Angiographic and clinical characteristics associated with the development of Q-wave and non-Q-wave myocardial infarction in the thrombolysis in myocardial infarction (TIMI) 14 trial.
In the absence of thrombolytic therapy, patients with non-Q-wave myocardial infarction (MI) have previously been shown to have lower long-term mortality rates than patients with Q-wave MI. The goal of our study was to examine the angiographic and clinical differences between non-Q-wave MI and Q-wave MI in patients with ST elevation MI (STEMI) in the era of thrombolytic and combination therapy of thrombolytics plus glycoprotein IIb/IIIa inhibitors. Angiography was performed 90 minutes after thrombolytic administration in the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. The development of a non-Q-wave MI was assessed on electrocardiogram performed at the time of hospital discharge. Angiographic findings were assessed at an angiographic core laboratory by blinded investigators. The qualifying episode of ST elevation developed into a non-Q-wave MI in 36% of patients (315/878) and into a Q-wave MI in 64% of patients (563/878). In patients in whom non-Q-wave MI developed, the rate of TIMI grade 3 flow was higher, peak creatine kinase level was lower, mean left ventricular ejection fraction was greater, corrected TIMI frame counts (CTFCs) were lower (ie, faster blood flow), and chest pain duration after thrombolytic administration was shorter. Patients in whom non-Q-wave MI developed less frequently underwent a percutaneous coronary intervention (PCI), and when they did, they had faster post-PCI CTFCs and higher rates of post-PCI TIMI grade 3 flow. Patients in whom a non-Q-wave MI developed had lower rates of severe recurrent ischemia. There were no differences in 30-day or in-hospital mortality rates or recurrent MI between patients with Q-wave MI and patients with non-Q-wave MI. After thrombolytic therapy in STEMI with or without abciximab, ejection fractions were higher, the duration of ischemia was shorter, and coronary blood flow at both 90 minutes and after PCI was faster in patients who sustained non-Q-wave MI than in patients who sustained Q-wave MI. No differences in mortality or recurrent MI rates were detected in patients who sustained a Q-wave MI and patients in whom a Q-wave MI did not evolve in the modern thrombolytic era.


Diagnosis of reversible versus irreversible cerebral ischemia by the intravenous administration of naloxone.
Naloxone was given as an I.V. bolus of 0.8 mgs to four groups of patients with stroke: 1) 20 patients with C.T. proven cerebral infarcts of longer than 7 days duration; 2) 20 patients with acute cerebral ischemia of less than 24 hours; 3) 5 patients with C.T. proven intracerebral hemorrhage of less than 24 hours, and; 4) 3 patients with hyperacute cerebral ischemia which occurred during the performance of a cerebral angiogram. The patients with established cerebral infarctions of more than 7 days duration and the patients with intracerebral hematomas had no response to intravenous naloxone. Of 20 patients with acute cerebral ischemia of less than 24 hours duration, 7 had prompt, complete and long-lasting recovery. These patients had no subsequent evidence of cerebral infarct by C.T. scanner 48 hours after the onset of the cerebral ischemia and were asymptomatic when discharged. The 3 patients with hyperacute cerebral ischemia secondary to cerebral angiography had a dramatic response to the injection of naloxone. These findings suggest that intravenous naloxone may differentiate reversible versus irreversible cerebral ischemia.


Cytokines and tumors of the central nervous system.
Cytokines are a group of molecules with an extremely broad range of activities on a variety of target cells. This review summarizes the known cytokine and cytokine receptor expression in primary brain tumors and derived cell lines. These expression patterns are compared with those occurring in other CNS diseases, such as virus or bacterial infections, experimental allergic encephalitis, multiple sclerosis, and trauma. A variety of cytokines are expressed during CNS neoplasia; their potential involvement in tumor growth through a variety of mechanisms, such as autocrine or paracrine growth stimulation, angiogenesis, and immune surveillance evasion, are discussed. Finally, results of preliminary therapeutic approaches with cytokines are critically evaluated.


An inflammatory bowel disease-risk variant in INAVA decreases pattern recognition receptor-induced outcomes.
Inflammatory bowel disease (IBD) is characterized by dysregulation in both cytokines and responses to intestinal microbes, and proper regulation of pattern recognition receptor (PRR) signaling is critical for intestinal immune homeostasis. Altered functions for the IBD risk locus containing rs7554511, which encompasses the C1orf106 gene (recently named INAVA), and roles for the protein encoded by the INAVA gene are unknown. Here, we investigated the role of INAVA and INAVA genotype in regulating PRR-initiated outcomes in primary human cells. Both peripheral and intestinal myeloid cells expressed INAVA. Upon PRR stimulation, INAVA was required for optimal MAPK and NF-κB activation, cytokine secretion, and intracellular bacterial clearance. INAVA recruited 14-3-3τ, thereby contributing to recruitment of a signaling complex that amplified downstream signals and cytokines. Further, INAVA enhanced bacterial clearance by regulating reactive oxygen, reactive nitrogen, and autophagy pathways. Macrophages from rs7554511 C risk carriers expressed lower levels of INAVA RNA and protein. Lower expression was attributed in part to decreased transcription mediated directly by the intronic region containing the rs7554511 C variant. In rs7554511 C risk carrier macrophages, lower INAVA expression led to decreased PRR-induced activation of MAPK and NF-κB pathways, cytokines, and bacterial clearance pathways. Thus, IBD-associated polymorphisms in INAVA modulate PRR-initiated signaling, cytokines, and intracellular bacterial clearance, likely contributing to intestinal immune homeostasis.


Estimating the returns to UK publicly funded cancer-related research in terms of the net value of improved health outcomes.
Building on an approach developed to assess the economic returns to cardiovascular research, we estimated the economic returns from UK public and charitable funded cancer-related research that arise from the net value of the improved health outcomes. To assess these economic returns from cancer-related research in the UK we estimated: 1) public and charitable expenditure on cancer-related research in the UK from 1970 to 2009; 2) net monetary benefit (NMB), that is, the health benefit measured in quality adjusted life years (QALYs) valued in monetary terms (using a base-case value of a QALY of GB£25,000) minus the cost of delivering that benefit, for a prioritised list of interventions from 1991 to 2010; 3) the proportion of NMB attributable to UK research; 4) the elapsed time between research funding and health gain; and 5) the internal rate of return (IRR) from cancer-related research investments on health benefits. We analysed the uncertainties in the IRR estimate using sensitivity analyses to illustrate the effect of some key parameters. In 2011/12 prices, total expenditure on cancer-related research from 1970 to 2009 was £15 billion. The NMB of the 5.9 million QALYs gained from the prioritised interventions from 1991 to 2010 was £124 billion. Calculation of the IRR incorporated an estimated elapsed time of 15 years. We related 17% of the annual NMB estimated to be attributable to UK research (for each of the 20 years 1991 to 2010) to 20 years of research investment 15 years earlier (that is, for 1976 to 1995). This produced a best-estimate IRR of 10%, compared with 9% previously estimated for cardiovascular disease research. The sensitivity analysis demonstrated the importance of smoking reduction as a major source of improved cancer-related health outcomes. We have demonstrated a substantive IRR from net health gain to public and charitable funding of cancer-related research in the UK, and further validated the approach that we originally used in assessing the returns from cardiovascular research. In doing so, we have highlighted a number of weaknesses and key assumptions that need strengthening in further investigations. Nevertheless, these cautious estimates demonstrate that the returns from past cancer research have been substantial, and justify the investments made during the period 1976 to 1995.


[Effect of mutation in phoB and phoM genes for the positive control of alkaline phosphatase biosynthesis on Escherichia coli envelope proteins].
The suppression of some envelope proteins, localized in both the periplasm and the outer and inner membranes was shown in phoB and phoM phoR mutants of E. coli. Among these proteins are the proteins of the phosphate regulon and also those not pertaining them. As a result of phoB and phoM phoR mutations, the cytoplasmic membrane was found to be lacking in minor protein of 28,000 Mr, which belongs to the phosphate regulon. Besides, the phoM phoR mutation leads to the loss of protein of 55,000 Mr of the outer membranes, whereas phoB mutation causes loss of protein 37 000 Mr, identified as outer membrane protein OmpT. A damage in the phoB mutant of the protein proteolytic modification, probably determining the suppression of the biosynthesis of E. coli envelope secreted proteins is suggested.


Heavy Episodic Drinking in Early Adulthood: How Parents' Education Contextualizes the Effects of College Status.
Young adults who transition to college are at particular risk of heavy episodic drinking (HED), as they consume more alcohol than their same-aged peers who do not attend college. Yet the link between college attendance and HED during young adulthood may vary depending on social class origins. Building on life course and socio-structural perspectives that suggest that status characteristics give meaning to role transitions in ways that shape young adults' drinking behavior, this study situates the risk of HED within the sociological context of educational attainment, and examines how parents' education conditions the relationship between young adults' college status and HED. We suggest that the odds of HED are higher when a young adult's college status is "off-diagonal"-incongruent with her/his parents' educational attainment. Using data from Waves I and III of the National Longitudinal Study of Adolescent to Adult Health for a sample of 13,526 young adults, stratified by sex, results indicate that being off-diagonal increases the odds of HED, but not for everyone. Females whose parents have higher levels of education but who themselves do not attend college, and those whose parents have low levels of education but who themselves attend four-year colleges, have higher odds of HED. The results for males show no significant interactions between parents' education and own college status. For both females and males, there are pronounced racial/ethnic differences in HED odds, after controlling for educational mismatch. Findings suggest that HED policies targeting the archetypal four-year-college attending male should be expanded to other groups.


