drivers of this effect are from age-specific mechanisms, or whether the benefit of living in a greener neighbourhood is accumulated through childhood.


Endoscopic mucosal resection: learning curve for large nonpolypoid colorectal neoplasia.
Colorectal EMR for nonpolypoid neoplasia achieves better outcomes when performed by expert endoscopists. The time point at which the endoscopist achieves expert level remains to be defined. The objective of this study was to establish a learning curve of colorectal EMR for nonpolypoid neoplasia based on residual tissue on surveillance colonoscopy and adverse event rate. Five hundred seventy-eight consecutive patients underwent EMR of colorectal neoplasia by 1 of 3 primary endoscopists between December 2004 and September 2013 in a tertiary academic center. Primary analyses focused on the largest lesion for patients with more than 1 lesion (median age, 69 years; median polyp size, 30 mm; 51% en bloc resection). Data on surveillance colonoscopy were available for 74%. Learning curves were calculated for each of the 3 main outcome measurements: the presence of residual neoplasia on surveillance colonoscopy, endoscopic assessment of incomplete EMR, and the occurrence of an immediate bleeding adverse event. Residual neoplasia on surveillance colonoscopy was present for 23.2% of patients, the rate of endoscopist-assessed incomplete EMR was 27.6%, and immediate bleeding adverse events occurred in 6.9% of patients. Although there was between-endoscopist variability, the overall rates of residual neoplasia and incomplete EMR decreased to below 20% to 25% after 100 EMRs; initial decreases in both rates were observed for earlier EMRs. Immediate bleeding adverse events occurred at a low frequency for each endoscopist across all EMRs. Perforation requiring surgical intervention occurred in 1 patient (0.2%). This study demonstrated that an unexpectedly high number of 100 colorectal EMR procedures for large nonpolypoid colorectal neoplasia are required to achieve a plateau phase for crucial outcomes.


Changes in the concentration of cAMP, fructose 2,6-bisphosphate and related metabolites and enzymes in Saccharomyces cerevisiae during growth on glucose.
Changes in the concentration of several metabolites and enzymes related to carbohydrate metabolism were measured during the growth of Saccharomyces cerevisiae on a mineral medium containing glucose as the limiting nutrient. When about 50% of the original glucose was used the exponential phase ended and the culture entered a 'transition' phase before the complete exhaustion of glucose. In this transition phase several metabolic changes occurred. cAMP, that decreased along growth, reached a constant value of about 0.7 nmol/g dry weight. A pronounced drop in fructose-6-phosphate-2-kinase activity and in the concentration of fructose 2,6-bisphosphate and fructose 1,6-bisphosphate was observed accompanied by a less marked decrease in hexose monophosphates. Trehalase activity also dropped and reached a minimal value at the onset of the stationary phase when synthesis of trehalose began. Glycogen concentration and glycogen synthase activity increased sharply during the transition phase. Plasma membrane ATPase began to increase at the middle of the exponential phase and then, coincident with the glucose exhaustion, a 90% decrease in the measurable activity was observed.


Pre-gelation staining expansion microscopy for visualisation of the Plasmodium liver stage.
Fluorescence and light microscopy are important tools in the history of natural science. However, the resolution of microscopes is limited by the diffraction of light. One possible method to circumvent this physical restriction is the recently developed expansion microscopy (ExM). However, the original ultrastructure ExM (U-ExM) protocol is very time-consuming, and some epitopes are lost during the process. In this study, we developed a shortened pre-gelation staining ExM (PS-ExM) protocol and tested it to investigate the Plasmodium liver stage. The protocol presented in this study allows expanding of pre-stained samples, which results in shorter incubation times, better preservation of some epitopes and the advantage that non-expanded controls can be performed alongside using the same staining protocol. The protocol applicability was accessed throughout the Plasmodium liver stage, showing isotropic five-fold expansion. Furthermore, we used PS-ExM to visualise parasite mitochondria as well as the association of lysosomes to the parasitophorous vacuole membrane (PVM) as an example of visualising host-pathogen interaction. We are convinced that this new tool will be helpful for a deeper understanding of the biology of the Plasmodium liver stage.


