Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection.
Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function and protective stress signaling. However, the importance of membrane cholesterol content to cardiovascular function and myocardial responses to ischemia-reperfusion (I/R) and cardioprotective stimuli are unclear. We assessed the effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD) and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3) on cardiac function, I/R tolerance, and opioid receptor (OR)-mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02-1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25-min ischemia/45-min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically [sustained ligand-activated preconditioning (SLP)] were assessed. MβCD concentration dependently reduced normoxic contractile function and postischemic outcomes in association with graded (10-30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust and only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced, whereas Cav-3 OE improved, myocardial I/R tolerance. Protection via SLP remained equally effective in Cav-3 KO mice and was additive with innate protection arising with Cav-3 OE. These data reveal the membrane cholesterol dependence of normoxic myocardial and coronary function, I/R tolerance, and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3, whereas cardiac I/R tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression.


The impact of cultural issues on home care personnel and patients.
The United States faces increasing cultural diversity in its aging populations. This diversity provides opportunities for home care agencies to expand services as well as to improve patient care. By looking at the demographics, the benefits of comprehensive diversity programs become obvious--for both the agencies themselves and for the clients they serve.


[Mycoplasma meningoencephalitis and encephalomyelitis in children].
The authors report of some results of clinico-morphological studies in generalized mycoplasmic infections in 7 babies, who died from meningoencephalitis and encephalomyelitis. Morphological studies of the CNS demonstrated not only structural tissue changes, but permitted to detect the agent-mycoplasma. A clinical diagnosis of mycoplasmic lesions of the nervous system is of certain difficulty due to the polymorphism of neurological signs. The clinical picture of the nervous system affection consisted of disorders of cortical functions in combination with the pathology of the subcortical structures, disorders in the brain stem and the spinal cord. The initial symptom of the nervous system affection in 5 cases was a convulsive syndrome, in 2--bulbar disorders. The authors give some data testifying to a possibility of an intrauterine lesion of the CNS.


Transplant and ganglioside GM1 mediated neuronal recovery in rats with brain lesions.
Transplants of fetal brain tissue or injections of ganglioside GM1, given to rats with unilateral, left medial frontal cortex lesions, altered the concentrations of neuronal and glial marker proteins in cortex both adjacent and contralateral to the lesion. The markers were: the neural cell adhesion molecule (NCAM) and D3-protein, both present in neuronal and synaptic membranes; synaptophysin, present in synaptic vesicles; glial fibrillary acidic protein (GFAP) enriched in reactive astrocytes, and the astrocytic glutamine synthetase. After 21 days the concentrations of NCAM, D3 and synaptophysin in brain tissue adjacent to the lesions were decreased by 39, 32 and 42%, respectively, indicating neuronal damage. In the injured rats the GFAP concentration was increased 77%, indicating activation of astrocytes. However, astroglial proliferation was not altered as indicated by the nearly unchanged glutamine synthetase concentrations. The levels of the neuronal markers NCAM, D3 and synaptophysin showed significantly less decline in injured rats treated 7 days after the lesions with transplants or with daily injections of 30 mg/kg GM1. The decrease respectively constituted 23 (NCAM), 31 (D3) and 41% (synaptophysin) in rats with transplants and 23 (NCAM), 16 (D3) and 28% (synaptophysin) in rats treated with GM1. In another group of rats the efficacy of transplants was studied 34 days after lesions. NCAM and D3 in tissue adjacent to the lesions were decreased by 50 and 29%, respectively. In rats which received transplants the decrease was only 27 and 16%, respectively. Moreover, as measured by GFAP concentration, activation of astrocytes was less in rats with transplants (93% increased) compared with rats with lesions only (163%). In contralateral frontal cortex, the effects of lesions were similar but less pronounced. In this brain area also the treatments significantly counteracted the loss of neuronal and glial markers. Previous studies have demonstrated that synaptic remodelling is reflected by the ratios of NCAM to marker proteins for mature synapses. Twenty-one days after the initial injury to the brain the ratios of NCAM to D3 and synaptophysin were significantly increased in frontal cortex ipsilateral to the injury in rats with transplants (26 and 33%, respectively). In contrast, compared with values for injured rats, the calculated ratios were not changed, whereas all neuronal marker proteins were significantly increased in rats treated with GM1. The results suggest that transplants mediate neuronal recovery by inducing dendritic sprouting followed by synaptic remodelling whereas gangliosides mediate recovery by counteracting neuronal degeneration.


Acquiring Knowledge about the Use of a Newly Developed Electronic Fetal Heart Rate Monitor: A Qualitative Study Among Birth Attendants in Tanzania.
In an effort to reduce newborn mortality, a newly developed strap-on electronic fetal heart rate monitor was introduced at several health facilities in Tanzania in 2015. Training sessions were organized to teach staff how to use the device in clinical settings. This study explores skilled birth attendants' perceptions and experiences acquiring and transferring knowledge about the use of the monitor, also called Moyo. Knowledge about this learning process is crucial to further improve training programs and ensure correct, long-term use. Five Focus group discussions (FGDs) were carried out with doctors and nurse-midwives, who were using the monitor in the labor ward at two health facilities in Tanzania. The FGDs were analyzed using qualitative content analysis. The study revealed that the participants experienced the training about the device as useful but inadequate. Due to high turnover, a frequently mentioned challenge was that many of the birth attendants who were responsible for training others, were no longer working in the labor ward. Many participants expressed a need for refresher trainings, more practical exercises and more theory on labor management. The study highlights the need for frequent trainings sessions over time with focus on increasing overall knowledge in labor management to ensure correct use of the monitor over time.


VCAM1/VLA4 interaction mediates Ly6Clow monocyte recruitment to the brain in a TNFR signaling dependent manner during fungal infection.
Monocytes exist in two major populations, termed Ly6Chi and Ly6Clow monocytes. Compared to Ly6Chi monocytes, less is known about Ly6Clow monocyte recruitment and mechanisms involved in the recruitment of this subset. Furthermore, the role of Ly6Clow monocytes during infections is largely unknown. Here, using intravital microscopy, we demonstrate that Ly6Clow monocytes are predominantly recruited to the brain vasculature following intravenous infection with Cryptococcus neoformans, a fungal pathogen causing meningoencephalitis. The recruitment depends primarily on the interaction of VCAM1 expressed on the brain endothelium with VLA4 expressed on Ly6Clow monocytes. Furthermore, TNFR signaling is essential for the recruitment through enhancing VLA4 expression on Ly6Clow monocytes. Interestingly, the recruited Ly6Clow monocytes internalized C. neoformans and carried the organism while crawling on and adhering to the luminal wall of brain vasculature and migrating to the brain parenchyma. Our study reveals a substantial recruitment of Ly6Clow monocytes to the brain and highlights important properties of this subset during infection.


Prostaglandins as possible mediators of fever genesis in man.
Prostaglandin concentrations of cerebrospinal fluid (CSF) of 38 febrile patients (from infants up to adults) were compared with those of 19 afebrile adult control persons. CSF samples were extracted and the prostaglandins groups of the extract separated by column chromatography. Concentrations of prostaglandins of the E and F series were estimated by radioimmunoassay. In CSF of all feverish patients with meningitis, pneumonia, or pyelonephritis about 2-fold higher concentrations of prostaglandin E (PGE) were found that in those of the afebrile control persons. In contrast, concentrations of prostaglandin F (PGF) in adults and infants remained largely unchanged during fever; Solely, in 4 of the 8 babies examined, concentrations of PGF were also increased besides those of PGE. Repeated estimations of prostaglandin concentrations in CSF from the same patients showed, that concentrations of PGE, which had been elevated during fever, normalized after defervescence. The height of fever and the concentrations of PGE in CSF tended to correlate in a dose related manner. In correspondence with the results of animal experiments prostaglandins of the E series seem to act as mediators of fever during infectious diseases also in man.


Acute Ischemic Stroke Treatment, Part 2: Treatment "Roles of Capillary Index Score, Revascularization and Time".
Due to recent results from clinical intra-arterial treatment for acute ischemic stroke (IAT-AIS) trials such as the interventional management of stroke III, IAT-AIS and the merit of revascularization have been contested. Even though intra-arterial treatment (IAT) has been shown to improve revascularization rates, a corresponding increase in good outcomes has only recently been noted. Even though a significant percentage of patients achieve good revascularization in a timely manner, results do not translate into good clinical outcomes (GCOs). Based on a review of the literature, the authors suspect limited GCOs following timely and successful revascularization are due to poor patient selection that led to futile and possibly even harmful revascularization. The capillary index score (CIS) is a simple angiography-based scale that can potentially be used to improve patient selection to prevent revascularization being performed on patients who are unlikely to benefit from treatment. The CIS characterizes presence of capillary blush related to collateral flow as a marker of residual viable tissue, with absence of blush indicating the tissue is no longer viable due to ischemia. By only selecting patients with a favorable CIS for IAT, the rate of GCOs should consistently approach 80-90%. Current methods of patient selection are primarily dependent on time from ischemia. Time from cerebral ischemia to irreversible tissue damage seems to vary from patient to patient; so focusing on viable tissue based on the CIS rather than relying on an artificial time window seems to be a more appropriate approach to patient selection.


Prothrombinase is protected from inactivation by tissue factor pathway inhibitor: competition between prothrombin and inhibitor.
The inhibition of prothrombinase by tissue factor pathway inhibitor (TFPI) has been studied in the presence and absence of prothrombin. The rate constant of association of prothrombinase with full-length TFPI was 2.1x10(7) M-1.s-1 and 0.05x10(7) M-1.s-1 for the reaction with C-terminus truncated TFPI (TFPI1-161). The rate constant of dissociation was 0.65x10(-4) s-1 in both cases. The rate constant of inhibition of prothrombinase by TFPI1-161 was similar to that of solution-phase factor Xa. In contrast, phospholipids and factor Va enhanced the association rate of the reaction between factor Xa and full-length TFPI by approx. 20-fold. Although TFPI, and in particular the full-length variant of the molecule, is a potent inhibitor of prothrombinase (overall inhibition constant of 3 pM), we also found that prothrombin competed very effectively with TFPI for the active site of factor Xa in the prothrombinase complex. A 50% reduction of the rate constant of inhibition was measured in the presence of 4 nM prothrombin, i.e. 0.2% of the plasma concentration of prothrombin. The physiological significance of TFPI as an inhibitor of prothrombinase activity is thus questionable.


Granulomas at initial diagnosis of Crohn's disease signal a poor outcome.
Over time, most patients with Crohn's disease (CD) develop strictures or fistulas, resulting in hospitalisations and surgery. Timely therapy with immunomodulators and biologicals may alter this natural history, but carries a significant risk of side-effects. To identify factors to predict poor-outcome severe CD at diagnosis, and thus patients who would benefit most from early, aggressive medical therapies. CD patients (n=101) with uncomplicated non-stricturing, non-penetrating disease at diagnosis, and with follow-up >5 years, were retrospectively analysed using a predefined definition of severe CD (SCD) over the disease course. Clinical, demographic, laboratory and histological factors at diagnosis associated with SCD and poor outcome were evaluated by univariate and multivariate analysis. Overall 33.7% of the cohort developed SCD, and on multivariate Cox proportional hazard analysis the presence of granulomas on endoscopic biopsy at diagnosis was independently associated with development of SCD (hazard ratio (HR) 2.3; 95% confidence interval (CI) 1.15 - 4.64; p=0.02). Simple perianal disease was also associated with this outcome (HR 2.49; 95% CI 1.14 - 5.41; p=0.02). The presence of these variables had a specificity of 99% and a positive predictive value of 88%. At diagnosis, factors predictive of SCD in our referral centre were endoscopic biopsy granulomas and perianal disease. Patients with these risk factors should be considered for early, aggressive medical therapy, as benefit will probably outweigh risk. To our knowledge, this is the first study to show that endoscopic biopsy granulomas in patients with uncomplicated (non-stricturing, non-penetrating) CD predict the subsequent development of SCD.


Ataxia with isolated vitamin E deficiency in four siblings.
We describe 4 siblings of a consanguineous Bedouin family with Friedreich ataxia phenotype in whom low serum vitamin E levels without other indicators of fat malabsorption were detected. Although age of onset and some of the clinical features were alike in all 4 patients, the electrophysiological parameters were markedly abnormal in 2, but normal in the other 2. Erythrocytes revealed both membranous and intracellular evidence of oxidative damage. The mutations described in other families with ataxia with isolated vitamin E deficiency were not detectable, nor was an abnormal single-stranded conformation polymorphism pattern apparent in the three exons at the 3' region of the gene. Vitamin E administration in pharmacological doses improved the neurological condition in 2 patients and also corrected some of the patients' erythrocyte cell abnormalities. The finding of vitamin E deficiency in other cases of Friedreich ataxia phenotype may allow treatment at an early stage of the disease, when large dose Vitamin E therapy may reverse the neurological lesions.


P300 brain computer interface: current challenges and emerging trends.
A brain-computer interface (BCI) enables communication without movement based on brain signals measured with electroencephalography (EEG). BCIs usually rely on one of three types of signals: the P300 and other components of the event-related potential (ERP), steady state visual evoked potential (SSVEP), or event related desynchronization (ERD). Although P300 BCIs were introduced over twenty years ago, the past few years have seen a strong increase in P300 BCI research. This closed-loop BCI approach relies on the P300 and other components of the ERP, based on an oddball paradigm presented to the subject. In this paper, we overview the current status of P300 BCI technology, and then discuss new directions: paradigms for eliciting P300s; signal processing methods; applications; and hybrid BCIs. We conclude that P300 BCIs are quite promising, as several emerging directions have not yet been fully explored and could lead to improvements in bit rate, reliability, usability, and flexibility.


Cross-Sectional Analysis of Neurosurgical Residency Websites During the Virtual Interview Cycle.
The loss of in-person interviews during the COVID-19 pandemic warrants an investigation into what information is provided to applicants through neurosurgery residency program websites (NRPWs). This study examines NRPWs across the United States and Canada to determine what details are provided to applicants through their respective websites. Accreditation Council for Graduate Medical Education accredited neurologic surgery residency programs were identified through the American Association of Neurological Surgeons (AANS) website. NRPWs were searched for 48 criteria, including program overview, application requirements, and curriculum information. Small programs were defined as 1-2 residents per class, while large programs were classified as those with 3-4 residents per year. Content differences were analyzed between the top 20 and remaining programs per the Doximity Residency Navigator Rankings. The most prevalent information among 122 NRPWs was the neurosurgery residency overview (95%), names of faculty members (95%), and names of current residents (94%). Top-20 NRPWs were more likely to include post PGY-7 fellowships (90% vs. 61% P = 0.0108), operating room virtual reality experience (35% vs. 12% P = 0.0160), and faculty research (90% vs. 62% P = 0.0182) than the remainder of the programs. This study investigates NRPW content after the COVID-19 pandemic. We report broad variability in content provided by various neurosurgical training programs. Higher-ranked neurosurgery programs are more likely to include fellowship information, operating room virtual reality experience, and faculty research than lower-ranked programs.


Long-lived immunity to canine core vaccine antigens in UK dogs as assessed by an in-practice test kit.
To determine the utility of an in-practice test kit to detect protective serum antibody against canine distemper virus, canine adenovirus and canine parvovirus type 2 in a sample of the UK dog population. Serum samples from 486 dogs, last vaccinated between less than 1 month and 124 months previously, were tested with the VacciCheck™ test kit for protective antibodies against distemper, adenovirus and parvovirus type 2. A high proportion of the dogs tested (93·6%) had protective antibody against all three of the core vaccine antigens: 95·7% of the dogs were seropositive against canine distemper virus, 97·3% against canine adenovirus and 98·5% against canine parvovirus type 2. The small number of dogs that were seronegative for one or more of the antigens (n = 31) may have had waning of previous serum antibody or may have been rare genetic non-responders to that specific antigen. UK veterinarians can be reassured that triennial revaccination of adult dogs with core vaccines provides long-lived protective immunity. In-practice serological test kits are a valuable tool for informing decision-making about canine core revaccination.


CNN3 regulates trophoblast invasion and is upregulated by hypoxia in BeWo cells.
CNN3 is an ubiquitously expressed F-actin binding protein, shown to regulate trophoblast fusion and hence seems to play a role in the placentation process. In this study we demonstrate that CNN3 levels are upregulated under low oxygen conditions in the trophoblast cell line BeWo. Since hypoxia is discussed to be a pro-migratory stimulus for placental cells, we examined if CNN3 is involved in trophoblast invasion. Indeed, when performing a matrigel invasion assay we were able to show that CNN3 promotes BeWo cell invasion. Moreover, CNN3 activates the MAPKs ERK1/2 and p38 in trophoblast cells and interestingly, both kinases are involved in BeWo invasion. However, when we repeated the experiments under hypoxic conditions, CNN3 did neither promote cell invasion nor MAPK activation. These results indicate that CNN3 promotes invasive processes by the stimulation of ERK1/2 and/or p38 under normoxic conditions in BeWo cells, but seems to have different functions at low oxygen levels. We further speculated that CNN3 expression might be altered in human placentas derived from pregnancies complicated by IUGR and preeclampsia, since these placental disorders have been described to go along with impaired trophoblast invasion. Our studies show that, at least in our set of placenta samples, CNN3 expression is neither deregulated in IUGR nor in preeclampsia. In summary, we identified CNN3 as a new pro-invasive protein in trophoblast cells that is induced under low oxygen conditions.


Using a novel exercise programme for patients with muscular dystrophy. Part II: a quantitative study.
To quantitatively evaluate the effects of qigong in patients with muscular dystrophy. Thirty-six patients with muscular dystrophy were assigned to either a treatment or comparison group, by means of a stratified randomization procedure. The intervention period lasted for 3 months. Balance and respiratory function were assessed by means of Berg's Balance Scale and an electronic spirometer, respectively. Health-related quality of life was tested by means of a Swedish version of the Medical Outcome Study Short Form Health Survey (SF-36), coping levels by means of a Swedish version of the Ways of Coping Questionnaire and depression levels by means of a modified version of the Montgomery åsberg Depression Rating Scale. Perceived general health was maintained in the treatment group whereas this was not the case in the comparison group (p=0.05). Positive reappraisal coping decreased in the treatment group but not in the comparison group (p=0.05). There was a tendency to maintain balance function during training and performance of qigong whilst there was a decline when not training. Qigong may be useful as an adjunct therapy regimen in patients with muscular dystrophy in that it can bring about a decreased rate of decline in general health. The change in coping pattern in this study needs more investigation. More research is also needed in order to more fully investigate the effects of qigong on such physical variables as balance function.


Studies on schistosomiasis in Saudi Arabia.
During studies on schistosomiasis in Saudi Arabia, urine and stool samples from inhabitants of various areas (mostly rural) were examined, and 97 aquatic habitats in 46 localities were searched for snails. The results indicate the occurrence of both urinary and intestinal schistosomiasis in most parts of the country, with a patchy distribution and varying infection rates. The snail intermediate host of Schistosoma mansoni was found to be Biomphalaria arabica. For S. haematobium three species of snails, namely, Bulinus truncatus and B. beccarii in the west and B. reticulatus wrighti in the northeast, may transmit the infection; the susceptibility of the two former species has been confirmed in the laboratory. The limitation in the size of snail habitats--which consist of wells, small canals, cisterns, small swamps, interrupted streams, and ponds--creates a special type of transmission which can be defined as "oasis transmission," making control of the disease both simple and practical.


Schizophrenia and nicotinic receptors.
Patients with schizophrenia often cannot respond to important features of their environment and filter out irrelevant stimuli. This dysfunction could be related to an underlying defect in inhibition--i.e., the brain's ability to alter its sensitivity to repeated stimuli. One of the neuronal mechanisms responsible for such inhibitory gating involves the activation of cholinergic nicotinic receptors in the hippocampus. These receptors are diminished in many specimens of hippocampal brain tissue obtained postmortem from schizophrenic patients. In living schizophrenic patients, stimulation of cholinergic receptors by nicotine transiently restores inhibitory gating of evoked responses to sensory stimuli. Many people with schizophrenia are heavy smokers, but the properties of the nicotinic receptor favor only short-term activation, which may explain why cigarette smoking is only a transient symptomatic remedy. This paper reviews the clinical phenomenology of inhibitory gating deficits in people with schizophrenia, the neurobiology of such gating mechanisms, and the evidence that some individuals with the disorder may have a heritable deficit in the nicotinic cholinergic receptors involved in this neurobiological function. Inhibitory gating deficits are only partly normalized by neuroleptic drugs and are thus a target for new therapeutic strategies for schizophrenia.


Delayed Intervention With Pyridoxamine Improves Metabolic Function and Prevents Adipose Tissue Inflammation and Insulin Resistance in High-Fat Diet-Induced Obese Mice.
Obesity is associated with an increased risk for the development of type 2 diabetes and vascular complications. Advanced glycation end products are increased in adipose tissue and have been associated with insulin resistance, vascular dysfunction, and inflammation of adipose tissue. Here, we report that delayed intervention with pyridoxamine (PM), a vitamin B6 analog that has been identified as an antiglycating agent, protected against high-fat diet (HFD)-induced body weight gain, hyperglycemia, and hypercholesterolemia, compared with mice that were not treated. In both HFD-induced and db/db obese mice, impaired glucose metabolism and insulin resistance were prevented by PM supplementation. PM inhibited the expansion of adipose tissue and adipocyte hypertrophy in mice. In addition, adipogenesis of murine 3T3-L1 and human Simpson-Golabi-Behmel Syndrome preadipocytes was dose- and time-dependently reduced by PM, as demonstrated by Oil Red O staining and reduced expression of adipogenic differentiation genes. No ectopic fat deposition was found in the liver of HFD mice. The high expression of proinflammatory genes in visceral adipose tissue of the HFD group was significantly attenuated by PM. Treatment with PM partially prevented HFD-induced mild vascular dysfunction. Altogether, these findings highlight the potential of PM to serve as an intervention strategy in obesity.


Computation of bessel functions in light scattering studies.
Computations of light scattering require finding Bessel functions of a series of orders. These are found most easily by recurrence, but excessive rounding errors may accumulate. Satisfactory procedures for cylinder and sphere functions are described. If argument z is real, find Y(n)(z) by recurrence to high orders. From two high orders of Y(n)(z) estimate J(n)(z). Use backward recurrence to maximum J(n)(z). Correct by forward recurrence to maximum. If z is complex, estimate high orders of J(n)(z) without Y(n)(z) and use backward recurrence.


Efficacy of aquatic exercise in chronic musculoskeletal disorders: a systematic review and meta-analysis of randomized controlled trials.
Aquatic exercise (AE) is becoming ever more popular as a physical therapy, while it is unclear what precise improvements it will produce and how effective it will be in comparison with other non-surgical therapies. The study aimed to assess whether AE positively impacts chronic musculoskeletal disorder patients in terms of pain, physical function, and quality of life. PRISMA guidelines were followed, and our study protocol was published online at PROSPERO under registration number CRD42023417411. We searched PubMed, Embase, Web of Science, and Cochrane library databases for English-language articles published before April 11, 2023, including studies from all relevant randomized controlled trials (RCTs). After screening, we ultimately included 32 RCTs with a total of 2,200 participants. We also performed subgroup analyses for all included studies. This meta-analysis calculated standardized mean difference (SMD) with 95% confidence interval (CI), and the variance was estimated using a random-effects model. The quality of the included studies was assessed by using the Cochrane collaborative "risk of bias" assessment tool (version 2.0). Thus ensuring that the literature included is of high quality. This meta-analysis included 32 trials with 2,200 participants; these patients were all between the ages of 38-80. The study showed that compared to the no exercise (NE) group, patients in the AE group experienced a remarkable reduction in pain (SMD: -0.64, P < 0.001), a significant increase in physical function (SMD: 0.62, P < 0.001), and a statistically significant improvement in quality of life (SMD: -0.64, P < 0.001). When compared to land-based exercise (LE), AE significantly relieves patients' pain (SMD: -0.35, P = 0.03). This is the first systematic review and meta-analysis to study whether AE could improve chronic musculoskeletal disorders. The evidence suggests that AE benefits pain, physical function, and quality of life in adults with chronic musculoskeletal conditions compared to NE. Furthermore, when compared to LE, AE continues to provide a better improvement in patient pain. More long-term clinical trials are needed to confirm AE's positive effects and improvement mechanisms and the more existential advantages compared to LE.


A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats.
Ayahuasca is a plant concoction containing N,N-dimethyltryptamine (DMT) and certain β-carboline alkaloids from South America. Previous research in naturalistic settings has suggested that ingestion of ayahuasca can improve mental health and well-being; however, these studies were not placebo controlled and did not control for the possibility of expectation bias. This naturalistic observational study was designed to assess whether mental health changes were produced by ayahuasca or by set and setting. Assessments were made pre- and post-ayahuasca sessions in 30 experienced participants of ayahuasca retreats hosted in the Netherlands, Spain, and Germany. Participants consumed ayahuasca (N = 14) or placebo (N = 16). Analysis revealed a main effect of time on symptoms of depression, anxiety, and stress. Compared to baseline, symptoms reduced in both groups after the ceremony, independent of treatment. There was a main treatment × time interaction on implicit emotional empathy, indicating that ayahuasca increased emotional empathy to negative stimuli. The current findings suggest that improvements in mental health of participants of ayahuasca ceremonies can be driven by non-pharmacological factors that constitute a placebo response but also by pharmacological factors that are related to the use of ayahuasca. These findings stress the importance of placebo-controlled designs in psychedelic research and the need to further explore the contribution of non-pharmacological factors to the psychedelic experience.


[Course of superficial carcinoma of bladder (Ta-T1). Apropos of 171 cases].
171 patients with superficial bladder carcinoma (Ta-T1) treatment by endoscopic surgery only, were followed during the period from 1.1.1976 to 31.12.1980. The effect of previous tumors in case history, multiplicity, cellular differentiation and tumor size on the frequency of recurrence and tendency to tumor progression was investigated. It was established that the size of tumor most influences the frequency of recurrence, followed by tumors in case history, multiplicity and epithelial anaplasia. A tendency to muscular invasion during recurrence depends mainly on the tumors size and its grade of cellular anaplasia.


Robust reconstruction and analysis of outbreak data: influenza A(H1N1)v transmission in a school-based population.
The rapid spread of the new influenza virus A(H1N1)v in young age groups in 2009 has been partly attributed to a high transmission intensity in schools. However, detailed characterization of the spread of influenza in school populations has been difficult to obtain, simply because it is very hard to identify who infected whom in a large outbreak. