Integrating Surface-Based Temperature and Vegetation Abundance Estimates into Land Cover Classifications for Conservation Efforts in Savanna Landscapes.
Southern African savannas are an important dryland ecosystem, as they account for up to 54% of the landscape, support a rich variety of biodiversity, and are areas of key landscape change. This paper aims to address the challenges of studying this highly gradient landscape with a grass-shrub-tree continuum. This study takes place in South Luangwa National Park (SLNP) in eastern Zambia. Discretely classifying land cover in savannas is notoriously difficult because vegetation species and structural groups may be very similar, giving off nearly indistinguishable spectral signatures. A support vector machine classification was tested and it produced an accuracy of only 34.48%. Therefore, we took a novel continuous approach in evaluating this change by coupling in situ data with Landsat-level normalized difference vegetation index data (NDVI, as a proxy for vegetation abundance) and blackbody surface temperature (BBST) data into a rule-based classification for November 2015 (wet season) that was 79.31% accurate. The resultant rule-based classification was used to extract mean Moderate Resolution Imaging Spectroradiometer (MODIS) NDVI values by season over time from 2000 to 2016. This showed a distinct separation between each of the classes consistently over time, with woodland having the highest NDVI, followed by shrubland and then grassland, but an overall decrease in NDVI over time in all three classes. These changes may be due to a combination of precipitation, herbivory, fire, and humans. This study highlights the usefulness of a continuous time-series-based approach, which specifically integrates surface temperature and vegetation abundance-based NDVI data into a study of land cover and vegetation health for savanna landscapes, which will be useful for park managers and conservationists globally.


Immunogenicity Threshold in Allogeneic Cells Impacts CTL Response to Nondominant Congenic Antigens.
Transplantation and cancer expose the immune system to neoantigens, including immunogenic (dominant and subdominant) and nonimmunogenic Ags with varying quantities and affinities of immunodominant peptides. Conceptually, immunity is believed to mainly target dominant Ags when subdominant or nondominant Ags are linked within the same cell due to T cell interference. This phenomenon is called immunodominance. However, our previous study in mice showed that linked nonimmunogenic Ags (OVA and GFP) containing immunodominant peptides mount immunity irrespective of the MHC-matched allogeneic cell's immunogenicity. Consequently, we further explored 1) under what circumstances does the congenic marker CD45.1 provoke immunity in CD45.2 mice, and 2) whether linking two dominant or subdominant Ags can instigate an immune response. Our observations showed that CD45.1 (or CD45.2), when connected to low-immunogenic cell types is presented as an immunogen, which contrasts with its outcome when linked to high-immunogenic cell types. Moreover, we found that both dominant and subdominant Ags are presented as immunogens when linked in environments with lower immunogenic thresholds. These findings challenge the existing perception that immunity is predominantly elicited against dominant Ags when linked to subdominant or nondominant Ags. This study takes a fundamental step toward understanding the nuanced relationship between immunogenic and nonimmunogenic Ags, potentially opening new avenues for comprehending cancer immunoediting and enhancing the conversion of cold tumors with low immunogenicity into responsive hot tumors.


Open repair, endovascular repair, and conservative management of true splenic artery aneurysms.
True splenic artery aneurysms (SAAs) are a rare but potentially fatal pathology. For many years, open repair (OPEN) and conservative management (CONS) were the treatments of choice, but throughout the last decade endovascular repair (EV) has become increasingly used. The purpose of the present study was to perform a systematic review and meta-analysis evaluating the outcomes of the three major treatment modalities (OPEN, EV, and CONS) for the management of SAAs. A systematic review of all studies describing the outcomes of SAAs treated with OPEN, EV, or CONS was performed using seven large medical databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to ensure a high-quality review. All articles were subject to critical appraisal for relevance, validity, and availability of data regarding characteristics and outcomes. All data were systematically pooled, and meta-analyses were performed on several outcomes, including early and late mortality, complications, and number of reinterventions. Original data of 1321 patients with true SAAs were identified in 47 articles. OPEN contained 511 patients (38.7%) in 31 articles, followed by 425 patients (32.2%) in CONS in 16 articles and 385 patients (29.1%) in EV in 33 articles. The CONS group had fewer symptomatic patients (9.5% vs 28.7% in OPEN and 28.8% in EV; P < .001) and fewer ruptured aneurysms (0.2% vs 18.4% in OPEN and 8.8% in EV; P < .001), but no significant differences were found in existing comorbidities. CONS patients were usually older and had smaller-sized aneurysms than patients in the OPEN and EV groups. The only identified difference in baseline characteristics between OPEN and EV was the number of ruptured aneurysms (18.4% vs 8.8%; P < .001). OPEN had a higher 30-day mortality than EV (5.1% vs 0.6%; P < .001), whereas minor complications occurred in a larger number of the EV patients. EV required more reinterventions per year (3.2%) compared with OPEN (0.5%) and CONS (1.2%; P < .001). The late mortality rate was higher in patients treated with CONS (4.9% vs 2.1% in OPEN and 1.4% in EV; P = .04). EV of SAA has better short-term results compared with OPEN, including significantly lower perioperative mortality. OPEN is associated with fewer late complications and fewer reinterventions during follow-up. Patients treated with CONS showed a higher late mortality rate. Ruptured SAAs are predictors of a significantly higher perioperative mortality compared with nonruptured SAAs in the OPEN and EV groups.


Computational Models for Understanding of Structure, Function and Pharmacology of the Cardiac Potassium Channel Kv11.1 (hERG).
The rapid delayed rectifier current IKr is one of the major K+ currents involved in repolarization of the human cardiac action potential. Various inherited or drug-induced forms of the long QT syndrome (LQTS) in humans are linked to functional and structural modifications in the IKr conducting channels. IKr is carried by the potassium channel Kv11.1 encoded by the gene KCNH2 (commonly referred to as human ether-a-go-go-related gene or hERG) [1, 2]. The first necessary step for predicting emergent drug effects on the heart is determining and modeling the binding thermodynamics and kinetics of primary and major off-target drug interactions with subcellular targets. The bulk of drugs that target hERG channels are known to have complex interactions at the atomic scale. Accordingly, one of the goals for this review is to provide comprehensive guide in the universe of computational models aiming to refine our understanding of structure-function relations in Kv11.1 and its isoforms. The special emphasis is placed on the mapping of drug binding sites and tentative mechanisms of channel inhibition and activation by drugs. An overview over recent structural models and mapping of binding sites for blockers and activators of IKr current along with the discussion on agreements and discrepancies among different models is presented. There is an apparent reciprocity or feedback loop between drug binding and action potential of the cardiac myocytes. Thus one has to connect drug binding to a particular receptor so that its functional consequences impact on the action potential duration. The natural pathway is to develop multi-scale models that connect between receptor and cellular scales. The potential for such multi-scale model development is discussed through the lens of common gating models. Accordingly, the second part of this review covers an ongoing development of the kinetic models of gating transitions and cardiac ion currents carried by hERG channels with and without drug bound.


Transphosphorylation of kinase-dead HER3 and breast cancer progression: a new standpoint or an old concept revisited?
Although neither kinase-dead human epidermal growth factor receptor (HER)3 nor orphan HER2 can be activated by HER-related ligands on their own, the formation of HER2/HER3 heterodimers creates the most mitogenic and transforming receptor complex within the HER (erbB) family of transmembrane receptor tyrosine kinases. The incorporation of markers such as HER3 transactivation, HER2/HER3 dimer, or others that may provide information regarding the level of HER pathway engagement has been demonstrated to allow identification of patients who respond to or escape HER-targeted therapies. Pioneering studies showed that high expression of kinase-dead HER3 can predict early escape from the anti-HER2 monoclonal antibody trastuzumab. Also, the growth-inhibitory effects of HER1/2 tyrosine kinase inhibitors (TKIs) were previously found to be attenuated in the presence of heregulin, which is a high-affinity combinatorial ligand for HER3. All of these concepts are being revisited with respect to the efficacy of HER family TKI therapies; in particular, HER3 signalling buffered against incomplete inhibition of HER2 kinase activity has been suggested to be the mechanism that allows HER2 over-expressing breast cancer cells to escape HER TKIs. It remains to be elucidated whether reactivation of HER3 signalling can also account for the poor efficacy of HER TKIs in treating breast carcinomas that contain low overall levels of HER2 receptors. However, it appears that regardless of the mechanism that triggers the formation of oncogenic HER2/HER3 heterodimers (HER2 over-expression or overall low HER2 but high levels of the HER3 ligand heregulin), HER3 transphosphorylation is a common response of breast cancer cells upon treatment with current inhibitors of the HER receptor tyrosine kinase network. Because kinase-inactive HER3 is not presently an amenable target for forthcoming HER TKIs, molecular approaches that can efficiently block heregulin-triggered HER3 transactivation or nucleocytoplasmic trafficking of heregulin might offer novel strategies with which to manage HER-driven breast cancer disease.


Reproducibility of [11C]choline-positron emission tomography and effect of trastuzumab.
This study sought to evaluate the reproducibility of [(11)C]choline-positron emission tomography and the effect of trastuzumab in breast cancer. Twenty-one patients with newly diagnosed and recurrent breast cancer stage II-IV had a baseline dynamic [(11)C]choline-PET scan, 10 patients had a second [(11)C]choline-PET scan to examine reproducibility, and 6 patients had a second scan within a month after trastuzumab. Analysis of [(11)C]choline uptake was measured as the semiquantitative standardized uptake value at 30 and 60 minutes (SUV(30) and SUV(60)), and quantitatively as the net irreversible retention of the radiotracer at steady-state (Ki) and plasma to tissue exchange at 60 minutes (IRF60min). Breast tumor lesions in all patients were visualized by [(11)C]choline PET. The difference in tumor versus normal tissue uptake was significant for SUV(30), SUV(60), Ki, and IRF60 minutes (Wilcoxon P < 0.0001). At 60 minutes postinjection, 15.1 +/- 2.16% of plasma radioactivity was due to unmetabolized [(11)C]choline radioactivity. [(11)C]Choline uptake was reproducible in breast tumor lesions (r(2) = 0.9 for SUV, 0.9 for Ki, and 0.8 for IRF60). Early responses to trastuzumab measured by [(11)C]choline-PET were significant in three lesions occurring in two patients who responded clinically. [(11)C]Choline-PET uptake variables can be reproducibly assessed. Initial studies show that trastuzumab decreases [(11)C]choline uptake.


[Uremic encephalopathy in regular dialysis treatment: uremic stroke?].
This case report a 59 years-old male in regular dialysis treatment with neurologic emergency characterized by neurologic signs as deep sopor the cause of which was uremic encephalopathy. At presentation, laboratory investigations revealed creatinine 12,75 mg/dl, BUN 174 mg/% and hyperkalemia 7,5 mq/L. The most common abnormal test results were EEG and ECG. CT brain showed no evidence of hemorrhagic areas or hematoma subdural. The patient was treated with hemodialysis and after the first hour of hemodialysis, laboratory control revealed hypokaliemia with metabolic acidosis due to arteiovenous fistula recirculation. After placement of jugular venous hemodialysis catheter and intensive treatment, the patient showed gradual improvement of uremic stroke due to arteriovenous fistula recirculation for high grade venous stenoses. Arteriovenous fistula dysfunction remains a major contributor to the morbidity and mortality of hemodialysis patients. The failure of a newly created AVF to mature and to develop stenosis in an estabilished AVF are two common clinical predicaments. The goal is to identify a dysfunctional AVF early enough to intervene in a timely manner, either to assist the maturation process or to prevent thrombosis. Most clinical features of neurologic complications in uremics are nonspecific and do not reliable, but it is important to identify specific causes such as vascular access recirculation for adequate treatment and regression of uremic stroke.


N-of-1 randomized trials for psychological and health behavior outcomes: a systematic review protocol.
Randomized controlled trials are the sine qua non of causal inference; however, heterogeneity of treatment effects for many chronic conditions and for many symptoms often limits their utility. Single-patient studies in which patients select a treatment after trying a randomized sequence of treatments (i.e., multiple crossover trials) offer an alternative to traditional randomized controlled trials by providing scientifically valid results in a practical manner that can be used by patients and their providers to decide upon their personally optimal treatment. Although N-of-1 trials have been used in the medical literature, their use for interventions that consist of psychological or health behavior outcomes is unknown. This systematic review thus aims to describe the interventions and outcomes and assess the quality of N-of-1 trials for psychological or health behavior outcomes. Electronic databases (Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, and the six databases in the Cochrane Library) will be searched using all relevant subject headings and free-text terms to represent N-of-1 trials and psychological or behavioral interventions. Full text review and bibliography searching will be conducted. Unpublished studies will be sought by searching trial registries and contacting authors of included studies. Eligibility criteria are the following: population, all human participants for whom N-of-1 trials with psychological or health behavior outcomes have been conducted; interventions, all interventions for which N-of-1 trials have been conducted; comparison, placebo or active treatment control; and outcome, psychological and health behavior outcomes including self-perceived disease severity and psychological phenomena such as mood and affect. Studies that do not contain sufficient trial detail, describe only design or statistical analytic issues in N-of-1 trials without presentation of an N-of-1 trial itself, and/or are not written in the English language are ineligible. Screening, data extraction, and quality assessment will be conducted by two independent reviewers with disagreements resolved through discussion. This systematic review will describe the interventions and outcomes and assess the quality of N-of-1 trials for psychological or health behavior outcomes. The results will clarify the use of this research methodology in the health psychology and behavioral medicine literature and may pave the way for additional N-of-1 trials to be conducted. PROSPERO CRD42015017853.


Quasi-free-standing epitaxial graphene on SiC (0001) by fluorine intercalation from a molecular source.
We demonstrated a novel method to obtain charge neutral quasi-free-standing graphene on SiC (0001) from the buffer layer using fluorine from a molecular source, fluorinated fullerene (C(60)F(48)). The intercalated product is stable under ambient conditions and resistant to elevated temperatures of up to 1200 °C. Scanning tunneling microscopy and spectroscopy measurements are performed for the first time on such quasi-free-standing graphene to elucidate changes in the electronic and structural properties of both the graphene and interfacial layer. Novel structures due to a highly localized perturbation caused by the presence of adsorbed fluorine were produced in the intercalation process and investigated. Photoemission spectroscopy is used to confirm these electronic and structural changes.


A calcitonin gene-related peptide receptor antagonist prevents the development of tolerance to spinal morphine analgesia.
Tolerance to morphine analgesia is believed to result from a neuronal adaptation produced by continuous drug administration, although the precise mechanisms involved have yet to be established. Recently, we reported selective alterations in rat spinal calcitonin gene-related peptide (CGRP) markers in morphine-tolerant animals. In fact, increases in CGRP-like immunostaining and decrements in specific [125]hCGRP binding in the superficial laminae of the dorsal horn were correlated with the development of tolerance to the spinal antinociceptive action of morphine. Other spinally located peptides such as substance P, galanin, and neuropeptide Y were unaffected. Thus, the major goal of the present study was to investigate whether the development of tolerance to spinally infused morphine could be modulated by the blockade of dorsal horn CGRP receptors using the potent CGRP antagonist hCGRP(8-37). Indeed, cotreatments with hCGRP(8-37) prevented, in a dose-dependent manner, the development of tolerance to morphine-induced analgesia in both the rat tail-flick/tail-immersion and paw-pressure tests. Moreover, alterations in spinal CGRP markers seen in morphine-tolerant animals were not observed after a coadministration of morphine and hCGRP(8-37). These results demonstrate the existence of specific interaction between CGRP and the development of tolerance to the spinal antinociceptive effects of morphine. They also suggest that CGRP receptor antagonists could become useful adjuncts in the treatment of pain and tolerance to the antinociceptive effects of morphine.


Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects.
The reverse transcriptase (RT) inhibitor tenofovir (TFV) is highly effective in the simian immunodeficiency virus (SIV) macaque model of human immunodeficiency virus infection. The current report describes extended safety and efficacy data on 32 animals that received prolonged (>or=1- to 13-year) daily subcutaneous TFV regimens. The likelihood of renal toxicity (proximal renal tubular dysfunction [PRTD]) correlated with plasma drug concentrations, which depended on the dosage regimen and age-related changes in drug clearance. Below a threshold area under the concentration-time curve for TFV in plasma of approximately 10 microg x h/ml, an exposure severalfold higher than that observed in humans treated orally with 300 mg TFV disoproxil fumarate (TDF), prolonged TFV administration was not associated with PRTD based on urinalysis, serum chemistry analyses, bone mineral density, and clinical observations. At low-dose maintenance regimens, plasma TFV concentrations and intracellular TFV diphosphate concentrations were similar to or slightly higher than those observed in TDF-treated humans. No new toxicities were identified. The available evidence does not suggest teratogenic effects of prolonged low-dose TFV treatment; by the age of 10 years, one macaque, on TFV treatment since birth, had produced three offspring that were healthy by all criteria up to the age of 5 years. Despite the presence of viral variants with a lysine-to-arginine substitution at codon 65 (K65R) of RT in all 28 SIV-infected animals, 6 animals suppressed viremia to undetectable levels for as long as 12 years of TFV monotherapy. In conclusion, these findings illustrate the safety and sustained benefits of prolonged TFV-containing regimens throughout development from infancy to adulthood, including pregnancy.


Multiple thermoregulatory effectors with independent central controls.
This review first considers how mammalian body temperature regulation evolved, and how the brain's responses to thermoregulatory challenges are likely to be organised differently from the way an engineer would design them. This is because thermoregulatory effector mechanisms would have evolved one at a time, with each being superimposed on pre-existing mechanisms. There may be no functional need for the final ensemble of control loops to be coordinated by neural cross-connections: appropriate thermal thresholds would solve the problem sufficiently. Investigations first into thermoregulatory behaviours and later into unconscious thermoregulatory mechanisms (autonomic and shivering) have led investigators to the realisation that multiple control loops exist in the brain, with each effector system apparently regulated by its own central temperature sensors. This theme is developed with reference to data on four temperature-regulated neural outflows that have been studied on anaesthetized rats under standard conditions in the authors' laboratory. Direct comparisons were made between the behaviour of sympathetic nerves supplying the tail vasculature, vessels in the proximal hairy skin, interscapular brown adipose tissue (BAT) and fusimotor fibres to hind limb muscle. All four outflows were activated by cooling the skin, and all were silenced by neuronal inhibition in the medullary raphé. Their thermal thresholds were quite different, however, as were their relative responsiveness to core temperature. This was ranked as: tail > back skin > BAT > fusimotor. These and other data indicate that the four thermoeffector outflows are driven by separate neural pathways, each regulated by independent brain temperature sensors.


Capillary Microfluidics for Monitoring Medication Adherence.
Medication adherence is a medical and societal issue worldwide, with approximately half of patients failing to adhere to prescribed treatments. The goal of this Minireview is to examine how recent work on microfluidics for point-of-care diagnostics may be used to enhance adherence to medication. It specifically focuses on capillary microfluidics since these devices are self-powered, easy to use, and well established for diagnostics and drug monitoring. Considering that an improvement in medication adherence can have a much larger effect than the development of new medical treatments, it is long overdue for the research communities working in chemistry, biology, pharmacology, and material sciences to consider developing technologies to enhance medication adherence. For these reasons, this Minireview is not meant to be exhaustive but rather to provide a quick starting point for researchers interested in joining this complex but intriguing and exciting field of research.