Recent advances in predicting gene-disease associations.
Deciphering gene-disease association is a crucial step in designing therapeutic strategies against diseases. There are experimental methods for identifying gene-disease associations, such as genome-wide association studies and linkage analysis, but these can be expensive and time consuming. As a result, various in silico methods for predicting associations from these and other data have been developed using different approaches. In this article, we review some of the recent approaches to the computational prediction of gene-disease association. We look at recent advancements in algorithms, categorising them into those based on genome variation, networks, text mining, and crowdsourcing. We also look at some of the challenges faced in the computational prediction of gene-disease associations.


Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression.
Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways. This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC.


Synchronization of surface reactions via Turing-like structures.
We discuss an alternative to the traditional gas-phase coupling approach in order to explain synchronized global oscillations in CO oxidation on Pt(110). We use a microscopic model which includes structural Pt surface reconstruction via front propagation, and large diffusion rates for CO. The synchronization mechanism is associated with the formation of a Turing-like structure of the substrate. By using large parallel microscopic simulations we derive scaling laws which allow us to extrapolate to realistic diffusion rates, pattern size, and oscillation periods.


Bronchogenic carcinoma of squamous cells in a young pregnant woman.
Lung cancer continues to be the most incident neoplasia in the world and also the most frequent cause of death by cancer, with more than 900000 new cases per year. Women present greater risk of developing bronchogenic carcinoma, possibly because of differences in metabolism of the carcinogens associated with tobacco and also because of hormonal differences because estrogens can promote the appearance of lung cancer, including during pregnancy. We have described the case of a 25-year-old patient who developed squamous cell carcinoma of the lung during her third pregnancy, with a progressive worsening of her general condition and progression until death. We believe that the pregnancy could have contributed to the evolution of the disease, especially because of the increased levels of gestational hormones, particularly the estrogen, because its receptors have an important role in regulating growth and in the differentiation of several tissues facilitating like this, the development of the neoplasia, and complicating its early diagnosis.


Graph-mining algorithm for the evaluation of bond formability.
The formability of a bond in a target molecule is a bond property related to the problem of finding a reaction that synthesizes the target by forming the bond: the easier this problem, the higher the formability. Bond formability provides an interesting piece of information that might be used for selecting strategic bonds during a retrosynthesic analysis or for assessing synthetic accessibility in virtual screening. The article describes a graph-mining algorithm called GemsBond that evaluates formability of bonds by mining structural environments contained in several thousand molecular graphs of reaction products. When tested on reaction databases, GemsBond recognizes most formed bonds in reaction products and provides explanations consistent with knowledge in organic synthesis.


Complications of peripheral nerve blocks.
Complications of peripheral nerve blocks are fortunately rare, but can be devastating for both the patient and the anaesthesiologist. This review will concentrate on current knowledge about peripheral nerve injury secondary to nerve blocks, complications from continuous peripheral nerve catheter techniques, and local anaesthetic systemic toxicity.


Synthesis of Deuterated and Sulfurated Polymers by Inverse Vulcanization: Engineering Infrared Transparency via Deuteration.
The synthesis of deuterated, sulfurated, proton-free, glassy polymers offers a route to optical polymers for infrared (IR) optics, specifically for midwave IR (MWIR) photonic devices. Deuterated polymers have been utilized to enhance neutron cross-sectional contrast with proteo polymers for morphological neutron scattering measurements but have found limited utility for other applications. We report the synthesis of perdeuterated d14-(1,3-diisopropenylbenzene) with over 99% levels of deuteration and the preparation of proton-free, perdeuterated poly(sulfur-random-d14-(1,3-diisopropenylbenzene)) (poly(S-r-d14-DIB)) via inverse vulcanization with elemental sulfur. Detailed structural analysis and quantum computational calculations of these reactions demonstrate significant kinetic isotope effects, which alter mechanistic pathways to form different copolymer microstructures for deutero vs proteo poly(S-r-DIB). This design also allows for molecular engineering of MWIR transparency by shifting C-H bond vibrations around 3.3 μm/3000 cm-1 observed in proteo poly(S-r-DIB) to 4.2 μm/2200 cm-1. Furthermore, the fabrication of thin-film MWIR optical gratings made from molding of deuterated-sulfurated, proton-free poly(S-r-d14-DIB) is demonstrated; operation of these gratings at 3.39 μm is achieved successfully, while the proteo poly(S-r-DIB) gratings are opaque at these wavelengths, highlighting the promise of MWIR sensors and compact spectrometers from these materials.