Variables Associated With Resolution and Persistence of Ovarian Cysts.
To estimate surveillance intervals of incident ovarian cysts, and describe variables associated with cyst resolution times. The UK-OCST (University of Kentucky Ovarian Cancer Screening Trial) was a prospective cohort that enrolled 47,762 individuals over 30 years, including 2,638 individuals with incident cysts. Cyst diameter and structure and patient age, body mass index, use of hormone therapy (HT), family history of ovarian cancer, and menopausal status were examined as variables associated with cyst resolution using t tests, χ 2 test, Kaplan Meier, and Cox multiple regression. Of 2,638 individuals with incident cysts, 1,667 experienced resolution (63.2%) within 1.2 years, and 971 experienced persistence (36.8%). Within 1 year, unilocular and septated cysts had similar resolution rates (35.4% and 36.7%, respectively, P >.05), but time to resolution was shorter for unilocular cysts compared with septated cysts (mean 1.89 years vs 2.58 years, respectively, P <.001). Both unilocular and septated cysts smaller than 3 cm resolved faster than cysts larger than 6 cm ( P <.001). Variables associated with percent resolution included being of younger age, premenopausal status (but not for synchronous bilateral cysts), and those reporting a family history of ovarian cancer ( P <.05). Variables associated with a faster cyst resolution rate included being older than age 70 years and not using hormone therapy. Body mass index and family history were not associated with cyst resolution time. Different surveillance times may be appropriate depending on cyst structure and size and patient age and HT use. ClinicalTrials.gov , NCT04473833.


Pathfinding by neuronal growth cones in grasshopper embryos. II. Selective fasciculation onto specific axonal pathways.
In the previous paper (Raper, J.A., M. Bastiani, and C.S. Goodman (1983) J. Neurosci. 3:20-30) we showed that the growth cones of two sibling neurons, the G and C cells, follow the same route in the developing grasshopper neuropil until they reach a stereotypic choice point. Here their growth cones diverge from each other as G turns and extends anteriorly and C turns and extends posteriorly. In this paper we show that the G and C growth cones fasciculate and extend in opposite directions upon a specific bundle of four axons. This occurs even though many other axons are within filopodial reach of the G and C growth cones. We identified the four neurons (the A1, A2, P1, and P2 cells) whose axons form the bundle that G and C extend upon by filling individual axons with Lucifer Yellow and viewing the filled cells in living embryos and by filling individual neurons with HRP and reconstructing the axon bundle from electron micrographs. The G neuron extends anteriorly in the bundle containing these four axons; the C neuron extends posteriorly in the same bundle only after several other axons have joined in. These results suggest that the growth cones of the G and C neurons are determined to recognize and extend upon labeled axons, leading us to propose the "labeled pathways" hypothesis.


Dietary n-3 and n-6 polyunsaturated fatty acid intake interacts with FADS1 genetic variation to affect total and HDL-cholesterol concentrations in the Doetinchem Cohort Study.
The delta-5 and delta-6 desaturases, encoded by the FADS1 and FADS2 genes, are rate-limiting enzymes in polyunsaturated fatty acid (PUFA) biosynthesis. Single nucleotide polymorphisms in the FADS gene cluster region have been associated with both PUFA concentrations in plasma or erythrocyte membrane phospholipids and cholesterol concentrations in recent genome-wide association studies. We examined whether genetic variations in the FADS gene cluster region interact with dietary intakes of n-3 (omega-3) and n-6 (omega-6) PUFAs to affect plasma total, HDL-, and non-HDL-cholesterol concentrations. Dietary intakes of n-3 and n-6 PUFAs, plasma concentrations of total and HDL cholesterol, and rs174546, rs482548, and rs174570 in the FADS gene cluster region were measured in 3575 subjects in the second survey of the Doetinchem Cohort Study. Significant associations between rs174546 genotypes and total and non-HDL-cholesterol concentrations were observed in the group with a high intake of n-3 PUFAs (> or =0.51% of total energy; P = 0.006 and 0.047, respectively) but not in the low-intake group (P for interaction = 0.32 and 0.51, respectively). The C allele was associated with high total and non-HDL-cholesterol concentrations. Furthermore, the C allele was significantly associated with high HDL-cholesterol concentrations in the group with a high intake of n-6 PUFAs (> or =5.26% of total energy, P = 0.004) but not in the group with a low intake (P for interaction = 0.02). Genetic variation in the FADS1 gene potentially interacts with dietary PUFA intakes to affect plasma cholesterol concentrations, which should be investigated further in other studies.


Inhibition of fibronectin matrix assembly by the heparin-binding domain of vitronectin.
The deposition of fibronectin into the extracellular matrix is an integrin-dependent, multistep process that is tightly regulated in order to ensure controlled matrix deposition. Reduced fibronectin deposition has been associated with altered embryonic development, tumor cell invasion, and abnormal wound repair. In one of the initial steps of fibronectin matrix assembly, the amino-terminal region of fibronectin binds to cell surface receptors, termed matrix assembly sites. The present study was undertaken to investigate the role of extracellular signals in the regulation of fibronectin deposition. Our data indicate that the interaction of cells with the extracellular glycoprotein, vitronectin, specifically inhibits matrix assembly site expression and fibronectin deposition. The region of vitronectin responsible for the inhibition of fibronectin deposition was localized to the heparin-binding domain. Vitronectin's heparin-binding domain inhibited both beta(1) and non-beta(1) integrin-dependent matrix assembly site expression and could be overcome by treatment of cells with lysophosphatidic acid, an agent that promotes actin polymerization. The interaction of cells with the heparin-binding domain of vitronectin resulted in changes in actin microfilament organization and the subcellular distribution of the actin-associated proteins alpha-actinin and talin. These data suggest a mechanism whereby the heparin-binding domain of vitronectin regulates the deposition of fibronectin into the extracellular matrix through alterations in the organization of the actin cytoskeleton.


[Diagnosis and the dynamics of alcoholism in the elderly].
A comprehensive clinical examination of 462 patients (391 men and 71 women) with alcohol addiction has been conducted to identify gender-related characteristics of alcohol addiction in the elderly (over 60 years old) in relation to the time of their first doctor visit. Men and women were split into two groups (less or over 60 years old). It has been established that alcohol addiction in the elderly had gender-related clinical and dynamic differences with regard to the age at onset of alcohol consumption, progress of alcoholism and severity of psychological and social consequences. The identified clinical and dynamic characteristics require active differential treatment and prevention measures.


Generation of fluoroscopy-alike radiographs as alternative datasets for deep learning in interventional radiology.
In fluoroscopy-guided interventions (FGIs), obtaining large quantities of labelled data for deep learning (DL) can be difficult. Synthetic labelled data can serve as an alternative, generated via pseudo 2D projections of CT volumetric data. However, contrasted vessels have low visibility in simple 2D projections of contrasted CT data. To overcome this, we propose an alternative method to generate fluoroscopy-like radiographs from contrasted head CT Angiography (CTA) volumetric data. The technique involves segmentation of brain tissue, bone, and contrasted vessels from CTA volumetric data, followed by an algorithm to adjust HU values, and finally, a standard ray-based projection is applied to generate the 2D image. The resulting synthetic images were compared to clinical fluoroscopy images for perceptual similarity and subject contrast measurements. Good perceptual similarity was demonstrated on vessel-enhanced synthetic images as compared to the clinical fluoroscopic images. Statistical tests of equivalence show that enhanced synthetic and clinical images have statistically equivalent mean subject contrast within 25% bounds. Furthermore, validation experiments confirmed that the proposed method for generating synthetic images improved the performance of DL models in certain regression tasks, such as localizing anatomical landmarks in clinical fluoroscopy images. Through enhanced pseudo 2D projection of CTA volume data, synthetic images with similar features to real clinical fluoroscopic images can be generated. The use of synthetic images as an alternative source for DL datasets represents a potential solution to the application of DL in FGIs procedures.


[Temporary balloon occlusion as therapy of uncontrollable arterial hemorrhage in multiple trauma patients].
Presentation of temporary balloon occlusion as an interventional radiological method for managing hemorrhage in multiply injured patients with uncontrollable loss of blood. Temporary, non-selective arterial occlusion by introduction of a balloon catheter contralaterally to the source of bleeding has been performed since 1992 on 7 patients with multiple injuries, hemorrhagic shock requiring reanimation, and angiographic demonstration of an arterial hemorrhage in the supply region of the internal iliac artery with complex pelvic fracture. In each case a PTA balloon catheter was introduced transfemorally, non-selectively positioned proximal to the bleeding source, and left in place for 24-48 h under manometric control. Control angiographies were performed prior to catheter removal. The bleeding was stopped immediately in all 7 patients. The hemodynamic stability made transport and thus further surgical management and/or a short-term treatment in the intensive-care station possible. Control angiographies confirmed that the bleeding had stopped in all patients. We recommend temporary balloon occlusion as a rapid and effective method for the management of bleeding in otherwise uncontrollable traumatic hemorrhages in the supply region of the internal iliac artery.


Phase I Dose-Escalation Study of Once Weekly or Once Every Two Weeks Administration of High-Dose Sunitinib in Patients With Refractory Solid Tumors.
Dose and schedule optimization of treatment with tyrosine kinase inhibitors is of utmost importance. On the basis of preclinical data, a phase I clinical trial of once weekly or once every 2 weeks administration of high-dose sunitinib in patients with refractory solid malignancies was conducted. Patients with advanced cancer refractory to standard treatment were eligible. With use of a standard 3 + 3 phase I design, patients received escalating doses of sunitinib, in 100 mg increments, starting at 200 mg once weekly. In both the once weekly and once every 2 weeks cohorts, 10 more patients were included at the maximum tolerated dose level. Primary end points were safety and tolerability. Sixty-nine patients with advanced cancer, predominantly colorectal cancer (42%), were treated with this alternative dosing regimen. Maximum tolerated dose was established at 300 mg once weekly and 700 mg once every 2 weeks, resulting in nine- and 18-fold higher maximum plasma concentrations compared with standard dose, respectively. Treatment was well tolerated, with fatigue (81%), nausea (48%), and anorexia (33%) being the most frequent adverse events. The only grade 3 or 4 treatment-related adverse event in 5% or more of patients was fatigue (6%). Sixty-three percent of patients had significant clinical benefit, with a 30% progression-free survival of 5 months or more. Sunitinib administered once weekly at 300 mg or once every 2 weeks at 700 mg is feasible, with comparable tolerability as daily administration. Administration of 700 mg once every 2 weeks can be considered as the most optimal schedule because of the highest maximum plasma concentration being reached. The promising preliminary antitumor activity of this alternative schedule in heavily pretreated patients warrants further clinical evaluation and might ultimately indicate a class characteristic of tyrosine kinase inhibitors.


[Endogenous and Exogenous Attention in Alzheimer Type of Dementia: Effect of Target Position].
Endogenous attention (EnA) is an ability in goal-driven processes, controlled by top-down mechanisms and exogenous attention (ExA) is an ability in stimulus-driven processes, controlled by bottomup mechanisms. In the present research, it was aimed to investigate in Alzheimer's disease (AD) the EnA and ExA processes in relation to target position (right/left) by using the Spatial Cueing Paradigm (SCP). The study was conducted with the participants of 65-90 year age range, consisting of 14 female and 14 male (n=28) participants diagnosed with AD and 12 female and 12 male (n=24) healthy volunteers as controls. The group variable (AD, Control) was tested on the intergroup basis; and the attention type (EnA, ExA), trial type (valid /VT+ and invalid/ VT-) and the target position (left/right) variables were tested on the intra-subject basis (within subject design). Two separate factorial ANOVAs were conducted for mean reaction time and accuracy measures obtained from SCP. In comparison to the control group, the AD group participants gave slow and wrong reactions to stimuli for EnA and ExA. The AD group responses were faster in the VT+s and more accurate in the VT-s to stimuli on the left as compared to those on the right; and the responses of AD patients to the stimuli on the left as compared to those on the right was more accurate in VT-s under ExA condition. AD causes impairment of EnA and ExA. Faster reactions by AD participants to the target on the left in VT+s and more accurate reactions to the target on the left in VT-s are in agreement with reports in the literature on the lateralization of visual-spatial attention (VSA) in the right hemisphere. In this study, also in agreement with previous reports, lateralization in AD was noted in favour of the stimuli on the left in ExA.


Correlation between the histological features of corneal surface pannus following ocular surface burns and the final outcome of cultivated limbal epithelial transplantation.
To report the influence of histological features of corneal surface pannus following ocular surface burn on the outcome of cultivated limbal epithelial transplantation (CLET). On retrospectively reviewing the medical records of the patients who underwent autologous CLET from April 2002 to June 2012 at L V Prasad Eye Institute, Hyderabad, India, we could trace the histological reports in only 90 records. These 90 records, besides clinical parameters, were reviewed for the influence of various histological features on the final outcome of CLET. The histological features include epithelial hyperplasia (21.1%), surface ulceration (2.2%), goblet cells (62.2%), squamous metaplasia (11.1%), active fibrosis (31.1%), severe inflammation (8.9%), multinucleated giant cells (3.3%), stromal calcification (8.9%) and active proliferating vessels (5.6%). Among these histological features, patients with either hyperplasia or calcification in their excised corneal pannus show an unfavourable outcome compared with patients without hyperplasia (p=0.003) or calcification (p=0.018). A similar unfavourable outcome was not seen with other histological features and various clinical parameters. Presence of either calcific deposits or hyperplasia in the excised corneal pannus provides poor prognostication; hence, a proper counselling of such patients is mandatory along with a close follow-up.


Application of MR spectroscopy and treatment approaches in a patient with extrapituitary growth hormone secreting macroadenoma.
MR spectroscopy (MRS) of hormonally active pituitary adenomas has not been published in literature. We report MR imaging and spectroscopy findings in a 41-year-old man with extrapituitary growth hormone-secreting adenoma. Application of the single voxel proton MRS, SE 135 technique, with voxel size 11x11x11 mm, revealed the elevated choline peak (resonance at 3.2 ppm) in the paramedial aspect of the tumor, while no metabolic activity in the mentioned region was noted using the same method 11 months after Lanreotide treatment. Elevation of choline peak in functional pituitary adenomas could represent an active marker of cellular proliferation, compatible with increased hormonal activity.


Defect Engineering of WO3 by Rapid Flame Reduction for Efficient Photoelectrochemical Conversion of Methane into Liquid Oxygenates.
Photoelectrochemical (PEC) conversion is a promising way to use methane (CH4) as a chemical building block without harsh conditions. However, the PEC conversion of CH4 to value-added chemicals remains challenging due to the thermodynamically favorable overoxidation of CH4. Here, we report WO3 nanotube (NT) photoelectrocatalysts for PEC CH4 conversion with high liquid product selectivity through defect engineering. By tuning the flame reduction treatment, we carefully controlled the oxygen vacancies of WO3 NTs. The optimally reduced WO3 NTs suppressed overoxidation of CH4 showing a high total C1 liquid selectivity of 69.4% and a production rate of 0.174 μmol cm-2 h-1. Scanning electrochemical microscopy revealed that oxygen vacancies can restrain the production of hydroxyl radicals, which, in excess, could further oxidize C1 intermediates to CO2. Additionally, band diagram analysis and computational studies elucidated that oxygen vacancies thermodynamically suppress overoxidation. This work introduces a strategy for understanding and controlling the selectivity of photoelectrocatalysts for direct conversion of CH4 to liquids.


Diabetes-related quality of life and the demands and burdens of diabetes care among emerging adults with type 1 diabetes in the year after high school graduation.
The roles of glycemic control, diabetes management, diabetes care responsibility, living independently of parents, and time since high school graduation in predicting diabetes-related quality of life (DQOL) were examined in 184 emerging adults with type 1 diabetes. Data were collected at graduation and 1 year later. Analyses controlling for selected covariates were completed using generalized linear mixed models. Better diabetes management was associated with more positive responses on all four dimensions of DQOL. Impact and worry of DQOL were greater in the presence of depressive symptoms, and life satisfaction was lower. DQOL life satisfaction was lower in those living independently of parents. Young women reported poorer diabetes-related health status than did young men. Time since graduation was not linked to DQOL. Further research is needed on ways to improve DQOL in conjunction with diabetes management and on ways that families can support DQOL when youth live independently.


Modification of K conductance of the squid axon membrane by SITS.
The effects of 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) on the K conductance, gK, were studied in internally perfused giant axons from squid, Doryteuthis. SITS at 3-200 microM was applied intracellularly by adding the reagent to the internal perfusion fluid. Three remarkable changes in gK were noted: there was a slowing of the opening and closing rates of the K channel in the whole voltage region; K channels modified with SITS started to open at voltages below -100 mV, and thus 30% of total K channels were open at the level of normal resting potential (approximately -60 mV) after the maximal drug effect was attained (less than 30 microM); there was a disappearance of gK inactivation that became distinct at relatively high temperature (greater than 8 degrees C). These drug effects depended solely on the drug concentration, not on factors such as repetitive alterations of the membrane potential, and the changes in gK were almost irreversible. Another disulfonic stilbene derivative, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), had similar effects on gK, but the effects were approximately 1.5 times stronger. These changes in gK were somewhat similar to alterations in gNa produced by an application of veratridine, batrachotoxin, and grayanotoxin, which are known as Na channel openers.


Association of plasma chromium with metabolic syndrome among Chinese adults: a case-control study.
Chromium has been suggested playing a role in alleviating diabetes, insulin resistance and lipid anomalies, but the effect on metabolic syndrome (MetS) in humans remains controversial. We conducted a matched case-control study in a Chinese population, involving 2141 MetS cases and 2141 healthy controls, which were 1:1 matched by age (±2 years) and sex. Plasma chromium was measured by inductively coupled plasma mass spectrometry. Plasma chromium levels were lower in MetS group than in control group (mean: 4.36 μg/L and 4.66 μg/L, respectively, P < 0.001), and progressively decreased with the number of MetS components (P for trend < 0.001). After adjustment for potential confounding factors, the odds ratios (95% confidence intervals) for MetS across increasing quartiles of plasma chromium levels were 1 (reference), 0.84 (0.67-1.05), 0.76 (0.61-0.95), and 0.62 (0.49-0.78), respectively (P for trend < 0.001). For the components of MetS (high waist circumference, high triglycerides and high blood glucose), the odds ratios (95% confidence intervals) of the highest quartiles were 0.77 (0.61-0.95), 0.67 (0.55-0.80), and 0.53 (0.44-0.64), respectively (P for trend < 0.05). Our results indicated that plasma chromium levels were inversely associated with MetS in Chinese adults. The association may be explained by the relations between plasma chromium levels and high waist circumference, and the triglycerides and blood glucose levels.


[Delivery of healthcare to patients with infectious diseases during the pre-hospital stage].
In the field infectious military hospital work with double-triple overcharge. It leads to reduction of health care to patients, requires the additional hospital departments or evacuation of contagious patients to other hospitals. That is why the pre-hospital care is of prime importance. According to modem concept the number of interim stages is minimal--1 stage--on site of definition of contagious patients (isolator of medical station of military unit) and 2 stage--infectious military hospital. Main measures of health care to contagious patients during the pre-hospital stage are early active detection of patients or suspected of having infection, early clinical diagnosis, medical sorting, delivery of emergency care, treatment in isolators in case of delay of evacuation and evacuation in infectious military hospital.


A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update.
Chronic hepatitis B (CHB) is an important public health problem worldwide and in the United States, with approximately 25% of patients infected as neonates dying prematurely from cirrhosis or liver cancer. A treatment algorithm for CHB previously developed and published by a panel of United States hepatologists was revised based on new developments in the understanding of CHB, the availability of more sensitive molecular diagnostic testing, the addition of new treatments, and better understanding of the advantages and disadvantages of approved therapies. This updated algorithm is based on available evidence using a systematic review of the scientific literature. Where data are lacking, the panel relied on clinical experience and consensus expert opinion. Serum HBV DNA can be detected at levels as low as 10 IU/mL using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest levels possible. The threshold level of HBV DNA for determination of candidacy for therapy is 20,000 IU/mL or more for patients with hepatitis B e antigen-positive CHB. A lower serum HBV DNA threshold of 2000 IU/mL or more is recommended for patients with hepatitis B e antigen-negative CHB, and 200 IU/mL or more for those with decompensated cirrhosis. Interferon alfa-2b, lamivudine, adefovir, entecavir, and peginterferon alfa-2a all are approved as initial therapy for CHB and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost.


Effects of ozone on normal and potentially sensitive human subjects. Part III: Mediators of inflammation in bronchoalveolar lavage fluid from nonsmokers, smokers, and asthmatic subjects exposed to ozone: a collaborative study.
To provide bases of comparison between the studies described in Parts I and II of this Research Report, concentrations of interleukin 6 (IL-6)*, interleukin 8 (IL-8), and alpha 2-macroglobulin (a2M) were measured in airway lavage fluids obtained in the Balmes study (Part I) and compared with the same measurements in the Frampton study (Part II). For healthy subjects in the Balmes study, IL-6 and a2M, but not IL-8, increased in association with ozone exposure. Statistical analyses suggested that effects of ozone on IL-8 levels observed in the first exposure and bronchoscopy may have carried over to the second exposure and bronchoscopy, which may have obscured an effect of ozone on IL-8 after the second exposure. For asthmatic subjects in the Balmes study, IL-6 and IL-8 increased in both bronchial and alveolar lavage fluid, but not in proximal airway lavage fluid. The mean interval between exposures was longer for asthmatic subjects than for healthy subjects, and no carryover effects were seen. When the Balmes and Frampton data were analyzed together, subject groups in the two studies (nonsmokers, smokers, and subjects without and with asthma) did not differ significantly in the response of cytokines to ozone exposure. The finding of possible carryover effects in one group suggests that subtle effects of ozone exposure, or bronchoscopy including proximal airway lavage and biopsy, or both, may persist for three weeks in some subjects.


Surgical treatment for infective endocarditis--decision tree for the treatment and introduction of translocation method.
Persistent fever during active-phase IE is an indication for surgical treatment in the light of the causative organism and the underlying disease. To counter worsening hemodynamics, surgery may be the only feasible way. Surgery is performed when the patient does not respond to vasodilators and he shows an FS of less than 25%. The introduction of translocation provides a solution for the treatment of active IE. Lesions, vegetations more than 5 mm in diameter, periannular abscess, and mycotic aneurysm that could never be overlooked by two-dimensional echocardiography may hasten the early-stage decision of ways to treat IE.


Generalized pustular psoriasis with hypoparathyroidism.
A 36-year-old Japanese woman with pustular psoriasis associated with hypoparathyroidisum was reported. The patient showed hypocalcemia and was treated with calcium supplements and calcitriol. When the serum calcium level became normal, the pustules disappeared and erythroderma completely resolved. Histopathological features consisted of the formation of intraepidermal pustules including spongiform pustules underneath the stratum corneum, and acantholysis was observed in the epidermis. It was suggested that generalized pustular psoriasis may have been induced by hypocalcemia due to hypoparathyroidism in this case, and that acantholysis may be caused by hypocalcemia, since intercellular junctional components such as cadherins are highly dependent on calcium in the epidermis.


Applications of Hadamard transform-gas chromatography/mass spectrometry for the detection of hexamethyldisiloxane in a wafer cleanroom.
The Hadamard transform-gas chromatography/mass spectrometry (HT-GC/MS) technique was successfully employed for the detection of hexamethyldisiloxane (HMDSO, C(6)H(18)OSi(2)) at the sub-nL/L level in a semiconductor wafer cleanroom. Indoor air samples were collected from the room, according to EPA Method TO-17 using a Tedlar bag where the air samples were allowed to pass through an absorption tube for 24 h. The condensed components were then heated and simultaneously injected into a GC column through a Hadamard-injector, which was operated in accordance with the Hadamard codes. Compared to the single injection used in most GC/MS systems, the signal-to-noise (S/N) ratios were substantially improved after the inverse Hadamard transformation of the encoded chromatogram. Under optimized conditions, when cyclic S-matrix orders of 255, 1023 and 2047 were used, the S/N ratios of the HMDSO signals were substantially improved by 7.4-, 15.1- and 20.1-fold, respectively. These improvements are in good agreement with theoretically calculated values (8.0-, 16.0- and 22.6-fold, respectively). We found that when the HT-GC/MS technique was applied, HMDSO could be detected at the 0.1 nL/L level.


Using computerized posturography to explore the connection between bmi and postural stability in long-term tai chi practitioners - biomed 2011.
Obesity is a major health concern because of its linkage to chronic diseases such as type 2 diabetes, heart disease, and cancer. Another less studied outcome is the observed increase in the incidence of accidental falls. According to CDC, medical costs associated with fall injuries exceeded $16 billion in 2000 and by 2020 will exceed $54 billion. To reduce the impact on society and individuals, it is essential to explore mechanisms to reduce the frequency of falls. For example, a short 12-week intervention of Tai Chi reduced the risk of accidental falls in an elderly population. However, there are few studies exploring the effect of the long-term practice of Tai Chi on postural stability, particularly in individuals with a BMI greater than 30. In this study, the connection between postural stability and BMI in long-term Tai Chi practitioners is investigated using a convenience sample study design. Participants at a 1-week Tai Chi workshop held in June of 2010 were contacted and forty-four individuals attending the workshop enrolled in the study (ranging in age from 22 to 84, mean age 61). The participants' weight distribution was similar to the general population with 38% having a BMI less than 25. Comparison between the normal and obese groups indicated that there were no differences in stability scores in the most challenging category: standing on a compliant surface with eyes closed. Additional studies are needed to determine whether Tai Chi is as an effective intervention to prevent falls in the obese population.


Control of C-H Bond Activation by Mo-Oxo Complexes: pKa or Bond Dissociation Free Energy (BDFE)?
A density functional theory (DFT) study (BMK/6-31+G(d)) was initiated to investigate the activation of benzylic carbon-hydrogen bonds by a molybdenum-oxo complex with a potentially redox noninnocent supporting ligand-a simple mimic of the active species of the enzyme ethylbenzene dehydrogenase (EBDH)-through deprotonation (C-H bond heterolysis) or hydrogen atom abstraction (C-H bond homolysis) routes. Activation free-energy barriers for neutral and anionic Mo-oxo complexes were high, but lower for anionic complexes than neutral complexes. Interesting trends as a function of substituents were observed that indicated significant Hδ+ character in the transition states (TS), which was further supported by the preference for [2 + 2] addition over HAA for most complexes. Hence, it was hypothesized that C-H activation by these EBDH mimics is controlled more by the pKa than by the bond dissociation free energy of the C-H bond being activated. Therefore, the results suggest promising pathways for designing more efficient and selective catalysts for hydrocarbon oxidation based on EBDH active-site mimics.


Ofatumumab is more efficient than rituximab in lysing B chronic lymphocytic leukemia cells in whole blood and in combination with chemotherapy.
Ofatumumab (OFA) is a human anti-CD20 Ab approved for treatment of fludarabine-refractory B chronic lymphocytic leukemia (B-CLL). The efficacy of different immunotherapeutic strategies is best investigated in conditions that are as physiologic as possible. We have therefore compared the activity OFA and rituximab (RTX), alone or in combination with chemotherapeutic agents in unmanipulated whole blood assays, using flow cytometry. OFA (10-100 μg/ml) lysed B-CLL targets in whole blood more efficiently and with faster kinetics than RTX, with a mean 56% lysis at 24 h compared with 16%. This activity of OFA was fully complement dependent, as shown by >99% inhibition by anti-C5 Ab eculizumab and a lack of NK cell activation in whole blood. OFA-mediated NK cell activation was blocked by complement. OFA-mediated lysis could be increased an additional 15% by blocking CD55 and CD59 complement inhibitors. Interestingly, OFA-mediated lysis correlated significantly with CD20 expression levels (r(2) = 0.79). OFA showed overlapping dose response curves similar to those for RTX in phagocytosis assays using either human macrophages or neutrophils. However, phagocytosis was inhibited in the presence of serum or whole blood. Finally, combined treatment with mafosfamide and fludarabine showed that these therapeutic drugs are synergistic in B-CLL whole blood assays and show superior activity when combined with OFA compared with RTX. These results confirm in B-CLL samples and in physiologic conditions the superior complement mediated cytotoxicity induced by OFA alone compared with RTX, the lack of NK cell activation, and phagocytosis in these conditions and suggest effective chemoimmunotherapy strategies using this new generation anti-CD20 Ab.


[Characteristics of the spermatogenic epithelium in the testis of newborn rats--the offspring of female rats with chronic liver injury of various genesis].
The effect of chronic injury of hepatobiliary system of various genesis in females rats on the formation of spermatogenic epithelium in the testis of their newborn offspring was studied. The models of toxic (CCl4) and medicinal (tetracycline, paracetamol) liver injury were used. The state of the seminiferous epithelium was assessed on the serial histological sections of the testis with the use of the morphometric device. In experimental animals, a reduction of the diameter and the area of the seminiferous tubules (ST) was detected, associated with the decline of the total number of spermatogenic cells, spermatogonia of various generations, total number of spermatocytes and Sertoli cells. At the same time, in the newborn rats of all the experimental groups, the number of ST with the desquamated epithelium, and that one of the multinucleated spermatogenic cells with fragmented and pyknotic nuclei were increased.


Mechanism of C-C and C-H bond cleavage in ethanol oxidation reaction on Cu2O(111): a DFT-D and DFT+U study.
The performance of transition metal catalysts for ethanol oxidation reaction (EOR) in direct ethanol fuel cells (DEFCs) may be greatly affected by their oxidation. However, the specific effect and catalytic mechanism for EOR of transition metal oxides are still unclear and deserve in-depth exploitation. Copper as a potential anode catalyst can be easily oxidized in air. Thus, in this study, we investigated C-C and C-H bond cleavage reactions of CHxCO (x = 1, 2, 3) species in EOR on Cu2O(111) using PBE+U calculations, as well as the specific effect of +U correction on the process of adsorption and reaction on Cu2O(111). It was revealed that the catalytic performance of Cu2O(111) for EOR was restrained compared with that of Cu(100). Except for the C-H cleavage of CH2CO, all the reaction barriers for C-C and C-H cleavage were higher than those on Cu(100). The most probable pathway for CH3CO to CHCO on Cu2O(111) was the continuous dehydrogenation reaction. Besides, the barrier for C-C bond cleavage increased due to the loss of H atoms in the intermediate. Moreover, by the comparison of the traditional GGA/PBE method and the PBE+U method, it could be concluded that C-C cleavage barriers would be underestimated without +U correction, while C-H cleavage barriers would be overestimated. +U correction was proved to be necessary, and the reaction barriers and the values of the Hubbard U parameter had a proper linear relationship.


Plasma glutathione concentrations in non-infected infants born from HIV-infected mothers: developmental profile.
Glutathione (GSH) is the primary antioxidant in humans. Oxidative cellular injury is postulated to be centrally involved in diverse processes including aging, cancer, cardiovascular disease, and Human Immunodeficiency Virus (HIV) disease progression. Normal plasma GSH concentrations have been well characterized in healthy children and adults, but not during infant development. The objectives of this study were to: a) measure plasma GSH concentrations in non-infected infants born from HIV-infected mothers, to b) assess the developmental variations with age and gender, and c) evaluate for possible associations with growth, anemia, and other maternal and infant variables. One hundred and seventy (170) plasma samples from 44 HIV-uninfected infants (birth to 18 mos.) born to HIV-infected mothers from the Women and Infant Transmission Study (Puerto Rico site) were analyzed. The total plasma GSH geometric mean concentration for all samples analyzed was 1.94 (1.06) mumoles/L. A developmental effect of age was seen with lower concentrations in younger infants (0-2 months) than in older infants 4-18 months. There was no significant effect of gender, anemia, zidovudine exposure, maternal age, maternal CD4 cell percent, or infant growth, although a trend towards increasing GSH concentration was seen with increasing weight for height z-score. These findings have multiple clinical ramifications including prediction of capacity to detoxify oxidants at different ages, and partial explanation for the increased viral loads seen in HIV-infected infants.


We are not even allowed to call them patients anymore: Conceptions about person-centred care.
Although the implementation of person-centred care (PCC) has gained momentum in healthcare systems, it is not always obvious why it is an important objective in clinical settings and educational institutions that train future healthcare professionals. Various conceptions about PCC have flourished, such as that it only works in certain healthcare contexts, it is the same as the patient making all their own healthcare decisions, it is too demanding for most patients, the word 'patient' may no longer be used, the care provided is already person-centred, and that there is simply not enough time and resources to achieve it. This viewpoint paper aims to problematize these conceptions and may be used for didactical and reflective exercises that support the transition towards more person-centred healthcare. PATIENT OR PUBLIC CONTRIBUTION: The Person Council for patients and carers at the University of Gothenburg provided focus group input on and validated the occurrence of the conceptions discussed in the present paper. The person council consists of a group of persons with many years of personal experiences of health care, either as patients and/or relatives/carers. One member of the person council who is also a designer and artist created the illustration for the article.


Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial.
Background and Purpose- Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods- The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were ≥4 mm in thickness or had a mobile thrombus present. Results- Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; P<0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; P=0.002), and aortic valvulopathy (10 versus 20 versus 20; P<0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA (P=0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53-2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions- Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.


Horses associate individual human voices with the valence of past interactions: a behavioural and electrophysiological study.
Brain lateralization is a phenomenon widely reported in the animal kingdom and sensory laterality has been shown to be an indicator of the appraisal of the stimulus valence by an individual. This can prove a useful tool to investigate how animals perceive intra- or hetero-specific signals. The human-animal relationship provides an interesting framework for testing the impact of the valence of interactions on emotional memories. In the present study, we tested whether horses could associate individual human voices with past positive or negative experiences. Both behavioural and electroencephalographic measures allowed examining laterality patterns in addition to the behavioural reactions. The results show that horses reacted to voices associated with past positive experiences with increased attention/arousal (gamma oscillations in the right hemisphere) and indicators of a positive emotional state (left hemisphere activation and ears held forward), and to those associated with past negative experiences with negative affective states (right hemisphere activation and ears held backwards). The responses were further influenced by the animals' management conditions (e.g. box or pasture). Overall, these results, associating brain and behaviour analysis, clearly demonstrate that horses' representation of human voices is modulated by the valence of prior horse-human interactions.


Blood sample volumes: emerging trends in clinical practice and laboratory medicine.
Blood loss because of phlebotomy for diagnostic laboratory tests is a well-recognized risk to neonates, particularly low-birthweight infants. In contrast, the risk of anemia from blood drawing in adults is relatively poorly studied. A few clinical studies have demonstrated the magnitude of this issue for critical care patients; most adult patients can easily tolerate the loss of blood volumes typically used for laboratory tests. Recommendations for promoting blood conservation in adults who frequently are phlebotomized include using smaller collection tubes, but more importantly organizing blood draws to eliminate duplicate and other unnecessary test requests and consolidating multiple collections into as few as possible by scheduling them. Emerging trends in medicine that will bear on the practice of blood conservation are "bloodless surgery," standardization of collection tubes for laboratory automation systems, and smart laboratory information systems that provide instant feedback to ordering physicians.


The effect of system intervention on the cognitive control of preschool children.
In response to the high rate of learning problems among socially deprived children, the Baltimore Early School Admission Project set up a system intervention model engaging three points of entry: parents, educators, and mental health workers. The emphasis was on: a) the redefinition of the roles of all participants; b) the school as a self-reliant system, discouraging referrals to outside agencies; c) the development of the children's functioning and adaptive potentials, based on their individual cognitive styles. The program included five public schools. Ninety-one children between the ages of 4 and 5 years were involved. All of these were selected from a hard core socioeconomically deprived population. Eighty-three percent were black and 17 per cent white. Fifteen children were identified as "vulnerable" according to specific criteria provided to the teachers and the parents. Of the vulnerable group, nine children's learning problems were related primarily to emotional and environmental factors, five had perceptual, sensory-motor dysfunction mixed with emotional factors, and one suffered primarily from brain damage. Results indicated that only one of the vulnerable children required referral outside of that provided in the above design. Eleven vulnerable children performed as well as the nonvulnerable group, and three showed a moderate improvement. Furthermore, five children with serious learning problems responded to the systemic intervention as well as they might have with specialized professional help.


Calpain-induced light scattering by crystallins from three rodent species.
The purpose of the present investigation was to compare in vitro light scattering in the soluble proteins from rodent lenses after hydrolysis by the calcium-activated protease, m-calpain (EC 22.214.171.124). Light scattering was measured in solutions of lens proteins from mice, rats, and guinea pigs after activation of endogenous m-calpain or after addition of purified m-calpain. We found for the first time that, in addition to rat, crystallins from another rodent lens, young mouse, were susceptible to calpain-induced light scattering. As in rats, aging of mouse lens prevented calpain-induced light scattering. Although crystallins from guinea pig lens were also partially hydrolysed by calpain, appreciable light scattering did not occur. Limited proteolysis may cause common changes in the biophysical properties of mouse and rat crystallins to decrease their solubility. Discovery of the nature of these biophysical changes may help our understanding as to why crystallins precipitate under cataractous conditions.


Immunosuppressive and immunomodulatory therapies for neuromuscular diseases. Part II: New and novel agents.
While traditional immunosuppressive and immunomodulatory therapies remain the cornerstone of immune-mediated neuromuscular disease management, new and novel agents including antigen-specific, monoclonal antibody drugs, have emerged as important treatment options. This article is the second of a two-part series that reviews immune-based therapies in neuromuscular diseases. The first article provides an update on the use of traditional immune-based therapies such as corticosteroids, plasma exchange, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin G. This second article focuses on new and novel immune-based therapies, including eculizumab, a complement inhibitor approved for acetylcholine receptor antibody-positive myasthenia gravis; rituximab, a B-cell depletion therapy with evolving indications in neuromuscular diseases; and the subcutaneous formulation of immunoglobulin G that gained approval for use in chronic inflammatory demyelinating polyradiculoneuropathy in 2018. Finally, several novel antigen-specific drugs at different stages of investigation in neuromuscular disease are also reviewed.


Echocardiographic parameters associated with biventricular circulation and right ventricular growth following right ventricular decompression in patients with pulmonary atresia and intact ventricular septum: Results from a multicenter study.
In patients with pulmonary atresia, intact ventricular septum (PA/IVS) following right ventricular (RV) decompression, RV size and morphology drive clinical outcome. Our objectives were to (1) identify baseline and postdecompression echocardiographic parameters associated with 2V circulation, (2) identify echocardiographic parameters associated with RV growth and (3) describe changes in measures of RV size and changes in RV loading conditions. We performed a retrospective analysis of patients who underwent RV decompression for PA/IVS at four centers. We analyzed echocardiograms at baseline, postdecompression, and at follow up (closest to 1-year or prior to Glenn circulation). Eighty-one patients were included. At last follow-up, 70 (86%) patients had 2V circulations, 7 (9%) had 1.5 ventricle circulations, and 4 (5%) had single ventricle circulations. Follow-up echocardiograms were available in 43 (53%) patients. The majority of patients had improved RV systolic function, less tricuspid regurgitation (TR), and more left-to-right atrial shunting at a median of 350 days after decompression. Multivariable analysis demonstrated that larger baseline tricuspid valve (TV) z-score (P = .017), ≥ moderate baseline TR (P = .045) and smaller baseline RV area (P < .001) were associated with larger increases in RV area. Baseline RV area ≥6 cm2 /m2 had 93% sensitivity and 80% specificity for identifying patients who ultimately achieved 2V circulation. All patients with RV area ≥8 cm2 /m2 at follow up achieved 2V circulation. This finding was confirmed in a validation cohort from a separate center (N = 25). Factors associated with achieving RV area ≥8 cm2 /m2 included larger TV z-score (P = .004), ≥ moderate baseline TR (P = .031), and ≥ moderate postdecompression pulmonary regurgitation (P = .002). Patients with PA/IVS and smaller TV annuli are at risk for poor RV growth. Volume-loading conditions signal increased capacity for growth sufficient for 2V circulation.