Event-Related Potentials to Changes in Sound Intensity Demonstrate Alterations in Brain Function Related to Depression and Aging.
Measures of the brain's automatic electrophysiological responses to sounds represent a potential tool for identifying age- and depression-related neural markers. However, these markers have rarely been studied related to aging and depression within one study. Here, we investigated auditory event-related potentials (ERPs) in the brain that may show different alterations related to aging and depression. We used an oddball condition employing changes in sound intensity to investigate: (i) sound intensity dependence; (ii) sensory gating; and (iii) change detection, all within a single paradigm. The ERPs of younger (18-40 years) and older (62-80 years) depressed female participants and age-matched non-depressed participants were measured. Intensity dependence was examined as the difference between N1 responses to repeated high- and low-intensity sounds, sensory gating as N1 responses to rare and repeated sounds, and change detection as indexed by the mismatch negativity (MMN). We found that intensity dependence was greater in older participants than younger ones, indicating effects related to aging but not to depression. For sensory gating, we found depression- and age-related alterations as increased N1 responses. No group differences were found for MMN. Although a sensory gating deficit was expected in older adults, this study is the first to demonstrate age-related overexcitability in sound intensity dependency. The results indicate that automatic brain responses to sound intensity changes are suitable for studying age- and depression-related neural markers but may not be sensitive enough to differentiate the effects of aging and depression.


Active Versus Passive Anchoring Vascular Closure Devices Following Percutaneous Coronary Intervention: A Safety and Efficacy Comparative Analysis.
We evaluate the prevalence of complications and failure rates between the most commonly used "active" anchoring vascular closure device (VCD), AngioSeal™ and the "passive" anchoring VCD, Mynx™, in all-comers undergoing percutaneous coronary intervention (PCI). A total of 4,074 patients between 2008 and 2014, representing an era when both devices were available, were included. Thirty-two percent were acute coronary syndromes (37% STEMI). VCD choice was at the operator's discretion and included AngioSeal (n = 2,910) or Mynx (1,164). Cardiogenic shock or patients receiving intra-aortic balloon pumps were excluded. Safety was assessed by vascular complications defined as either vascular injury (perforation, dissection, acute limb ischemia, arteriovenous fistula, pseudoaneurysm with thrombin injection, or surgical repair) or access-site bleed (hemoglobin droP >3 g/dL requiring transfusion, retroperitoneal bleed, or hematoma >5 cm, or the composite of both. Efficacy was evaluated by device failure and defined as inability to achieve immediate hemostasis or use of additional hemostatic mechanisms. Outcomes at 30-days were evaluated. Groups (AngioSeal vs Mynx) were fairly balanced with regards to bleeding risk factors of gender (male, 65% vs 66%), body mass index (30 ± 6 vs 30 ± 7), heart failure class III/IV (5% vs 6%), chronic kidney disease (15% vs 17%), use of glycoprotein IIb/IIIa inhibitor (5% vs 4%), or bivalirudin (86% vs 88%), all P >0.5. The AngioSeal group was slightly younger (64 ± 12 vs 65 ± 12, P < 0.001) with less peripheral arterial disease (11.3% vs 13.9%, P = 0.03), and increased 7F sheath use compared with Mynx (59% vs 22%, P < 0.001). Safety and efficacy outcomes were similar between groups. AngioSeal and Mynx appear to be equally safe and efficacious VCDs following PCI. The passive anchoring system may prove desirable as no intra-arterial anchor remains upon device removal.


Screening and Stepped Care Targeting Psychological Distress in Patients With Metastatic Colorectal Cancer: The TES Cluster Randomized Trial.
This study evaluated the effectiveness of a screening and stepped care program (the TES program) in reducing psychological distress compared with care as usual (CAU) in patients with metastatic colorectal cancer starting with first-line systemic palliative treatment. In this cluster randomized trial, 16 hospitals were assigned to the TES program or CAU. Patients in the TES arm were screened for psychological distress with the Hospital Anxiety and Depression Scale and the Distress Thermometer/Problem List (at baseline and 10 and 18 weeks). Stepped care was offered to patients with distress or expressed needs, and it consisted of watchful waiting, guided self-help, face-to-face problem-solving therapy, or referral to specialized mental healthcare. The primary outcome was change in psychological distress over time, and secondary outcomes were quality of life, satisfaction with care, and recognition and referral of distressed patients by clinicians. Linear mixed models and effect sizes were used to evaluate differences. A total of 349 patients were randomized; 184 received the TES program and 165 received CAU. In the TES arm, 60.3% of the patients screened positive for psychological distress, 26.1% of which entered the stepped care program (14.7% used only watchful waiting and 11.4% used at least one of the other treatment steps). The observed low use of the TES program led us to pursue a futility analysis, which showed a small conditional power and therefore resulted in halted recruitment for this study. No difference was seen in change in psychological distress over time between the 2 groups (effect size, -0.16; 95% CI, -0.35 to 0.03; P>.05). The TES group reported higher satisfaction with the received treatment and better cognitive quality of life (all P<.05). As a result of the low use of stepped care, a combined screening and treatment program targeting psychological distress in patients with metastatic colorectal cancer did not improve psychological distress. Our results suggest that enhanced evaluation of psychosocial concerns may improve aspects of patient well-being.


Is lobular endocervical glandular hyperplasia a cancerous precursor of minimal deviation adenocarcinoma?: a comparative molecular-genetic and immunohistochemical study.
Although lobular endocervical glandular hyperplasia (LEGH) was originally described as a distinct hyperplastic glandular lesion of the uterine cervix, recent studies have raised a question that LEGH may be a cancerous precursor of minimal deviation adenocarcinoma (MDA) and other mucinous adenocarcinomas (MACs) of the uterine cervix. In the present study, we studied LEGH, MDA, and MAC by using molecular-genetic and immunohistochemical methods for chromosomal imbalance, microsatellite instability, human papillomavirus (HPV) infection, and gastric pyloric-type mucin secretion to clarify their relationship. Comparative genomic hybridization revealed recurrent chromosomal imbalances, that is, gains of chromosome 3q and a loss of 1p, which were common to MDA and MAC, in 3 of 14 LEGHs analyzed (21%). LEGHs with chromosomal imbalances showed a degree of cellular atypia in the hyperplastic glandular epithelium. Dual-color fluorescence in situ hybridization confirmed a gain of chromosome 3 fragment in these cervical glandular lesions. HPV in situ hybridization revealed that high-risk HPV (types 16 and 18) was positive in over 80% of MACs, but negative in all LEGHs and MDAs examined. Microsatellite instability was rarely detected in these cervical glandular lesions. Our present study results demonstrated a molecular-genetic link between LEGH and cervical mucinous glandular malignancies including MDA and MAC, and are thought to support the hypothesis that a proportion of LEGHs are cancerous precursors of MDA and/or MAC.


In vivo guidance and assessment of liver radio-frequency ablation with acoustic radiation force elastography.
The initial results from clinical trials investigating the utility of acoustic radiation force impulse (ARFI) imaging for use with radio-frequency ablation (RFA) procedures in the liver are presented. To date, data have been collected from 6 RFA procedures in 5 unique patients. Large displacement contrast was observed in ARFI images of both pre-ablation malignancies (mean 7.5 dB, range 5.7-11.9 dB) and post-ablation thermal lesions (mean 6.2 dB, range 5.1-7.5 dB). In general, ARFI images provided superior boundary definition of structures relative to the use of conventional sonography alone. Although further investigations are required, initial results are encouraging and demonstrate the clinical promise of the ARFI method for use in many stages of RFA procedures.


Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells.
A bias of T cell immunity towards type 2 (Th2) is thought to be critical for normal pregnancy. Pathological pregnancies, such as pre-eclampsia, are characterised by cell-mediated (Th1) immune dominance. The Th1/Th2 paradigm, however, is too simplistic. Normal pregnancy is associated with a systemic inflammatory response which increases throughout gestation. This inflammatory response is exaggerated in pre-eclampsia, a syndrome of the third trimester. T helper (Th) cells are considered the primary mediators of these altered immune responses, and other T cells, i.e. T cytotoxic (Tc) cells, and lymphocytes of the innate immune system, i.e. natural killer (NK) and NKT cells, have been largely disregarded. In this study, we have used novel pan type 1 (IL-18 receptor) and pan type 2 (ST2L) lymphocyte function markers in four-colour flow cytometry to broadly characterise peripheral blood lymphocyte populations from non-pregnant, normal pregnant and pre-eclamptic women. There were no changes in the Th1/Th2 or Tc1/Tc2 cell ratios between the three groups; however, the NK1/NK2 and NKT1/NKT2 cell ratios were significantly decreased in normal pregnancy compared with non-pregnant (p <0.001 and p <0.01, respectively) and pre-eclamptic women (p <0.05). These results confirm that immunoregulation occurs in pregnancy, but suggest a dominant role of the innate rather than the adaptive immune system.


Treatment of Lyme disease: a medicolegal assessment.
Lyme disease is the most common tick-borne disease in the world today. Despite extensive research into the complex nature of Borrelia burgdorferi, the spirochetal agent of Lyme disease, controversy continues over the diagnosis and treatment of this protean illness. This report will focus on two aspects of the treatment of Lyme disease. First, the medical basis for diagnostic and therapeutic uncertainty in Lyme disease, including variability in clinical presentation, shortcomings in laboratory testing procedures, and design defects in therapeutic trials. Second, the standard of care and legal issues that have resulted from the clinical uncertainty of Lyme disease diagnosis and treatment. Specifically, the divergent therapeutic standards for Lyme disease are addressed, and the difficult process of creating treatment guidelines for this complex infection is explored. Consideration by healthcare providers of the medicolegal issues outlined in this review will support a more rational approach to the diagnosis and treatment of Lyme disease and related tick-borne illnesses.


The course of vocational functioning in patients with schizophrenia: Re-examining social drift.
Vocational functioning is markedly impaired in people with schizophrenia. In addition to low rates of employment, people with schizophrenia have been reported to be underachieved compared to other family members. Among the causes of this vocational impairment may be cognitive deficits and other skills deficits, as well as social factors impacting on opportunities for employment. In this study, we examined two separate samples of people with schizophrenia who differed in their educational and social backgrounds. We compared personal and maternal education in people with schizophrenia attending an outpatient rehabilitation facility (n = 57) or receiving outpatient services at a VA medical center (n = 39). The sample as a whole showed evidence of decline in vocational status from their best job to their most recent job. Patients attending a rehabilitation facility had completed less education than their mothers, while the VA patients completed more. Differences between personal and maternal education predicted the difference in status between best and latest jobs in the sample as a whole. VA patients were more likely to be living independently and performed better on a measure of functional capacity than the rehabilitation sample. These data implicate vocational decline in schizophrenia and also suggest that this decline may originate prior to the formal onset of the illness. At the same time, vocational outcomes appear to be related to social opportunities.