Unmet mental health care need 10-11 years after the 9/11 terrorist attacks: 2011-2012 results from the World Trade Center Health Registry.
There is little current information about the unmet mental health care need (UMHCN) and reasons for it among those exposed to the World Trade Center (WTC) terrorist attacks. The purpose of this study was to assess the level of UMHCN among symptomatic individuals enrolled in the WTC Health Registry (WTCHR) in 2011-2012, and to analyze the relationship between UMHCN due to attitudinal, cost, and access factors and mental health symptom severity, mental health care utilization, health insurance availability, and social support. The WTCHR is a prospective cohort study of individuals with reported exposure to the 2001 WTC attacks. This study used data from 9,803 adults who completed the 2003-2004 (Wave 1) and 2011-2012 (Wave 3) surveys and had posttraumatic stress disorder (PTSD) or depression in 2011-2012. We estimated logistic regression models relating perceived attitudinal, cost and access barriers to symptom severity, health care utilization, a lack of health insurance, and social support after adjusting for sociodemographic characteristics. Slightly more than one-third (34.2%) of study participants reported an UMHCN. Symptom severity was a strong predictor of UMHCN due to attitudinal and perceived cost and access reasons. Attitudinal UMHCN was common among those not using mental health services, particularly those with relatively severe mental health symptoms. Cost-related UMHCN was significantly associated with a lack of health insurance but not service usage. Access-related barriers were significantly more common among those who did not use any mental health services. A higher level of social support served as an important buffer against cost and access UMHCN. A significant proportion of individuals exposed to the WTC attacks with depression or PTSD 10 years later reported an UMHCN, and individuals with more severe and disabling conditions, those who lacked health insurance, and those with low levels of social support were particularly vulnerable.


Perceptions of primary health care nurses and general practitioners in the care of older people with urinary incontinence.
To identify the challenges and opportunities among primary health care nurses and general practitioners (GPs) in the care of older people with urinary incontinence (UI) and other chronic conditions in China. UI is highly prevalent among community-dwelling older people with chronic conditions but is underreported and poorly managed. Understanding the factors that affect primary health care professionals' practices in their care for this population is imperative to foster nurse-led UI care services. A qualitative descriptive study. Four focus groups were held with 24 primary health care nurses and GPs in Changsha, Hunan Province, China, between July and September 2021. A reflective thematic analysis was used to identify themes. This study revealed misconceptions regarding older people living with UI and other chronic conditions in primary care health professional participants. Moreover, primary health care nurses had very limited autonomy in UI diagnosis and initiating care interventions for this patient population. By reflecting on practices, participants recognized various practical solutions to improve the detection and management of UI. Participants also identified barriers to accessing care services in older people with UI. They suggested changes in the health care system to achieve universal access to UI care services for older people. Nurse-led UI care services in primary health care for community-dwelling older people with chronic conditions are in high demand but are underdeveloped due to professional and health care system factors. Findings from this study provide new insights into challenges faced by primary health care professionals and illuminate practical solutions to address these challenges. Adherence to COREQ guidelines was maintained. No patient or public contribution.


Increases in extreme heat stress in domesticated livestock species during the twenty-first century.
Anthropogenic climate change is expected to have major impacts on domesticated livestock, including increased heat stress in animals in both intensive and extensive livestock systems. We estimate the changes in the number of extreme heat stress days per year for animals raised outdoors that can be expected in the major domesticated animal species (cattle, sheep, goats, poultry, and pigs) across the globe during this century. We used the temperature humidity index as a proxy for heat stress, calculated using temperature and relative humidity data collated from an ensemble of CMIP6 climate model output for mid and end century. We estimate changes in the proportions of different livestock species that may be at increased risk of extreme heat stress under two contrasting greenhouse gas emission scenarios. Results are discussed in relation to changes in the suitability of different climate conditions for domesticated livestock during the current century. We find that by end century, extreme heat stress risk is projected to increase for all livestock species in many parts of the tropics and some of the temperate zones, and to become climatically more widespread, compared to 2000. Although adaptation options exist for both intensive and extensive livestock production systems, the increasing pervasiveness of extreme heat stress risk in the future will seriously challenge the viability of outdoor livestock keeping, particularly in the lower latitudes in lower and middle-income countries where the costs of adaptation may be challenging to address.