[Screening of preschool children. A multidisciplinary assessment of the development and rehabilitation needs].
Observation of preschool children (SBO) consists of multidisciplinary assessment of whether a child aged 0-7 years is developmentally retarded and requires special training. For this observation, the children are admitted as day patients and, in the course of four days, the motor, mental, linguistic and social developments are assessed and sight and hearing are assessed. A few days after this observation, a conference is held and the result of assessment is discussed and the necessary measures to be instituted considered. During the years, 1987-1988, a total of 47 children were admitted for observation on account of suspected retarded development. Twenty-one of the children were found to be generally psychomotorically handicapped and of these 16 children were, mentally retarded. Three children suffered from benign hypotonia. Seventeen children were dysphatic and eight of these had also hypotonia. Six children had behaviour difficulties. The measures recommended are reviewed. Where 42 of the children were concerned, these were instituted with benefit to the child and his family.


Hemagglutination inhibition for serogrouping of Neisseria meningitidis.
A hemagglutination inhibition (HI) test has been studied as an alternative to bacterial agglutination (BA) for serogrouping strains of Neisseria meningitidis isolated from clinical specimens. The HI test consists of polysaccharide antigens adsorbed to sheep red blood cells which were then agglutinated by group-specific antisera. Supernatant fluids from suspensions of meningococci were used to inhibit the agglutination. Results of the two tests agreed for 381 (80%) carrier strains. Of the remaining 95 strains, 82 (86%) were identified by HI although they were nongroupable by BA. Thus, the HI test has been shown to be more highly specific and sensitive and to be more economical of reagents and time than the BA test.


Prognostic impact of lung ultrasound detected B-lines on hospitalised ischaemic heart failure with mildly reduced ejection fraction patients.
Prognostic impact of lung ultrasound-derived B-lines (LUS-BL) in heart failure with mildly reduced left ventricular ejection fraction (HFmrEF) patients remains elusive. We evaluated the correlation between LUS-BL and prognosis in HFmrEF patients. This is a subgroup analysis based on our previously published retrospective study with 1691 HFmrEF patients. This subgroup analysis involved 574 patients with LUS-BL results at admission. After discharge, patients underwent clinical follow-up for a minimum of 1 year through telephone, clinical visits or community visits. The primary endpoint was defined as cardiovascular (CV) event, including CV-related mortality or HF hospitalisation at 90 days and 1 year after discharge. CV event at 90 days was significantly increased with higher LUS-BL number (0, 1-2, 3-9 and ≥10: 20%, 14%, 18% and 33%, p=0.008), while CV event rate at 1 year was similar among groups (45% vs 45% vs 42% vs 50%, p=0.573). Older age, hypertension (HR=2.06, 95% CI 1.31 to 3.25), higher right ventricular diameter (>23 mm, HR=2.008, 95% CI 1.37 to 2.94), increased ratio of early transmitral flow velocity to early mitral annular velocity (>24, HR=1.79, 95% CI 1.11 to 2.26) and higher LUS-BL number (>11, HR=1.510, 95% CI 1.01 to 2.26) were identified as independent determinants associated with increased risk of CV event at 90 days after discharge. The Harrell's C-Statistic analysis, based on the Cox regression models, demonstrated a significant improvement in the predictive ability of the model that incorporated both clinical and echocardiographic risk factors along with LUS-BL (areas under the curve (AUC)=0.72) compared with the model comprising only clinical risk factors and LUS-BL (AUC=0.69, p=0.036), or to the model with echocardiographic risk factors and LUS-BL (AUC=0.68, p=0.025). In HFmrEF patients with ischaemic heart disease, admission LUS-BL>11 is independently associated with an increased risk of CV event at 90 days following discharge.


Bisexual women in marriages.
A clinical sample of women who were currently or previously married were surveyed regarding demographics, homosexual experiences before marriage, problems in marriage, and sexual orientation. The average age of the 45 participants was 35.9. Before marriage, 21 (47%) were somewhat aware of their homosexual feelings but were much less likely to have thought of or identified themselves as homosexuals. Sexual difficulties were very common in these marriages (89%), the most cited sexual difficulty being a lack of sexual desire for their spouse (62%). Based upon Kinsey-type ratings, the sample could be described as almost exclusively heterosexual in behavior and fantasies before marriage. Some changes could be seen during marriage toward more of a homosexual orientation. The dramatic change, however, occurred following marriage, when the women reported even more of a homosexual orientation, tending toward the homosexual end of the Kinsey continuum. At the time of the study, a majority of the sample was, in fact, relating almost exclusively to other women. This study found that, compared to homosexual men who have been married, these women are more likely to marry at an earlier age, unlikely to be aware of their homosexual feelings prior to marriage, and more likely to terminate their marriage earlier because of conflicts arising as a result of their bisexual orientation and sexual dissatisfaction.


Novel microRNAs and microsatellite-like small RNAs in sexual and apomictic Boechera species.
Apomixis refers to plant asexual reproduction through seeds that give rise to progeny which are genotypically identical to the maternal parent. It has evolved from many different sexual taxa although the underlying genetic factors remain unknown. Previous analyses of the over-representation of transcription factors, in a comparison of microdissected ovules from apomictic and sexual Boechera, showed that many transcription factor mRNAs possessed microRNA (miRNAs) binding sites, thus pointing to miRNAs as potentially important factors that may be involved in the regulatory switch from sexual to apomictic reproduction. A microarray-based approach was used to identify (1) 673 microsatellitelike small RNAs (misRNAs) containing predominantly 2-7 repeats of (GAA)n/(CUU)n, (GCA)n/(CGU)n, (GGA)n/(CCU)n, (GGU)n/(CCA)n and (UGA)n/(ACU)n, and (2) 166 more typical non-repeat small RNAs. In total, 87 small RNAs were found to be located in cDNAs that could fold into stem-loop structures and thus represent miRNA molecules. In addition, 109 Boechera small RNAs including both misRNAs and non-repeat small RNAs, showed significant homology to 407 Arabidopsis thaliana small RNAs including the A. thaliana pollen-specific ath-miR5021. This indicates that only a fraction of the identified small RNAs are unique to Boechera. Ten small RNAs were validated using a Northern blot assay on flower and leaf tissues, eight of which showed flower-specific expression with varying abundance. The potential binding sites of many of the misRNAs and non-repeat small RNAs occur predominantly in exonic regions. This feature coupled with their flower-specific pattern of expression is suggestive of their probable role in post-transcriptional gene regulation. We propose that quantitative variation for misRNA target binding (and hence post-transcriptional gene regulation) could arise via microsatellite length polymorphisms occurring either in misRNA precursors or in their gene targets.


Strategies for realizing photonic crystal fiber bandpass filters.
Numerical design strategies are presented to achieve efficient broad or narrow band-pass filters based on index-guiding, solid-core, and single-mode photonic crystal fibers (PCFs). The filtering characteristics have been verified through BPM solver. By scaling the pitch constant, the bandpass window can be shifted accordingly. The fiber design constitutes a fluorine-doped central core, enlarged air-holes surrounding the down-doped core, and small air-holes in the cladding. The proposed bandpass filter is based on controlling the leakage losses, so one can tune filter characteristics simply by changing its length. From numerical simulations we show that for large values of air-hole diameter in the first ring, the bandpass window is narrow, while for low doping concentration and small sized air-holes in the first ring, bandpass window is very broad. We also simulate how the hole-size and number of rings in the PCF cladding affects the device characteristics. We find that a 5-cm long PCF with down-doped core and eleven rings of air-holes can result in approximately 440 nm 3-dB bandwidth with more than 90% of transmission. The longer device has reduced transmission and smaller 3-dB bandwidth. Tolerance analysis has also been performed to check the impact of fiber tolerances on the performance of the PCF bandpass filter. It has been observed that the decrement in cladding hole-diameter by 1% reduces the transmission to 21% from its peak value of 93%, however +/-1% tolerance in the inner hole-diameter degrades the transmission to 75% from its peak.


Clinical significance of magnetic resonance imaging findings in rectal cancer.
Staging of rectal cancer is essential to help guide clinicians to decide upon the correct type of surgery and determine whether or not neoadjuvant therapy is indicated. Magnetic resonance imaging (MRI) is currently one of the most accurate modalities on which to base treatment decisions for patients with rectal cancer. MRI can accurately detect the mesorectal fascia, assess the invasion of the mesorectum or surrounding organs and predict the circumferential resection margin. Although nodal disease remains a difficult radiological diagnosis, new lymphographic agents and diffusion weighted imaging may allow identification of metastatic nodes by criteria other then size. In light of this, we have reviewed the literature on the accuracy of specific MRI findings for staging the local extent of primary rectal cancer. The aim of this review is to establish a correlation between MRI findings, prognosis, and available treatment options.


A controlled comparison of cyclazocine and naloxone treatment of the paroled narcotic addict.
A controlled, double-blind study of the comparative effectiveness of the narcotic antagonists, cyclazocine and naloxone, was undertaken in a metropolitan narcotic clinic offering an abstinence program involving urine monitoring and ancillary counseling services. Seventy male addict parolees were randomly assigned to 6-month treatment with either cyclazocine, 4 mg administered on a daily basis, or naloxone, 500-2,000 mg administered on a locally developed and researched 'contingent' basis, i.e., whenever there was indication of narcotic drug use (daily and contingent placebos were utilized to preserve the double-blind). Criteria of treatment effectiveness included narcotic drug usage, clinic attendance, length of participation in the program, disposition at 6 months, and incidence of side effects. The two subsamples of 35 individuals were similar with respect to relevant demographic characteristics. Examination of comparative effects revealed little to no significant differences between the two groups in terms of measures of program adherence, treatment outcome, and personal and social adjustment. Side effects were more prevalent among cyclazocine patients. Typically, these included moderately severe somatic effects and perceptual and cognitive disturbances.


Resident-Sensitive Quality Measures in the Pediatric Emergency Department: Exploring Relationships With Supervisor Entrustment and Patient Acuity and Complexity.
This study explores the associations between resident-sensitive quality measures (RSQMs) and supervisor entrustment as well as between RSQMs and patient acuity and complexity for encounters in the pediatric emergency department (PED) in which residents are caring for patients. Pediatric residents rotating through Cincinnati Children's Hospital Medical Center PED as well as supervising pediatric emergency medicine faculty and fellows were recruited during the 2017-2018 academic year for the purpose of collecting the following data from the residents' patient encounters for 3 illnesses (acute asthma exacerbation, bronchiolitis, and closed head injury [CHI]): supervisor entrustment decision rating, RSQMs relevant to the care provided, and supervisor patient acuity and complexity ratings. To measure the association of RSQM composite scores with the other variables of interest, mixed models were used. A total of 83 residents cared for 110 patients with asthma, 112 with bronchiolitis, and 77 with CHI. Entrustment decision ratings were positively associated with asthma RSQM composite scores (beta coefficient = 0.03; P < .001). There was no significant association between RSQM composite scores and entrustment decision ratings for bronchiolitis or CHI. RSQM composite scores were significantly higher when acuity was also higher and significantly lower when acuity was also lower for both asthma (P < .001) and bronchiolitis (P = .01). However, RSQM composite scores were almost identical between levels of acuity for CHI (P = .94). There were no significant differences in RSQM composite scores when complexity varied. This study found limited associations between RSQM composite scores and entrustment decision ratings but offers insight into how RSQMs could be used for the purposes of resident assessment and feedback.


[Decline in hospital autopsies].
According to the new autopsy regulation from April 2004 the next to kin must be informed of an autopsy and the right to deny consent. The present study aims at documenting the impact of this regulation on the number of autopsies performed and to determine whether regular reminders and changed autopsy routines could reduce the time needed to complete autopsy reports. The following information was gathered; the number of autopsies before and after implementation of the regulation, the number of next to kin who had been informed and the number that had denied consent. The consequence of monthly reminders to the pathologists for the time needed to complete the autopsy report was examined for the years 2000 to 2004. The autopsy routine was altered for six weeks in 2005; the doctors performed autopsies for two successive weeks instead of one. The time to complete the report in this period was compared with that of the same period the year before. The chi-squared test, the Mann-Whitney test and the Kruskal-Wallis test H test were used. After the autopsy regulation was introduced the number of autopsies/year decreased from 432 (39%) to 332 (31%) of all who had died in the hospital (p < 0.001). For 211 (20%) of the deaths, the next to kin had not been informed. The number who denied consent increased from 258 (23%) to 373 (35%). Monthly reminders reduced the median time for completing the autopsy report from 58 to 38 days (p < 0.001). Altering the autopsy routine reduced the median time needed to complete the report from 46 days the year before to 14 days after the changed routine (p < 0.001). Better information to next to kin will probably increase the number of autopsies. The time needed for completing the autopsy report can be reduced by simple means.


A class-wide phylogenetic assessment of Dothideomycetes.
We present a comprehensive phylogeny derived from 5 genes, nucSSU, nucLSU rDNA, TEF1, RPB1 and RPB2, for 356 isolates and 41 families (six newly described in this volume) in Dothideomycetes. All currently accepted orders in the class are represented for the first time in addition to numerous previously unplaced lineages. Subclass Pleosporomycetidae is expanded to include the aquatic order Jahnulales. An ancestral reconstruction of basic nutritional modes supports numerous transitions from saprobic life histories to plant associated and lichenised modes and a transition from terrestrial to aquatic habitats are confirmed. Finally, a genomic comparison of 6 dothideomycete genomes with other fungi finds a high level of unique protein associated with the class, supporting its delineation as a separate taxon.


Potential therapeutic effects of exercise to the brain.
Exercise is a well-recognized facet of modern living; however, the threat of sedentary lifestyle is ever increasing with the arrival of the technological period. Although the beneficial effects of exercise to the health and function of the brain have been accepted by the scientific and medical community, much remains to be achieved to understand its mechanisms of action. With the advent of modern investigative tools, several more key molecular and cellular players have been implicated in the above process. Such include the family of neurotrophins (e.g. NGF and BDNF) and their receptors, some pro-inflammatory cytokines (L-1beta, IL-6, TNF-alpha, IFN-gamma), microglia and astrocytes, and the cholinergic neuronal cells in the forebrain. While experiments based on the voluntary exercise paradigm has been the preferred approach to studying the brain, less is known about the forced paradigm. We will discuss in this review how molecular players may feature differently in the context of exercise and more importantly how their actions converged to impact the structure, and function (learning and memory) of the CNS.


Spatial distribution of mast cells and macrophages around tumor glands in human breast ductal carcinoma.
Macrophages and mast cells are usually present in the tumor microenvironment and play an important role as regulators of inflammation, immunological response and angiogenesis in the tumor microenvironment. In this study, we have evaluated macrophage, mast cell, and microvessel density in a selected group of different grade of invasive breast carcinoma tumor specimens. Furthermore, we have investigated the pattern of distribution of CD68-positive macrophages and tryptase-positive mast cells around tumor glands. Results have shown that: A) Macrophages are more numerous in G2 and G3 breast cancer stages respect to controls, the per cent of macrophages in G1 samples was comparable to the controls, and the spatial relationship between macrophages and glands (as indicated by the mean cell-to-gland distance) correlated with CD31-positive vessels. B) Mast cells in G2 and G3 tumor specimens show a significant increase in their number as compared to control samples, and their spatial distribution around the glands did not show any significant difference among groups. Overall, the results of this study confirm the important role of macrophages and mast cells in tumor progression and angiogenesis in human ductal breast cancer, and pointed out the spatial relationship between tumor macrophages and glands, and its correlation with microvascular density.


CD40 engagement on synovial fibroblast up-regulates production of vascular endothelial growth factor.
We tested the impact of CD40 engagement on the production of vascular endothelial growth factor (VEGF) from rheumatoid synovial fibroblasts. Fibroblast-like synovial cells (FLS) were prepared from the synovial tissues of rheumatoid arthritis patients and cultured in the presence of CD40 ligand-transfected (CD40L+) L cells. VEGF levels were determined in the culture supernatants by ELISA. Stimulation of FLS by CD40L+ L cells increased the production of VEGF by 4.1-fold over the constitutive levels of unstimulated FLS. The CD40L on activated T cells from rheumatoid synovial fluid also up-regulated VEGF production from FLS. Neither indomethacin nor Abs to IL-1beta, TNF-alpha, and TGF-beta did affect CD40L-induced VEGF production. Stimulation of FLS with TNF-alpha, IL-1beta, and TGF-beta increased VEGF production by 1.6-, 2.0-, and 5.2-fold, respectively, and displayed an additive effect on the production of VEGF by CD40L. VEGF mRNA expression was also up-regulated by the stimulation of FLS with membranes from the CD40L+ L cells. Dexamethasone completely abrogated CD40L-induced VEGF production. In addition, pyrrolidine dithiocarbamate partially down-regulated CD40L-induced VEGF production, showing that the NF-kappaB pathway was partly involved in the signaling of CD40L leading to VEGF production. Collectively, these results suggest that the interaction between CD40 on synovial fibroblasts and CD40L expressed on activated T lymphocytes may be directly involved in the neovascularization in rheumatoid synovitis by enhancing the production of VEGF.


Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes.
Type 1 diabetes and thyroid disease are T cell-dependent autoimmune endocrinopathies. The standard substitutive administration of the deficient hormones does not halt the autoimmune process; therefore, development of immunotherapies aiming to preserve the residual hormonal cells, is of crucial importance. PTPN22 C1858T mutation encoding for the R620W lymphoid tyrosine phosphatase variant, plays a potential pathophysiological role in autoimmunity. The PTPN22 encoded protein Lyp is a negative regulator of T cell antigen receptor signaling; R620W variant, leading to a gain of function with paradoxical reduced T cell activation, may represent a valid therapeutic target. We aimed to develop novel wild type PTPN22 short interfering RNA duplexes (siRNA) and optimize their delivery into Jurkat T cells and PBMC by using liposomal carriers. Conformational stability, size and polydispersion of siRNA in lipoplexes was measured by CD spectroscopy and DLS. Lipoplexes internalization and toxicity evaluation was assessed by confocal microscopy and flow cytometry analysis. Their effect on Lyp expression was evaluated by means of Western Blot and confocal microscopy. Functional assays through engagement of TCR signaling were established to evaluate biological consequences of down-modulation. Both Jurkat T cells and PBMC were efficiently transfected by stable custom lipoplexes. Jurkat T cell morphology and proliferation was not affected. Lipoplexes incorporation was visualized in CD3+ but also in CD3- peripheral blood immunotypes without signs of toxicity, damage or apoptosis. Efficacy in affecting Lyp protein expression was demonstrated in both transfected Jurkat T cells and PBMC. Moreover, impairment of Lyp inhibitory activity was revealed by increase of IL-2 secretion in culture supernatants of PBMC following anti-CD3/CD28 T cell receptor-driven stimulation. The results of our study open the pathway to future trials for the treatment of autoimmune diseases based on the selective inhibition of variant PTPN22 allele using lipoplexes of siRNA antisense oligomers.