A pragmatic multi-centre randomised controlled trial of fluid loading and level of dependency in high-risk surgical patients undergoing major elective surgery: trial protocol.
Patients undergoing major elective or urgent surgery are at high risk of death or significant morbidity. Measures to reduce this morbidity and mortality include pre-operative optimisation and use of higher levels of dependency care after surgery. We propose a pragmatic multi-centre randomised controlled trial of level of dependency and pre-operative fluid therapy in high-risk surgical patients undergoing major elective surgery. A multi-centre randomised controlled trial with a 2 * 2 factorial design. The first randomisation is to pre-operative fluid therapy or standard regimen and the second randomisation is to routine intensive care versus high dependency care during the early post-operative period. We intend to recruit 204 patients undergoing major elective and urgent abdominal and thoraco-abdominal surgery who fulfil high-risk surgical criteria. The primary outcome for the comparison of level of care is cost-effectiveness at six months and for the comparison of fluid optimisation is the number of hospital days after surgery. We believe that the results of this study will be invaluable in determining the future care and clinical resource utilisation for this group of patients and thus will have a major impact on clinical practice. Trial registration number - ISRCTN32188676.


Bilateral Fascia Lata Flap: An Alternative for Massive Abdominal Wall Defect Repair.
The abdominal wall represents a unique structure of dermo-myotendinous conformation that is considered a surgical challenge. The musculocutaneous pedicled flap, using tensor fasciae latae muscle (TFL), is a technique of abdominal wall repair, and it is becoming a more frequent reconstructive procedure. It is a well-suited procedure because it provides both a semirigid fascia layer and adequate skin coverage. We present a case of a 61-year-old man with the diagnosis of squamous cell carcinoma of the bladder, clinical stage IV (T4bN1M1), complicated with an ileo-recal-urethrocutaneous fistula. We reconstructed a massive defect of the abdominal wall by rotating bilateral pedicled TFL flaps. The therapeutic plan comprised 2 surgical procedures. The first surgical intervention was intended to obtain and temporarily fix the flap, and to allow the delay phenomenon to occur. Three weeks later, we performed the abdominal wall reconstruction by repositioning the bilateral TFL flaps and placing a dual prolene with regenerated oxidized cellulose mesh. We performed a successful palliative procedure in a terminal oncologic patient. Combined with a massive oncologic procedure (done by the oncologic surgeon), we were able to solve the cutaneous fistula and provided a significant improvement in the quality of life. The patient was discharged with no procedure-related complications. He has remained healthy 18 months after surgery, and there has been no evidence of ventral hernia. Bilateral TFL flaps represent a viable alternative for primary or secondary abdominal wall reconstruction in selected cases. This reconstructive strategy should be considered when plastic and reconstructive surgeon faces large and complex abdominal wall defects, associated with significant lack of skin cover.


Tumor-Treating Fields: Nursing Implications for an Emerging Technology .
Tumor-treating fields (TTFields) are a new technology used for cancer treatment consisting of battery-powered, insulated electromagnetic transducers that are placed on the scalp. This wearable, adhesive device is a certified physician-prescribed therapy for patients with glioblastoma multiforme, a type of primary brain cancer. TTFields are being used concomitantly with temozolomide (Temodar®) in patients with newly diagnosed glioblastoma and as a monotherapy in patients with recurrent glioblastoma after radiation therapy and chemotherapy. Nursing professionals caring for patients using this emerging technology should be able to educate patients regarding proper use of TTFields and monitor for side effects. .


Kinetics of formation of exchanges and rejoining of breaks in human G0 and G2 lymphocytes after low-LET radiation.
To study the kinetics of chromosomal break rejoining and exchange formation in human G0 and G2 lymphocytes after low-LET irradiation using the premature chromosome condensation (PCC) technique. For the G0 experiments, isolated human lymphocytes were irradiated (1, 3 and 8 Gy) and immediate and delayed fusions (1, 3, 5, 8 and 24 h) were performed with CHO-cells, and 48-h cultures were set up simultaneously. Interphase and metaphase human chromosomes were hybridized with dual colour combination probes for chromosomes 2 and 4. For the G2 experiments, isolated lymphocytes from the same donor were cultured for 69 h, irradiated with 3 Gy 60Co gamma rays and fused with CHO cells immediately and after 1, 2 and 3 h. Chromatid breaks and exchanges were scored after Giemsa staining. In both G0 and G2 cells, exchanges were already observed at the first fusion and, at lower doses, their frequencies remained relatively stable over time. The exchange-type aberrations seen in G0 cells were mostly incomplete, especially in the first fusions, while the exchanges seen in metaphase were mostly complete. The frequency of complete exchanges increased by time during incubation, while the frequency of incomplete exchanges showed more variation and a general decline by time in the G0-PCC experiment. The number of breaks declined rapidly by time both in G0 and G2. The break rejoining rate was higher at 8 Gy than in the two lower doses in the G0-PCC. The overall aberration frequencies in G0 and G2 cells studied by PCC were higher than in the corresponding metaphase. The initial number of breaks in G2 was higher than in G0 and the break rejoining rate in the G2 was two-fold. The formation of complete exchanges in G0 is a delayed process. The incomplete exchanges appear unstable in G0. The decreasing proportion of incomplete exchanges and simultaneous increase in complete exchanges in G0-PCC indicates that formation of exchanges is not coordinated in time.


Catalytic properties of the A/H3N2 influenza neuraminidases: influence of antigenic variations.
Antigenic variation of the neuraminidase of A/H3N2 influenza viruses may be associated with modifications of the catalytic activity of this enzyme. We observed this phenomenon when studying two prototype strains: A/Hong Kong/1/68 (X31K) and A/Bangkok/2/79. For the neuraminidases of these strains, we determined their substrate specificity, initial velocity, optimum pH, optimum temperature, heat inactivation and Michaelis constants and their inactivation by chemical group-specific reagents. In order to examine the relationship between antigenic variation and enzyme activity of the influenza neuraminidases, three X31K monoclonal variants were selected using anti-neuraminidase monoclonal antibodies. Two of these (X31/NC92 and X31/NC56) were modified at a single neuraminidase epitope, and the third one (X31/NC92/NC56) at two epitopes. The neuraminidase activity of the monoclonal variants was analysed and compared to that of the prototype strains. Compared to A/Hong Kong/1/68, the A/Bangkok/2/79 strain neuraminidase was more susceptible to inactivation by physical (pH, temperature) and chemical agents [urea, dithiothreitol, 1-ethyl-3-(3-dimethylaminopropyl carbodiimide), iodoacetamide, acetic anhydride, 2,3-butanedione] and showed a twofold lower substrate affinity for N-acetylneuraminlactose. The neuraminidase activity of the monoclonal variants of X31K became more susceptible to inactivation by both physical and chemical agents than the original strain and exhibited various substrate affinities. Therefore, we conclude that the enzymic properties of the structurally conserved active sites of the neuraminidase molecule may be influenced by antigenic modifications that affect the variable areas of the neuraminidase and that the degree of this enzymic variation is related to the nature and number of the modified epitope(s). A local conformational change in the neuraminidase molecule reflected as antigenic variation could be involved in modification of enzyme activity.


Characteristics of patients requesting and receiving physician-assisted death.
Surveys have shown that physicians in the United States report both receiving and honoring requests for physician assistance with a hastened death. The characteristics of patients requesting and receiving physician aid in dying are important to the development of public policy. To determine patient characteristics associated with acts of physician-assisted suicide. Physicians among specialties involved in care of the seriously ill and responding to a national representative prevalence survey on physician-assisted suicide and euthanasia were asked to describe the demographic and illness characteristics of the most recent patient whose request for assisted dying they refused as well as the most recent request honored. Of 1902 respondents (63% of those surveyed), 379 described 415 instances of their most recent request refused and 80 instances of the most recent request honored. Patients requesting assistance were seriously ill, near death, and had a significant burden of pain and physical discomfort. Nearly half were described as depressed at the time of the request. The majority made the request themselves, along with family. In multivariate analysis, physicians were more likely to honor requests from patients making a specific request who were in severe pain (odds ratio, 2.4; 95% confidence interval, 1.01-5.7) or discomfort (odds ratio, 6.5; 95% confidence interval, 2.6-16.1), had a life expectancy of less than 1 month (odds ratio, 4.3; 95% confidence interval, 1.7-10.8), and were not believed to be depressed at the time of the request (odds ratio, 0.2; 95% confidence interval, 0.1-0.5). Persons requesting and receiving assistance in dying are seriously ill with little time to live and a high burden of physical suffering.


Controlling Surface Chemical Inhomogeneity of Ni2 P/MoNiP2 /MoP Heterostructure Electrocatalysts for Efficient Hydrogen Evolution Reaction.
Crystalline/amorphous phase engineering is demonstrated as a powerful strategy for electrochemical performance optimization. However, it is still a considerable challenge to prepare transition metal-based crystalline/amorphous heterostructures because of the low redox potential of transition metal ions. Herein, a facile H2 -assisted method is developed to prepare ternary Ni2 P/MoNiP2 /MoP crystalline/amorphous heterostructure nanowires on the conductive substrate. The characterization results show that the content of the MoNiP2 phase and the crystallinity of the MoP phase can be tuned by simply controlling the H2 concentration. The obtained electrocatalyst exhibits a superior alkaline hydrogen evolution reaction performance, delivering overpotentials of 20 and 76 mV to reach current densities of 10 and 100 mA cm-2 with a Tafel slope of 30.6 mV dec-1 , respectively. The catalysts also reveal excellent stability under a constant 100 h operation, higher than most previously reported electrocatalysts. These striking performances are ascribed to the optimized hydrogen binding energy and favorable hydrogen adsorption/desorption kinetics. This work not only exhibits the potential application of ternary Ni2 P/MoNiP2 /MoP crystalline/amorphous heterostructure nanowires catalysts for practical electrochemical water splitting, but also paves the way to prepare non-noble transition metal-based electrocatalysts with optimized crystalline/amorphous heterostructures.