Contextual Determinants in Alcohol, Tobacco and Cannabis Consumption, Mood and Bullying during Adolescence.
The present study aimed to explore the differences in the consumption of alcohol, tobacco and cannabis, mood and bullying between adolescents. A cross-sectional study was carried out in five regions of Northern Spain (one in Galiza and four in central Catalonia) that share similar socioeconomic characteristics and encompass around 10,000 inhabitants each. Students living in Burela, Galiza (N = 71) were compared to those of Central Catalonia (N = 193). The independent variable was the municipality of residence. The dependent variables encompassed: weekly available pocket money, Family Affluence Scale, self-classified academic qualification, place of origin, alcohol consumption, tobacco and cannabis smoking, negative mood and bullying. The mean age and their 95% confidence intervals (95% CI) of participants were similar between the regions (Burela: 15.90 years (15.68-16.13) and Central Catalonia: 15.36 years (15.28-15.44)). More than half of the participants were females (Burela, Galiza (53.5%) and Catalonia (54.9%)). Prevalence ratios (PR) and their 95% CI were estimated using Poisson regression models. In comparison with adolescents from Burela (Galiza), those living in Central Catalonia had higher prevalence of diverse academic levels (adjusted PR = 3.92 (1.78-8.66)), tobacco consumption (adjusted PR = 2.41 (1.47-3.97)) and negative mood (adjusted PR = 5.97 (3.05-11.70)). Even when dealing with regions with similar socioeconomic characteristics and number of inhabitants, differences exist in terms of the socioeconomic level, tobacco consumption, mood and bullying, as reported by adolescents.


Efficacy and safety of controlled-release versus immediate-release oxycodone: randomized, double-blind evaluation in patients with chronic back pain.
To compare the efficacy and safety of controlled-release oxycodone given every 12 hours with immediate-release oxycodone given four times daily in patients with persistent back pain. Randomized, double-blind, active-controlled, two-period crossover trial. Fifty-seven adult outpatients with stable, chronic, moderate-to-severe low back pain despite analgesic therapy were enrolled; 47 were randomized; 11 discontinued for side effects, most commonly nausea and vomiting. Controlled-release oxycodone tablets given every 12 hours; immediate-release oxycodone tablets given four times daily; dose titration with controlled-release or immediate-release for up to 10 days; double-blind treatment for 4-7 days each. Patients' pain scores (0 = none, 1 = slight, 2 = moderate, 3 = severe). Pain intensity decreased from moderate to severe at baseline to slight at the end of titration with both oxycodone formulations. The daily oxycodone dose was 40 mg or less in 68% of patients. During double-blind treatment, mean pain intensity was maintained at 1.2 (0.1 SE) with controlled-release and at 1.1 (0.1 SE) with immediate-release oxycodone. The most common adverse events were constipation, nausea, pruritus, somnolence, and dizziness. Controlled-release oxycodone given every 12 hours was comparable with immediate-release oxycodone given four times daily in efficacy and safety, and it provides convenient, twice-daily, around-the-clock treatment for selected patients with persistent back pain that is inadequately controlled by nonopioids or as-needed opioid therapy.


Effect of oral pyridoxine hydrochloride supplementation on arterial blood pressure in patients with essential hypertension.
The purpose of this study was to test the effect of vitamin B6 (pyridoxine-HCl, CAS 58-56-0) supplementation on arterial blood pressure in essential hypertension. The trial comprised 9 normotensive subjects (7 men and 2 women, aged between 32-58 years; mean +/- SD, 48 +/- 11) and 20 patients with essential hypertension (16 men and 4 women, aged between 32-69 years; mean +/- SD, 56 +/- 12). The patients were treated during 4 weeks with a single oral dose of pyridoxine (5 mg/kg body weight/day). After a 5-min rest, measurements were made in the supine position. When compared with the normotensive subjects, the hypertensive subject group had a significantly higher systolic and diastolic blood pressure (p < 0.001) and higher level of plasma norepinephrine (NE) (p < 0.01) before pyridoxine treatment. On the other hand, there were no significant differences in plasma epinephrine (E) and heart rates. Treatment of hypertensive patients with pyridoxine significantly reduced systolic (p < 0.01) and diastolic blood pressure (p < 0.005), plasma NE (p < 0.005) and E (p < 0.05) within 4 weeks. However, there was no significant difference in heart rate at the end of pyridoxine treatment. These results indicate a relationship between pyridoxine status and arterial blood pressure in the essential hypertensive patients.


On the nature of the apparent free energy of inserting amino acids into membrane through the translocon.
The nature of the biological free energy scale (ΔGapp), obtained from translocon mediated insertion studies, has been a major puzzle and the subject of major controversies. Part of the problem has been the complexity of the insertion process that discouraged workers from considering the feasible kinetics schemes and left the possible impression that ΔGapp presents some simple partition. Here we extend and clarify our recent analysis of the insertion problem using well-defined kinetics schemes and a free energy profile. We point out that although the rate constants of some steps are far from being obvious, it is essential to consider explicitly such schemes in order to advance in analyzing the meaning of ΔGapp. It is then shown that under some equilibrium conditions the kinetics scheme leads to a simple formula that allows one to relate ΔGapp to the actual free energy of partitioning between the water, the membrane, and the translocon. Other options are also considered (including limits with irreversible transitions that can be described by linear free energy relationships (LFERs)). It is concluded that it is unlikely that a kinetics plus thermodynamic based analysis can lead to a result that identifies ΔGapp with the partition between the membrane and the translocon. Thus, we argue that unless such analysis is presented, it is unjustified to assume that ΔGapp corresponds to the membrane translocon equilibrium or to some other arbitrary definition. Furthermore, we point out that the presumption that it is sufficient to just calculate the PMF for going from the translocon (TR) to the membrane and then to assume irreversible diffusive motion to water and for further entrance to the membrane is not a valid analysis. Overall, we point out that it is important to try to relate ΔGapp to a well-defined kinetics scheme (regardless of the complication of the system) in order to determine whether the energies of inserting positively charged residues to the membrane are related to the corresponding ΔGapp. It is also suggested that deviations from our simple formula for equilibrium conditions can help in identifying and analyzing kinetics barriers.


Pegylated IFN-alpha2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients.
Treatment of hepatitis C virus (HCV) has become a major challenge in HIV-infected individuals. No data exist on the efficacy and tolerability of pegylated IFN (peg-IFN) plus ribavirin in HIV-co-infected patients. Subcutaneous peg-IFN (150 microg weekly during the first 12 weeks and 100 microg weekly thereafter) plus ribavirin (400 mg twice a day) was given to 68 HIV-infected patients with chronic hepatitis C, having CD4 cell counts greater than 300 cells/microl, plasma HIV-RNA less than 5000 copies/ml, and elevated aminotransferase levels. All were naive for IFN, and 73% were receiving antiretroviral drugs. Plasma HCV-RNA levels greater than 800 000 IU/ml were seen in 50%, and 35% carried HCV genotype 3. Adverse events leading to treatment discontinuation occurred in 10 patients (15%). One patient taking didanosine developed pancreatitis. Severe weight loss occurred in 70% of patients. Clearance of HCV-RNA at the end of therapy (6 months for HCV-3 and 12 months for HCV-1/4) occurred in 50% of patients (81% with HCV-3 versus 30% with HCV-1/4). As 30% relapsed, the overall sustained response rate was 35% (28% in the intent-to-treat analysis). The main predictors of response were infection with HCV-3 and low HCV load. Treatment with peg-IFN and ribavirin is relatively well-tolerated in HIV/HCV-co-infected patients, although new side-effects, including pancreatitis and severe weight loss, may result from the interaction of ribavirin with antiretroviral drugs. Overall, therapy provides cure to one third of patients, a rate significantly lower than that seen in HCV-monoinfected individuals. Given that relapses are common, extended periods of therapy should be investigated.