Assessment of automatic vessel tracking techniques in preoperative planning of transluminal aortic stent graft implantation.
To evaluate automatic vessel tracking techniques in the course of preoperative planning prior to transluminal aortic endograft implantation by comparing accuracy, reproducibility, and postprocessing time with source image and volume-rendered analysis methods. Multislice computed tomography datasets of 5 patients with abdominal aortic aneurysms were preoperatively examined, performing volumetric analysis of diameter and position of renal artery orifices, aneurysmal neck, maximal aneurysmal extension, aortic bifurcation, and iliac arteries and bifurcation. Analysis was realized by utilizing transverse datasets, volume rendering, and automated vessel tracking strategies (MxView, Philips, Best, The Netherlands). Measurement techniques were evaluated by 2 independent readers 3 times for each patient and measurement modality. Statistical analysis evaluated accuracy of the measurements and intra- and interobserver reliability. Postprocessing time was documented. Using transverse source datasets, intraobserver reliability ranged from 0.49 to 0.58. Intraobserver reliability improved to 0.7 to 0.98 when volume-rendered datasets were evaluated. Interobserver variability for transverse and volume-rendered datasets ranged from 0.49 to 0.76 and 0.70 to 0.96, respectively. Automated vessel tracking datasets did not demonstrate any intra- or interobserver variability. Based on transverse datasets, the length and diameter of iliac arteries and location and diameter of the aneurysmal neck were measured as statistically different in all cases in contrast to volume rendering and automated segmentation techniques. Postprocessing time consumption for measurements based on transverse, volume-rendered, and automated tracking segmentation datasets averaged 3.32 minutes, 25.43 minutes, and 2.24 minutes, respectively. Preoperative measurements improve significantly if datasets are evaluated based on volume-rendering techniques. This time-consuming procedure can be shortened, while further reducing observer variability, with automatic segmentation techniques.


Adaptive latitudinal cline of photoperiodic diapause induction in the parasitoid Nasonia vitripennis in Europe.
Living in seasonally changing environments requires adaptation to seasonal cycles. Many insects use the change in day length as a reliable cue for upcoming winter and respond to shortened photoperiod through diapause. In this study, we report the clinal variation in photoperiodic diapause induction in populations of the parasitoid wasp Nasonia vitripennis collected along a latitudinal gradient in Europe. In this species, diapause occurs in the larval stage and is maternally induced. Adult Nasonia females were exposed to different photoperiodic cycles and lifetime production of diapausing offspring was scored. Females switched to the production of diapausing offspring after exposure to a threshold number of photoperiodic cycles. A latitudinal cline was found in the proportion of diapausing offspring, the switch point for diapause induction measured as the maternal age at which the female starts to produce diapausing larvae, and the critical photoperiod for diapause induction. Populations at northern latitudes show an earlier switch point, higher proportions of diapausing individuals and longer critical photoperiods. Since the photoperiodic response was measured under the same laboratory conditions, the observed differences between populations most likely reflect genetic differences in sensitivity to photoperiodic cues, resulting from local adaptation to environmental cycles. The observed variability in diapause response combined with the availability of genomic tools for N. vitripennis represent a good opportunity to further investigate the genetic basis of this adaptive trait.


Flexible Antiferromagnetic FeRh Tapes as Memory Elements.
The antiferromagnetic to ferromagnetic transition occurring above room temperature in FeRh is attracting interest for applications in spintronics, with perspectives for robust and untraceable data storage. Here, we show that FeRh films can be grown on a flexible metallic substrate (tape shaped), coated with a textured rock-salt MgO layer, suitable for large-scale applications. The FeRh tape displays a sharp antiferromagnetic to ferromagnetic transition at about 90 °C. Its magnetic properties are preserved by bending (radii of 300 mm), and their anisotropic magnetoresistance (up to 0.05%) is used to illustrate data writing/reading capability.


Derivatives of Bst-like Gss-polymerase with improved processivity and inhibitor tolerance.
At the moment, one of the actual trends in medical diagnostics is a development of methods for practical applications such as point-of-care testing, POCT or research tools, for example, whole genome amplification, WGA. All the techniques are based on using of specific DNA polymerases having strand displacement activity, high synthetic processivity, fidelity and, most significantly, tolerance to contaminants, appearing from analysed biological samples or collected under purification procedures. Here, we have designed a set of fusion enzymes based on catalytic domain of DNA polymerase I from Geobacillus sp. 777 with DNA-binding domain of DNA ligase Pyrococcus abyssi and Sto7d protein from Sulfolobus tokodaii, analogue of Sso7d. Designed chimeric DNA polymerases DBD-Gss, Sto-Gss and Gss-Sto exhibited the same level of thermal stability, thermal transferase activity and fidelity as native Gss; however, the processivity was increased up to 3-fold, leading to about 4-fold of DNA product in WGA which is much more exiting. The attachment of DNA-binding proteins enhanced the inhibitor tolerance of chimeric polymerases in loop-mediated isothermal amplification to several of the most common DNA sample contaminants-urea and whole blood, heparin, ethylenediaminetetraacetic acid, NaCl, ethanol. Therefore, chimeric Bst-like Gss-polymerase will be promising tool for both WGA and POCT due to increased processivity and inhibitor tolerance.


An integral role for heme oxygenase-1 and carbon monoxide in maintaining peripheral tolerance by CD4+CD25+ regulatory T cells.
Over the past decade, a great deal of interest and attention has been directed toward a population of regulatory T cells (Treg) coexpressing the markers CD4 and CD25. The hallmark phenotype of this cell population resides in its ability to dominantly maintain peripheral tolerance and avert autoimmunity. Despite robust research interest in Treg, their mechanism of action and interaction with other cell populations providing immune regulation remains unclear. In this study, we present a model for Treg activity that implicates carbon monoxide, a by-product of heme oxygenase-1 activity, as an important and underappreciated facet in the suppressive capacity of Treg. Our hypothesis is based on recent evidence supporting a role for heme oxygenase-1 in regulating immune reactivity and posit carbon monoxide to function as a suppressive molecule. Potential roles for indoleamine 2,3-dioxygenase, costimulatory molecules, and cytokines in tolerance induction are also presented. This model, if validated, could act as a catalyst for new investigations into Treg function and ultimately result in novel methods to modulate Treg biology toward therapeutic applications.


Guideline implementation, drug sequencing, and quality of care in heart failure: design and rationale of TITRATE-HF.
Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline-directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real-world TITRATE-HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long-term outcomes in patients with de novo, chronic, and worsening HF. A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow-up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF-related hospitalizations, HF-related urgent visits with a need for intravenous diuretics, all-cause mortality, and cardiovascular mortality. TITRATE-HF is a real-world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.


Prostate specific antigen enhances the innate defence of prostatic epithelium against Escherichia coli infection.
This study investigated whether the increase in serum prostate specific antigen (PSA) typically seen during male urinary tract infection (UTI) is incidental or reflects an innate defence mechanism of the prostate. The protective roles of the whey-acid-motif-4-disulphide core (WFDC) proteins, secretory leukoproteinase inhibitor (SLPI) and WFDC2, in the prostate were also examined. UTI recurrence was assessed retrospectively in men following initial UTI by patient interview. PSA, SLPI, and WFDC2 gene expression were assessed using biopsy samples. LNCaP and DU145 in vitro prostate cell models were utilized to assess the effects of an Escherichia coli challenge on PSA and WFDC gene expression, and bacterial invasion of the prostate epithelium. The effects of PSA on WFDC antimicrobial properties were studied using recombinant peptides and time-kill assays. Men presenting with PSA >4 ng/ml at initial UTI were less likely to have recurrent (r) UTI than those with PSA <4 ng/ml [2/15 (13%) vs. 7/10 (70%), P < 0.01]. Genes encoding PSA, SLPI and WFDC2, were expressed in prostatic epithelium, and the PSA and SLPI proteins co-localized in vivo. Challenging LNCaP (PSA-positive) cells with E. coli increased PSA, SLPI, and WFDC2 gene expression (P < 0.05), and PSA synthesis (P < 0.05), and reduced bacterial invasion. Pre-incubation of DU145 (PSA-negative) cells with PSA also decreased bacterial invasion. In vitro incubation of recombinant SLPI and WFDC2 with PSA resulted in peptide proteolysis and increased E. coli killing. Increased PSA during UTI appears protective against rUTI and in vitro is linked to proteolysis of WFDC proteins supporting enhanced prostate innate defences.


Is there a feedback between N availability in siliceous and calcareous soils and Cistus albidus leaf chemical composition?
The effects of the Mediterranean shrub Cistus albidus on N cycling were studied in two siliceous (granitic-derived and schistic-derived) and one calcareous soil differentiated by their texture and acidity. We aimed to find out whether soils under C. albidus were affected by the release of C compounds from the canopy, and whether phenolic compound production in C. albidus changed depending on the soil N availability. Calcareous soils, with higher clay content and polyvalent cations, had a higher organic matter content but lower net N mineralization rates than siliceous soils, and C. albidus growing therein were characterized by lower foliar N and phenolic compound concentrations. Under C. albidus, all types of soils had higher phenolic compound concentrations and polyphenol oxidase activity. C. albidus presence and leachate addition decreased net N mineralization and increased soil respiration in siliceous soils, and these changes were related to a higher soil C/N ratio under the canopy. In calcareous soils, however, no significant effects of plant presence on N cycling were found. In the studied plant-soil system it is not likely that higher phenolic compound concentrations were selected during evolution to enhance nutrient conservation in soil because (1) higher phenolic compound concentrations were not associated with lower soil fertilities, (2) C compounds released from C. albidus accelerated N cycling by increasing N immobilization and no evidence was found for decreased gross N mineralization, and (3) soil organic N content was more related to soil chemical and physical properties than to the effects of the C. albidus canopy.