Fatigue-Crack Detection and Monitoring through the Scattered-Wave Two-Dimensional Cross-Correlation Imaging Method Using Piezoelectric Transducers.
Piezoelectric transducers are convenient enablers for generating and receiving Lamb waves for damage detection. Fatigue cracks are one of the most common causes for the failure of metallic structures. Increasing emphasis on the integrity of critical structures creates an urgent need to monitor structures and to detect cracks at an early stage to prevent catastrophic failures. This paper presents a two-dimensional (2D) cross-correlation imaging technique that can not only detect a fatigue crack but can also precisely image the fatigue cracks in metallic structures. The imaging method was based on the cross-correlation algorithm that uses incident waves and the crack-scattered waves of all directions to generate the crack image. Fatigue testing for crack generation was then conducted in both an aluminum plate and a stainless-steel plate. Piezoelectric wafer transducer was used to actuate the interrogating Lamb wave. To obtain the scattered waves as well as the incident waves, a scanning laser Doppler vibrometer was adopted for acquiring time-space multidimensional wavefield, followed with frequency-wavenumber processing. The proof-of-concept study was conducted in an aluminum plate with a hairline fatigue crack. A frequency-wavenumber filtering method was used to obtain the incident wave and the scattered wave wavefields for the cross-correlation imaging. After this, the imaging method was applied to evaluate cracks on a stainless-steel plate generated during fatigue loading tests. The presented imaging method showed successful inspection and quantification results of the crack and its growth.


Adolescent bereavement: embodied responses, coping and perceptions of a body awareness support programme.
This study describes the implementation and evaluation of a new Body Awareness Programme (BAP) in bereavement support for adolescents. The BAP's aims were to provide information and insight into adolescents bodily reactions, to help them develop a deeper understanding of the reasons for bodily reactions and to introduce adolescents to healthy coping techniques. Three main bodily reactions can follow a traumatic event such as the death of a loved one. The arousal of physical responses causes restlessness, concentration problems and disturbed sleep while 'flashbacks' of unpleasant memories contribute to increased tension. Active avoidance manifests as increased activity and avoidance of talking or thinking about unpleasant memories. These reactions may interfere with an adolescent's development and inhibit a healthy grieving process. A qualitative, hermeneutic-phenomenological design. Data were collected using the BAP together with in-depth interviews with adolescents, focusing particularly on their experiences or recollections of their bodily reactions and coping. Seven adolescents participated, aged 13-18 years, who use our bereavement services. The adolescents in our study internalised their struggles, and beneath their facade of coping, they reported having painful bodies that were stiff and restless. They were also anxious, experiencing painful thoughts of the deceased. The adolescents found the BAP helpful because they gained awareness of the body-behaviour-feelings connections, experiencing the techniques as helpful and possibly useful in their everyday lives. The results of this evaluation of the BAP are positive and suggest that this approach is both necessary and valuable in a bereavement support programme for adolescents. Adolescents must recognise their own embodied reactions and understand their underlying causes before they can change their attitudes or seek appropriate help during bereavement. Health professionals should see beyond adolescents' facades and offer them support.


Patients' preferences for information in bariatric surgery.
The decision to undergo bariatric surgery is multifactorial and made both by patient and doctor. Information is of the utmost importance for this decision. To investigate the bariatric surgery patient's preferences regarding information provision in bariatric surgery. A teaching hospital, bariatric center of excellence in Amsterdam, the Netherlands. All patients who underwent a primary laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy between September 2013 and September 2014 were approached by mail to participate. A questionnaire was used to elicit patient preferences for the content and format of information. Sociodemographic characteristics, clinicopathologic factors, and psychologic factors were explored as predictors for specific preferences. Of the 356 eligible patients, 112 (31.5%) participated. The mean age was 49.2 (±10.7) years, and 91 (81.3%) patients were female. Patients deemed the opportunity to ask questions (96.4%) the most important feature of the consult, followed by a realistic view on expectations-for example, results of the procedure (95.5%) and information concerning the consequences of surgery for daily life (89.1%). Information about the risk of complications on the order of 10% was desired by 93% of patients; 48% desired information about lower risks (.1%). Only 25 patients (22.3%) desired detailed information concerning their weight loss after surgery. Bariatric patients wished for information about the consequences of surgery on daily life, whereas the importance of information concerning complications decreased when their incidence lessened.


Reproduction of Oligosarcus hepsetus (Cuvier, 1829) (Characiforms) in the Serra do Mar State Park, São Paulo, Brazil.
The purpose of this study was to characterize the reproduction of Oligosarcus hepsetus in the Grande river (Santa Virginia Unit - Serra do Mar State Park) based on the reproductive period, length of first gonadal maturation for both sexes, sexual proportion, oocyte development, type of spawn and fecundity. The Grande river was sampled monthly from January through December 2004. The numerical frequency of the stages of maturity and the volumetric method were utilized to determine the reproductive period and fecundity, respectively. The reproduction of Oligosarcus hepsetus was characterized by a long period, relatively low fecundity, precocious length of first gonadal maturation and parceled spawning.


Systematic review: the efficacy of treatments for irritable bowel syndrome--a European perspective.
Irritable bowel syndrome (IBS) is a common, chronic disorder, characterized by abdominal pain/discomfort, bloating and altered bowel habit. To conduct a systematic evidence-based review of pharmacological therapies currently used, or in clinical development, for the treatment of IBS in Europe. The safety and tolerability of these therapies are the subject of an accompanying review. A literature search was completed for randomized controlled studies which included adult patients with IBS and an active or placebo control, assessed IBS symptoms, and were published in English between January 1980 and June 2005. The level of evidence for efficacy was graded according to the quality of the trial design and the study outcome. There is some evidence for improvement of individual IBS symptoms with antidiarrhoeals (diarrhoea), antispasmodics (abdominal pain/discomfort), bulking agents (constipation), tricyclic antidepressants (abdominal pain/discomfort) and behavioural therapy. In contrast, there is strong evidence for the improvement of global IBS symptoms with two new serotonergic agents: the 5-HT4 selective agonist tegaserod (IBS with constipation) and the 5-HT3 antagonist alosetron (IBS with diarrhoea). Further data are required for the 5-HT3 antagonist, cilansetron, and the mixed 5-HT3 antagonist/5-HT4 agonist renzapride before their utility in IBS can be appraised. There is limited evidence for the efficacy, safety and tolerability of therapies currently available in Europe for the treatment of IBS. Overall, there is an absence of pharmacological agents licensed specifically for the treatment of IBS subtypes, and new agents are awaited in Europe that will allow changes in clinical practice to focus on and improve global IBS symptoms.


APC and PIK3CA Mutational Cooperativity Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colorectal Liver Metastases.
The aim of the study was to determine the prognostic impact of co-existence of APC and PIK3CA mutations in patients undergoing preoperative chemotherapy and resection for colorectal liver metastases (CLM). Co-occurring genetic events have been shown to drive carcinogenesis in multiple malignancies. We identified 396 patients with primary colorectal cancer and known somatic mutation status by next-generation sequencing who underwent hepatectomy for CLM (2005-2015). Survival after hepatectomy in patients with double mutation of APC and PIK3CA and others was analyzed. Predictors of pathologic response and survival were determined. The prognostic value of double mutation was evaluated with a separate cohort of 157 patients with CLM undergoing chemotherapy alone. Forty-five patients had double mutation of APC and PIK3CA; 351 did not. Recurrence-free survival (RFS) and overall survival (OS) after hepatectomy were worse in patients with double mutation (3-year RFS, 3.1% vs 20% [P < 0.001]; 3-year OS, 44% vs 84% [P < 0.001]). Independent predictors of major pathologic response were bevacizumab use (odds ratio [OR] 2.22; P = 0.001), tumor size <3 cm (OR 1.97; P = 0.004), wild-type RAS (OR 2.00; P = 0.003), and absence of double mutation (OR 2.91; P = 0.002). Independent predictors of worse OS were primary advanced T category (hazard ratio [HR] 2.12; P = 0.021), RAS mutation (HR 1.74; P = 0.015), and double mutation (HR 3.09; P < 0.001). In the different medical cohort, patients with double mutation had worse 3-year OS of 18%, compared with 35% without double mutation (P = 0.023). Double mutation of APC and PIK3CA predicts inferior response to preoperative chemotherapy and poor survival in patients with CLM.


Feelings of powerlessness in patients with diabetic foot ulcers.
The purpose of this study was to assess feelings of powerlessness in patients with diabetic foot ulcers. Chronic wounds affect the emotional state of patients, who may experience negative emotions including a sense of loss and powerlessness. The assessment of these feeling should contribute to the planning of interventions aimed at minimizing the impact of diabetic foot ulcers on the daily lives of these patients. Fifty patients ≥ 18 years of age with type 1 or type 2 diabetes and foot ulcers were selected from 2 outpatient wound-care clinics to participate in the study. Of these patients, 50% were 61-70 years old, 72% were women, 74% were smokers, 10% were alcoholics, 40% had a diabetic foot ulcer for 3-6 years, and 22% for 7-10 years. Wound odor and exudate were present in 82% of patients. Individuals who were unable to respond to a questionnaire due to physical or cognitive deficit were excluded. All participants responded to the Powerlessness Assessment Tool for adult patients (PAT), with scores ranging from 12-60, with higher scores corresponding to feelings of more intense powerlessness. Total PAT scores ranged from 31-40 for 5 (10%) patients, 51-60 for 28 (56%) patients and from 41-50 for 17 (34%) patients. All patients reported total and subscale PAT scores ≥ 34 (moderate to high scores), with a mean total score of 50.12. The maximum PAT score of 60 was reported on the "self-perception of decision-making capacity" domain. These results indicate that patients with diabetic foot ulcers had strong feelings of powerlessness.


[Ascorbic acid content in the blood serum and lymphoid organs in antigenic exposure].
Seven and 14 days following immunization with sheep red blood cells, the guinea-pigs incapable of synthesizing ascorbic acid showed its pronounced decrease in blood serum accompanied by elevation of ascorbate content in the thymus and spleen, central organs responsible for immunogenesis. Immunization of rats capable of synthesizing ascorbic acid did not lead to its changes in the blood serum, thymus or spleen.


Immune reconstitution during Pneumocystis lung infection: disruption of surfactant component expression and function by S-nitrosylation.
Pneumocystis pneumonia (PCP), the most common opportunistic pulmonary infection associated with HIV infection, is marked by impaired gas exchange and significant hypoxemia. Immune reconstitution disease (IRD) represents a syndrome of paradoxical respiratory failure in patients with active or recently treated PCP subjected to immune reconstitution. To model IRD, C57BL/6 mice were selectively depleted of CD4(+) T cells using mAb GK1.5. Following inoculation with Pneumocystis murina cysts, infection was allowed to progress for 2 wk, GK1.5 was withdrawn, and mice were followed for another 2 or 4 wk. Flow cytometry of spleen cells demonstrated recovery of CD4(+) cells to >65% of nondepleted controls. Lung tissue and bronchoalveolar lavage fluid harvested from IRD mice were analyzed in tandem with samples from CD4-depleted mice that manifested progressive PCP for 6 wks. Despite significantly decreased pathogen burdens, IRD mice had persistent parenchymal lung inflammation, increased bronchoalveolar lavage fluid cellularity, markedly impaired surfactant biophysical function, and decreased amounts of surfactant phospholipid and surfactant protein (SP)-B. Paradoxically, IRD mice also had substantial increases in the lung collectin SP-D, including significant amounts of an S-nitrosylated form. By native PAGE, formation of S-nitrosylated SP-D in vivo resulted in disruption of SP-D multimers. Bronchoalveolar lavage fluid from IRD mice selectively enhanced macrophage chemotaxis in vitro, an effect that was blocked by ascorbate treatment. We conclude that while PCP impairs pulmonary function and produces abnormalities in surfactant components and biophysics, these responses are exacerbated by IRD. This worsening of pulmonary inflammation, in response to persistent Pneumocystis Ags, is mediated by recruitment of effector cells modulated by S-nitrosylated SP-D.


The ultrastructure of patch-clamped membranes: a study using high voltage electron microscopy.
We have developed techniques for studying patch-clamped membranes inside glass pipettes using high voltage electron microscopy (HVEM). To preserve the patch structure with the least possible distortion, we rapidly froze and freeze dried the pipette tip. The pipette is transparent for more than 50 microns from the tip. HVEM images of patches confirm light microscopy observations that the patch is not a bare bilayer, but a membrane-covered bleb of cytoplasm that may include organelles and cytoskeleton. The membrane that spans the pipette is commonly tens of micrometers from the tip of the pipette and occasionally as far as 100 microns. The structure of patches taken from a single cell type is variable but there are consistent differences between patches made from different cell types. With suction applied to the pipette before seal formation, we have seen in the light microscope vesicles swept from the plasmalemma up the pipette. These vesicles are visible in electron micrographs, particularly those made from chick cardiac muscle. Colloidal gold labeling of the patch permitted identification of lectin-binding sites and acetylcholine receptors. In young cultures of Xenopus myocytes, the receptors were diffuse. In 1-wk-old cultures, the receptors formed densely packed arrays. The patch pipette can serve, not only as a recording device, but as a tool for sampling discrete regions of the cell surface. Because the pipette has a constant path length for axial rotation, it is a unique specimen holder for microtomography. We have made preliminary tomographic reconstructions of a patch from Xenopus oocyte.


Cancer and the bromodomains of BAF180.
Chromatin remodelling complexes alter the structure of chromatin and have central roles in all DNA-templated activities, including regulation of gene expression and DNA repair. Mutations in subunits of the PBAF (polybromo/Brg1-associated factor) or SWI/SNF-B remodelling complex, including BAF180, are frequently associated with cancer. There are six potential acetyl-lysine-binding BDs (bromodomains) in BAF180, which may function to target the PBAF complex to promoters or sites of DNA repair. In the present review, we discuss what is currently known about the BDs of BAF180 and their potential significance in cancer.


Whole genome sequencing and annotation of Scleroderma yunnanense, the only edible Scleroderma species.
Scleroderma yunnanense, an ectomycorrhizal fungus, is a popular edible mushroom within the Yunnan Province of Southwest China that holds great ecological and economic implications. However, despite its significance, there remains limited information about this species. Therefore, we sequenced S. yunnanense genome to identify the functional genes of S. yunnanense involved in secondary metabolite and carbohydrate production pathways. First, we present the 40.43 Mb high-quality reference genome for S. yunnanense, distributed across 35 contigs; moreover, the N50 contig size was found to reach 3.31 Mb and contained 8877 functional genes. Finally, genome annotation was conducted to compare the functional genes of S. yunnanense with protein sequences from different publicly available databases. Taken together, we identified 12 biosynthetic gene clusters across 10 contigs; among these were 13 key mevalonate (MVA) pathway enzymes, a key tyrosinase enzyme in the 3,4-dihydroxyphenylalanine (DOPA) pathway that is responsible for producing DOPA melanins, and 16 enzymes involved in uridine diphosphate glucose biosynthesis. Overall, this study presents the first genome assembly and annotation of S. yunnanense; ultimately, this information will be important in the elucidation of the biological activities and artificial domestication of this fungus.


[Anuran richness and composition in the Eastern region of Iberá Wetlands Provincial Nature Reserve, Corrientes, Argentina].
In recent decades, the concern for biodiversity conservation has increased in importance, especially due to the loss of highly biodiverse natural areas such as wetlands. Despite the high fauna diversity inhabiting the Iberá, the information about its composition, structure and dynamics is scarce, and amphibians are typical and conspicuous representatives of these Neotropical areas. To generate new information about this group, the amphibian composition from two villages (Paraje Galarza and Colonia Carlos Pellegrini), belonging to two different fitogeographic regions in the Eastern edge of the Iberá, were described and compared. Samples were taken, from a respective area of 100km2 that included five landscape units (wetlands, streams and swamps, grasslands, forest and a permanent/temporal pond) each, during the four seasons between January 2007 and March 2008. The techniques applied were the Complete Species Inventories (Unrestricted direct search) and Visual Encounter Surveys (VES). A total of 28 species were found, and represented the 70% of the previously registered taxa for the whole wetland. Scinax similis and Rhinella azarai were recorded for the first time in the Iberá Wetlands. No significant differences were found in the anuran specific richness between the surveyed villages, since the 95% of confidence intervals for the species accumulation curves were superimposed. In both villages, the wetlands, streams and swamps, and the permanent pond landscapes, showed the higher species richness when compared to the others. According to the Chao2, Jacknifel and ICE estimators, the inventory completeness of species, oscillated among 88% and 98% for the whole area. The dendrogram analysis based on the Jaccard similarity index, showed that wetlands, streams and swamps were grouped and well separated from grasslands. To guarantee the conservation of the high anuran richness that inhabit the Iberá Wetland, we recommend that representative areas of each landscape must be protected.


Sodium orthovanadate diuresis in rats.
The renal actions of differing doses of sodium orthovanadate were studied in conscious and anesthetized female Wistar rats. In conscious rats, sodium orthovanadate was given by i.v. or i.p. injections or by mouth. The most pronounced renal effects were seen after a 5 mg/kg i.p. injection of sodium orthovanadate. Urine flow and sodium excretion increased approximately 400% and urine osmolality fell from 1108 to 549 mOsmol/kg . H2O. Higher doses of sodium orthovanadate (20, 30 and 50 mg/kg) injected i.p. did not cause diuresis and were toxic. In anesthetized rats undergoing a 0.9% NaCl diuresis, i.v. infusion of sodium orthovanadate at a dose of 5 mg/kg/hr significantly increased urine flow and the excretion of sodium, calcium, phosphorus, sulfur, magnesium and chlorine, whereas glomerular filtration rate was unaltered. In anesthetized rats undergoing a water diuresis, i.v. infusion of sodium orthovanadate (5 mg/kg/hr) markedly reduced free-water clearance, indicating that this compound inhibits tubular reabsorption of sodium and chloride in diluting nephron segments. Blood and renal tissue levels of vanadium, measured using emission spectrographic analysis, in rats infused with sodium orthovanadate were 4 times higher than the concentration of sodium orthovanadate (1--10 microM) needed to inhibit 50% of the Na-K-adenosine triphosphate activity of rat renal homogenates in vitro. These data suggest that sodium orthovanadate produces diuresis at least in part by inhibiting Na-K-adenosine triphosphatase and solute transport in the distal nephron, likely the ascending limb of the loop of Henle.


Survey of the management of patients with bronchiectasis: a pilot investigation in Asian populations.
Although international guidelines for bronchiectasis management have been published in Western countries, there is a lack of data about their application in Asian populations including patients with different phenotypes. We aimed to investigate the current status of bronchiectasis management in Asian populations. A nationwide questionnaire survey was performed of Asian respiratory specialists from South Korea, Japan, Taiwan, Singapore, Vietnam, and Sri Lanka. Participants were invited by e-mail to answer a questionnaire comprising 25 questions based on international guidelines for the management of bronchiectasis. A total of 221 physicians participated in the survey. About half of them were Korean (50.2%), with the next most common nationalities being Japanese (23.1%), Taiwanese (13.6%), and Singaporean (7.7%). Only 18 (8.1%) responders had local guidelines for bronchiectasis. While 85 (38.5%) responders checked sputum acid-fast bacillus smear/culture about 1 to 3 times per year, only a small proportion of responders routinely performed a serum immunoglobulin test (36/221, 16.3%) or evaluated for allergic bronchopulmonary aspergillosis (41/221, 18.6%). Less than half (43.4%) of responders performed eradication treatment in patients with drug-sensitive Pseudomonas aeruginosa infection, mainly due to the limited availability of inhaled antibiotics (34.8%). In addition, 58.6% of responders considered physiotherapy such as airway clearance and pulmonary rehabilitation. Discrepancies might exist between guideline recommendations and practice for bronchiectasis management in Asian populations, partly due to the limited availability of treatment in each country. The development of local guidelines that consider the phenotypes and situation will help to standardize and improve the management of bronchiectasis.


Developmental stage influences chromosome segregation patterns and arrangement in the extremely polyploid, giant bacterium Epulopiscium sp. type B.
Few studies have described chromosomal dynamics in bacterial cells with more than two complete chromosome copies or described changes with respect to development in polyploid cells. We examined the arrangement of chromosomal loci in the very large, highly polyploid, uncultivated intestinal symbiont Epulopiscium sp. type B using fluorescent in situ hybridization. We found that in new offspring, chromosome replication origins (oriCs) are arranged in a three-dimensional array throughout the cytoplasm. As development progresses, most oriCs become peripherally located. Siblings within a mother cell have similar numbers of oriCs. When chromosome orientation was assessed in situ by labeling two chromosomal regions, no specific pattern was detected. The Epulopiscium genome codes for many of the conserved positional guide proteins used for chromosome segregation in bacteria. Based on this study, we present a model that conserved chromosomal maintenance proteins, combined with entropic demixing, provide the forces necessary for distributing oriCs. Without the positional regulation afforded by radial confinement, chromosomes are more randomly oriented in Epulopiscium than in most small rod-shaped cells. Furthermore, we suggest that the random orientation of individual chromosomes in large polyploid cells would not hamper reproductive success as it would in smaller cells with more limited genomic resources.


NAD+ attenuates experimental autoimmune encephalomyelitis through induction of CD11b+ gr-1+ myeloid-derived suppressor cells.
To investigate the effects of nicotinamide adenine dinucleotide (NAD+) on the pathogenesis of the animal model for multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE). EAE model was induced by myelin oligodendrocyte protein (MOG 35-55). Clinical scores of EAE were measured in mice with or without NAD+ treatment. Hematoxylin and Eosin (HE) and Luxol Fast Blue (LFB) staining were performed to assess inflammation and demyelination, respectively. Expressions of target proteins were measured by Western blot. The numbers of myeloid-derived suppressor cells (MDSCs) were measured by immunofluorescent staining and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to measure the expressions of inflammatory cytokine in serum. NAD+ treatment could decrease inflammatory cells and demyelination foci, attenuate the clinical scores of EAE and slightly delay disease onset. Western blot showed that NAD+ treatment up-regulated the expression of phosphorylated-STAT6 (p-STAT6) and SIRT1. Besides, NAD+ treatment up-regulated the expression of p-IκB and down-regulated the expression of p-NF-κB. In addition, NAD+ treatment could increase the numbers of CD11b+ gr-1+ MDSCs and the expression of Arginase-1. Moreover, NAD+ treatment up-regulated the expressions of IL-13 and down-regulated the expression of IFN-γ and IL-17. The present study demonstrated that NAD+ treatment may induce the CD11b+ gr-1+ MDSCs to attenuate EAE via activating the phosphorylation of STAT6 expression. Therefore, NAD+ should be considered as a potential novel therapeutic strategy for MS.


Unusually large upward shifts in cold-adapted, montane mammals as temperature warms.
The largest and tallest mountain range in the contiguous United States, the Southern Rocky Mountains, has warmed considerably in the past several decades due to anthropogenic climate change. Herein we examine how 47 mammal elevational ranges (27 rodent and 4 shrew species) have changed from their historical distributions (1886-1979) to their contemporary distributions (post 2005) along 2,400-m elevational gradients in the Front Range and San Juan Mountains of Colorado. Historical elevational ranges were based on more than 4,580 georeferenced museum specimen and publication records. Contemporary elevational ranges were based on 7,444 records from systematic sampling efforts and museum specimen records. We constructed Bayesian models to estimate the probability a species was present, but undetected, due to undersampling at each 50-m elevational bin for each time period and mountain range. These models leveraged individual-level detection probabilities, the number and patchiness of detections across 50-m bands of elevation, and a decaying likelihood of presence from last known detections. We compared 95% likelihood elevational ranges between historical and contemporary time periods to detect directional change. Responses were variable as 26 mammal ranges changed upward, 6 did not change, 11 changed downward, and 4 were extirpated locally. The average range shift was 131 m upward, while exclusively montane species shifted upward more often (75%) and displayed larger average range shifts (346 m). The best predictors of upper limit and total directional change were species with higher maximum latitude in their geographic range, montane affiliation, and the study mountain was at the southern edge of their geographic range. Thus, mammals in the Southern Rocky Mountains serve as harbingers of more changes to come, particularly for montane, cold-adapted species in the southern portion of their ranges.


Steel factor induces serine phosphorylation of Stat3 in human growth factor-dependent myeloid cell lines.
Steel factor (SLF) acts synergistically with various hematopoietic growth factors that use the Jak-Stat pathways in vivo and in vitro, although the contribution by SLF to this pathway is unknown. We show here that SLF induces time- and dose-dependent phosphorylation of Stat3 in the human growth factor-dependent cell lines MO7e and TF-1. This phosphorylation occurs exclusively on serine residues. Simultaneous stimulation with SLF plus other cytokines that induce tyrosine phosphorylation of Stat3, such as interleukin-9 (IL-9) in MO7e cells or IL-6 in TF-1 cells, resulted in tyrosine phosphorylation and enhanced serine phosphorylation of Stat3. Serine phosphorylation alone did not promote nuclear translocation or DNA binding activity to the sis-inducible element of Stat3. However, costimulation with SLF plus IL-9 in MO7e cells resulted in the nuclear translocation of serine-hyperphosphorylated Stat3. Serine phosphorylation of Stat3 was also observed by the stimulation of cells with granulocyte-macrophage colony-stimulating factor and IL-3, which do not induce tyrosine phosphorylation of Stat3. These results suggest that SLF might modulate the Jak-Stat3 pathway by serine phosphorylation and that the Jak-Stat pathway may be differentially regulated by the combinational stimulation of two or more cytokines.


Link removal for the control of stochastically evolving epidemics over networks: a comparison of approaches.
For many communicable diseases, knowledge of the underlying contact network through which the disease spreads is essential to determining appropriate control measures. When behavior change is the primary intervention for disease prevention, it is important to understand how to best modify network connectivity using the limited resources available to control disease spread. We describe and compare four algorithms for selecting a limited number of links to remove from a network: two "preventive" approaches (edge centrality, R0 minimization), where the decision of which links to remove is made prior to any disease outbreak and depends only on the network structure; and two "reactive" approaches (S-I edge centrality, optimal quarantining), where information about the initial disease states of the nodes is incorporated into the decision of which links to remove. We evaluate the performance of these algorithms in minimizing the total number of infections that occur over the course of an acute outbreak of disease. We consider different network structures, including both static and dynamic Erdös-Rényi random networks with varying levels of connectivity, a real-world network of residential hotels connected through injection drug use, and a network exhibiting community structure. We show that reactive approaches outperform preventive approaches in averting infections. Among reactive approaches, removing links in order of S-I edge centrality is favored when the link removal budget is small, while optimal quarantining performs best when the link removal budget is sufficiently large. The budget threshold above which optimal quarantining outperforms the S-I edge centrality algorithm is a function of both network structure (higher for unstructured Erdös-Rényi random networks compared to networks with community structure or the real-world network) and disease infectiousness (lower for highly infectious diseases). We conduct a value-of-information analysis of knowing which nodes are initially infected by comparing the performance improvement achieved by reactive over preventive strategies. We find that such information is most valuable for moderate budget levels, with increasing value as disease spread becomes more likely (due to either increased connectedness of the network or increased infectiousness of the disease).


Oncologic Safety of Close Margins in Patients With Low- to Intermediate-Grade Major Salivary Gland Carcinoma.
Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence. To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins. The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023. Main outcomes were risk factors for local recurrence. A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group. In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.


Iron phosphorus trichalcogenide ultrathin nanosheets: enhanced photoelectrochemical activity under visible-light irradiation.
Exploiting novel visible-light sensitive materials for the photoelectrochemical (PEC) technique is deeply meaningful for energy conversion and analytic detection. Owing to the tunable bandgap structure and strong absorption of visible light, the rising-star two-dimensional (2D) metal phosphorus trichalcogenide (MPX3) nanomaterials are expected to be promising photochemical sensitizers toward PEC biosensors. Moreover, guided by DFT calculations, the FePS3 nanosheets possessed a narrower bandgap than the bulk form, thereby enabling high availability of visible-light absorption for the FePS3 nanosheets. In this work, 2D FePS3 nanosheets were successfully synthesized by a facile salt-templated method. By tuning the proportion of the salt template, the thickness of the FePS3 nanosheets could be manipulated. As a result, the FePS3 nanosheets exhibited an obviously enhanced photoelectrochemical behavior with visible light and sensitive detection towards glucose. Being the first experimental report regarding the MPS3 nanosheets toward PEC activity, our finding can be an essential stepping stone in the pursuit of the further exploration of other 2D materials for the PEC technology.


13-year-old girl with recurrent, episodic, persistent vomiting: out of the pot and into the fire.
Cyclic vomiting syndrome (CVS) is a well-established cause of recurrent vomiting in the pediatric population. Severe vomiting with chronic cannabis use, known as cannabinoid hyperemesis syndrome, has recently been more widely recognized as an etiology of persistent episodic vomiting. In turn, patients presenting with frequent episodes of CVS are now increasingly being screened for cannabinoid use. Because patients with persistent vomiting are also frequently prescribed a proton pump inhibitor (PPI) for their gastrointestinal symptoms, it is important to be aware of the potential for a PPI to cause an interaction that can lead to false-positive urine cannabinoid screening. We describe a case of a false-positive urine cannabinoid screen in a patient with CVS who received a dose of intravenous pantoprazole. The primary reference regarding drug screen interference from PPIs can be found in the pantoprazole package insert that refers to pre-Food and Drug Administration approval data. Although multiple sources on the Internet report the possibility of positive cannabinoid screens from pantoprazole, there are no known published reports of the phenomenon in the medical literature.


Molecular dynamics simulations of TC4 titanium alloy with mechanical property calculations after various heat treatments.
This work explores the relationship between the microstructure and mechanical properties of TC4 titanium alloy using molecular dynamics simulations. The stress-strain curves are calculated from tensile and shear tests. For the TC4 model with initial HCP structure, tensile strength along the [0001] crystal direction is larger than along the [01-10] and [2-1-10] directions. The tensile strength also increases with larger strain rate. During tensile deformation, phase transformation from HCP to BCC structure is observed, which is caused by dislocations along the close-packed direction [-1-120]. A band of amorphous structure is formed in the middle of shearing, which causes the abrupt drop in shear stress. By setting a temperature control, the heating, holding and cooling stages of heat treatment are simulated to mimic the impact of annealing, solid solution and aging. The results confirm a general trend of improved tensile and shear strength with annealing and additional solid solution and aging. With higher solid solution temperature, the amount of α phase also increases, giving rise to higher tensile and shear strength simultaneously. At the same 811 K for aging, shear strength also increases with solid solution temperature. But at the same 1227 K for the solid solution, shear strength decreases with aging temperature, in agreement with experimental results.


Antitoxin-in-membrane and antitoxin-in-well assays for detection of toxigenic Corynebacterium diphtheriae.
The Elek culture plate precipitin test is routinely used for the detection of exotoxin from toxigenic strains of Corynebacterium diphtheriae. Recently, the World Health Organization standardized this test to ensure accuracy, reliability, and reproducibility. In this study, we further modified the standard Elek test by using the antitoxin-in-membrane (AIM) and antitoxin-in-well (AIW) approaches. In the AIM tests, each strain was stabbed and streaked backwards and away from a point approximately 7 mm from the edge of a sterile cellulose acetate-cellulose nitrate filter membrane disk (pore size, 0.45 microm; diameter, 25 mm) containing 25 IU of diphtheria antitoxin. For AIW tests, a central well (diameter, 5 mm) containing 9 microl of antitoxin (4.5 IU) was surrounded by eight equidistant stab-streaks of each strain placed 10 mm from the well. In both methods, precipitin bands of identity typically were noted after 24- and 48-h incubations at 37 degrees C. Both toxigenic and weak toxigenic strains gave clear and reproducible results. Compared with the standard Elek test, the AIM and AIW tests each use 50% less medium and 75 and 87% less antitoxin, respectively. AIM has the potential to test up to 14 isolates and AIW has the potential to test up to 24 isolates on the same plate. Furthermore, clearer positives were noted with weak toxigenic strains. In a blinded test of 209 verified C. diphtheriae isolates, a 99.5% agreement with the standard Elek test was obtained overall. Both modifications conserve reagents and medium, permit the simultaneous testing of a larger number of strains, and may be particularly suitable for reference laboratories or hospitals involved in diphtheria epidemic settings.


Autonomy in participation in cerebral palsy from childhood to adulthood.
To determine the long-term development of autonomy in participation of individuals with cerebral palsy (CP) without intellectual disability. Individuals with CP (n=189, 117 males, 72 females; mean age [SD] 21y 11mo [4y 11mo], range 12-34y); were assessed cross-sectionally (46%) or up to four times (54%), between the ages of 12 and 34 years. Autonomy in participation was classified using phase 3 of the Rotterdam Transition Profile. A logistic generalized estimating equation regression model was used to analyse autonomy in six domains (independent variables: age, Gross Motor Function Classification System [GMFCS] level, and interaction between age and GMFCS level). Proportions of autonomy were compared to references using binomial tests (p<0.05). In most domains, over 90% of participants (n=189, 400 observations, 80% in GMFCS levels I and II) reached autonomy in participation in their late twenties, except for intimate/sexual relationships. Those in GMFCS levels III to V compared to those in GMFCS levels I and II had less favourable development of autonomy in the transportation, intimate relationships, employment, and housing domains, and more favourable development in the finances domain. Compared to references, fewer individuals with CP were autonomous in participation. This knowledge of autonomy may guide the expectations of young people with CP and their caregivers. Furthermore, rehabilitation professionals should address autonomy development in intimate relationships, employment, and housing, especially in individuals with lower gross motor function. Individuals with cerebral palsy without intellectual disability achieved autonomy in most participation domains. Regarding intimate relationships, they continued to have less experience compared to age-matched references. Development of autonomy was less favourable for individuals in Gross Motor Function Classification System levels III to V.


Critical review of the validity of patient satisfaction questionnaires pertaining to oral health care.
Review the validation process reported for oral healthcare satisfaction scales that intended to measure general oral health care that is not restricted to specific subspecialties or interventions. After preliminary searches, PUBMED and EMBASE were searched using a broad search strategy, followed by a snowball strategy using the references of the publications included from database searches. Title and abstract were screened for assessing inclusion, followed by a full-text screening of these publications. English language publications on multi-item questionnaires that report on a scale measuring patient satisfaction for oral health care were included. Publications were excluded when they did not report on any psychometric validation, or the scales were addressing specific treatments or subspecialities in oral health care. Fourteen instruments were identified from as many publications that report on their initial validation, while five more publications reported on further testing of the validity of these instruments. Number of items (range: 8-42) and dimension reported (range: 2-13) were often dissimilar between the assessed measurement instruments. There was also a lack of methodologies to incorporate patient's subjective perspective. Along with a limited reporting of psychometric properties of instruments, cross-cultural adaptations were limited to translation processes. The extent of validity and reliability of the included instruments was largely unassessed, and appropriate instruments for populations outside of those belonging to general adult populations were not present.


Stress-reinjection 201Tl scintigraphy without redistribution imaging: prediction of the effect of coronary artery bypass grafting on regional myocardial 201Tl uptake.
Reinjection of thallium-201 (201Tl) improves the detection of myocardial ischaemia in approximately 50% of irreversible defects present on 3 h redistribution images. Additional reinjection studies, however, may limit the capacity of the nuclear laboratory and they are not patient-friendly Previous studies have suggested that only severe persistent defects with less than 50% of maximal 201Tl uptake are irreversibly damaged, with little chance of recovery following coronary artery bypass grafting (CABG). We examined the ability of a modified stress-reinjection protocol without redistribution imaging to predict subsequent improvement in myocardial perfusion post-CABG. Thirty-seven patients underwent quantitative planar stress/3 h reinjection 201Tl scintigraphy before and after uncomplicated CABG. After stress, segments were classified as normal (> or = 75% maximum 201Tl uptake), moderate defect (50-75%) or severe defect (< 50%). After reinjection, they were classified as completely normalizing (> or = 75%), partially improving moderate defect (increase > or = 10% but < 75%), partially improving severe defect (increase > or = 10% but < 50%), persistent moderate defect (< 10% increase) or persistent severe defect (< 50% initial uptake with < 10% increase). Scintigraphic classification was compared with left ventricular wall motion and post-operative classification. Of 336 initial stress defects, 264 (79%) were moderate defects and 72 (21%) were severe defects. After reinjection, 146 (55%) moderate defects normalized, 25 (9%) improved partially and 93 (35%) persisted. Nineteen (26%) severe defects normalized, 33 (46%) improved to become moderate defects, 7 (10%) improved only slightly and 13 (18%) persisted. Post-CABG, 201T1 uptake was normal in 123 of 146 (84%) completely normalizing moderate defects, 15 of 25 (60%) partially improving moderate defects, 53 of 93 (57%) persistent moderate defects, 11 of 19 (58%) completely normalizing severe defects and 13 of 33 (39%) partially improving moderate defects. None of the partially improving severe defects or persistent severe defects normalized. The sensitivity and specificity of detection of viability with pre-CABG stress-injection scintigraphy were 66% and 72% respectively, with pre-CABG wall motion 80% and 40% respectively, whereas in combination they resulted in a sensitivity and specificity of 94% and 70% respectively. We conclude that stress/3 h reinjection without redistribution imaging is a clinically feasible method for predicting myocardial 201T1 uptake post-CABG. The severity of defects and the pattern of change of uptake after stress-injection are related to the likelihood of normal 201T1 uptake post-CABG. Severe defects after reinjection are very unlikely to recover.


Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs.
Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models; however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show an increased number of GFAP positive cells, likely astrocytes, increased spontaneous network activity, and depolarizing GABAergic transmission. Cortical brain organoid models show an increased number of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.


The relationship between PTSD arousal symptoms and depression among mothers exposed to the World Trade Center attacks.
Posttraumatic stress disorder (PTSD) is associated with greater risk of developing comorbid depression. However, little is known about the relationship between specific PTSD symptom clusters and comorbid depression. Approximately 4 years after the World Trade Center (WTC) attacks, we examined the association between PTSD symptom clusters and depression severity among 64 mothers directly exposed to the WTC attacks. Severity scores were computed for each PTSD symptom cluster by summing symptom frequency. Partial correlations with depression severity were calculated separately for PTSD symptom clusters, controlling for demographic variables, time elapsed since the attacks, WTC attack exposure, meeting PTSD criterion A, and the other cluster scores. Higher arousal symptom cluster scores were significantly correlated with persistent depression, but the re-experiencing and avoidance symptom clusters were not. Subsequent analyses isolating shared symptoms of PTSD and depression from those unique to PTSD suggest a complex interrelationship among symptoms of arousal, numbing, and depression.