Mitochondrial membrane protein mitofusin 2 as a potential therapeutic target for treating free fatty acid-induced hepatic inflammation in dairy cows during early lactation.
Inflammation is critical in the progression from benign hepatic lipidosis to pathological hepatic steatosis. The objective of this study was to examine the potential role of the outer mitochondrial membrane protein mitofusin 2 (MFN2) in the etiology of hepatic steatosis in dairy cows during early lactation. Using a nested case-control design, we compared blood and liver samples from 10 healthy cows and 10 age-matched cows with moderate fatty liver. Cows with moderate fatty liver had high liver triacylglycerols, elevated plasma concentrations of free fatty acids (FFA) and β-hydroxybutyrate, and low concentrations of glucose. Cows with moderate fatty liver had overactivated inflammatory pathways in the liver, as indicated by increased abundance of phosphorylated nuclear factor κB (NF-κB) p65, NLR family pyrin domain containing 3 (NLRP3) and caspase-1 inflammasome protein, and elevated plasma concentrations and hepatic mRNA abundance of their molecular targets IL-1β, IL-6, and tumor necrosis factor α (TNF-α). In the cell culture model, we were able to replicate our findings in cows with moderate fatty liver: 1.2 mM exogenous FFA decreased the abundance of MFN2 and upregulated phosphorylation levels of the inhibitor of NF-κB (IκB) α and NF-κB p65, the IκB kinase β activity, and the abundance of NLRP3, caspase-1, IL-1β, IL-6, and TNF-α. Whereas MFN2 knockdown potentiated the FFA-induced activation of these inflammatory pathways, overexpression of MFN2 attenuated the detrimental effect of excess exogenous FFA by improving mitochondrial function and decreasing the release of reactive oxygen species, suggesting that MFN2 may be a potential therapeutic target for FFA-induced hepatic inflammation in dairy cows during early lactation.


Switching on electrocatalytic activity in solid oxide cells.
Solid oxide cells (SOCs) can operate with high efficiency in two ways-as fuel cells, oxidizing a fuel to produce electricity, and as electrolysis cells, electrolysing water to produce hydrogen and oxygen gases. Ideally, SOCs should perform well, be durable and be inexpensive, but there are often competitive tensions, meaning that, for example, performance is achieved at the expense of durability. SOCs consist of porous electrodes-the fuel and air electrodes-separated by a dense electrolyte. In terms of the electrodes, the greatest challenge is to deliver high, long-lasting electrocatalytic activity while ensuring cost- and time-efficient manufacture. This has typically been achieved through lengthy and intricate ex situ procedures. These often require dedicated precursors and equipment; moreover, although the degradation of such electrodes associated with their reversible operation can be mitigated, they are susceptible to many other forms of degradation. An alternative is to grow appropriate electrode nanoarchitectures under operationally relevant conditions, for example, via redox exsolution. Here we describe the growth of a finely dispersed array of anchored metal nanoparticles on an oxide electrode through electrochemical poling of a SOC at 2 volts for a few seconds. These electrode structures perform well as both fuel cells and electrolysis cells (for example, at 900 °C they deliver 2 watts per square centimetre of power in humidified hydrogen gas, and a current of 2.75 amps per square centimetre at 1.3 volts in 50% water/nitrogen gas). The nanostructures and corresponding electrochemical activity do not degrade in 150 hours of testing. These results not only prove that in operando methods can yield emergent nanomaterials, which in turn deliver exceptional performance, but also offer proof of concept that electrolysis and fuel cells can be unified in a single, high-performance, versatile and easily manufactured device. This opens up the possibility of simple, almost instantaneous production of highly active nanostructures for reinvigorating SOCs during operation.


Treatment of the Kasabach-Merritt syndrome with pegylated recombinant human megakaryocyte growth and development factor in mice: elevated platelet counts, prolonged survival, and tumor growth inhibition.
Kasabach-Merritt Syndrome (KMS) is seen in children with large vascular tumors. KMS is characterized by very low platelet counts and a consumption of coagulation factors causing life-threatening complications. It has been proposed that thrombopenia in these patients is caused by intratumoral trapping of platelets. The truncated form of the cMpl-receptor ligand thrombopoietin, pegylated human megakaryocyte growth and development factor (Peg-rHuMGDF), is an agent that stimulates platelet production. We hypothesized that stimulation of the platelet production would prevent the life-threatening complications of patients with KMS owing to low platelet counts. In a mouse model of KMS, with tumors derived from a hemangioendothelioma cell line, we studied the effect of Peg-rHuMGDF. Treatment with Peg-rHuMGDF (10 microg/kg/day intraperitoneally) increased platelet counts by 7-8-fold compared with control tumor-bearing mice after 11 d of treatment (p < 0.001, n = 8). Survival was significantly increased, with 50% of treated animals alive at 1 mo versus 0% in untreated controls. Interestingly, we also observed an inhibition of tumor growth by 75% (p < 0.001, n = 8). Hematoxylin and eosin staining showed fresh fibrin clots in the treated tumors, suggesting that higher platelet counts caused intravascular thrombosis of tumor vessels. We conclude that increased platelet production in this model of KMS resulted in an antivascular tumor effect via platelet trapping. Further, we propose that thrombopoietin may be of critical value in preventing life-threatening complications from KMS.


Predictive models of natural history in primary biliary cirrhosis.
Primary biliary cirrhosis is a slow, progressive disease. Although many years may elapse before asymptomatic primary biliary cirrhosis patients begin experiencing symptoms of liver disease, their overall survival is significantly lower than the normal population. The Mayo natural history model has been developed to depict patient survival in the absence of effective therapeutic intervention. Although there are a number of caveats in applying this model, it has been validated using external data sets and established as an accepted tool for clinical or research purposes. Furthermore, recent data suggest that the Mayo natural history model continues to provide useful, predictive information in the presence of ursodeoxycholic acid therapy, which has been shown to lower the serum bilirubin to the natural history model for patient survival. In addition to the natural history model for patient survival, mathematical models have been developed to describe histologic progression and development of esophageal varices.


In vivo endoscopic Doppler optical coherence tomography imaging of the colon.
Colorectal cancer (CRC) remains the second deadliest cancer in the United States. Several screening methods exist; however, detection of small polyps remains a challenge. Optical coherence tomography (OCT) has been demonstrated to be capable of detecting lesions as small as 1 mm in the mouse colon, but detection is based on measuring a doubling of the mucosa thickness. The colon microvasculature may be an attractive biomarker of early tumor development because tumor vessels are characterized by irregular structure and dysfunction. Our goal was to develop an endoscopic method of detecting and segmenting colon vessels using Doppler OCT to enable future studies for improving early detection and development of novel chemopreventive agents. We conducted in vivo colon imaging in an azoxymethane (AOM)-treated mouse model of colorectal cancer using a miniature endoscope and a swept-source OCT system at 1,040 nm with a 16 kHz sweep rate. We applied the Kasai autocorrelation algorithm to laterally oversampled OCT B-scans to resolve vascular flow in the mucosa and submucosa. Vessels were segmented by applying a series of image processing steps: (i) intensity thresholding; (ii) two-dimensional matched filtering; and (iii) histogram segmentation. We observed differences in the vessels sizes and spatial distribution in a mature adenoma compared to surrounding undiseased tissue and compared the results with histology. We also imaged flow in four young mice (two AOM-treated and two control) showing no significant differences, which is expected so early after carcinogen exposure. We also present flow images of adenoma in a living mouse and a euthanized mouse to demonstrate that no flow is detected after euthanasia. We present, to the best of our knowledge, the first Doppler OCT images of in vivo mouse colon collected with a fiber-based endoscope. We also describe a fast and robust image processing method for segmenting vessels in the colon. These results suggest that Doppler OCT is a promising imaging modality for vascular imaging in the colon that requires no exogenous contrast agents. Lasers Surg. Med. 49:249-257, 2017. © 2016 Wiley Periodicals, Inc.


Prevalence of Inflammatory Back Pain and Axial Spondyloarthritis Among University Employees in Izmir, Turkey.
To estimate the prevalence of inflammatory back pain (IBP) and axial spondyloarthritis (axSpA) using the Assessment of SpondyloArthritis International Society (ASAS) classification criteria among employees in a university. In the first stage of the study, a face-to-face interview was done using a standard questionnaire to investigate IBP in 381 subjects randomly selected from 2894 employees at Dokuz Eylul University in Izmir, Turkey. In the second stage, subjects with back pain for ≥ 3 months and age at onset < 45 years were evaluated for axSpA using the ASAS criteria. Both the European Spondyloarthropathy Study Group (ESSG) criteria and Amor criteria were used for the classification of the whole group of spondyloarthritis (SpA). There were 131 male and 250 female subjects (mean age: 38.0 yrs). Twenty-five subjects (6.6%) were classified as having IBP according to the ASAS criteria. The prevalence of IBP according to the Berlin and Calin criteria was 7.1% and 21.5%, respectively. The prevalence of axSpA was estimated at 1.3% according to the ASAS classification criteria (0.5% for radiographic axSpA and 0.8% for nonradiographic axSpA). A total of 7 patients (1.8%) fulfilled both the Amor and ESSG criteria for the whole group of SpA. This is the first prevalence study of IBP and axSpA using ASAS classification criteria in the Turkish population. The prevalence estimates of IBP and axSpA reported here are within the upper range of other studies in European countries and the United States.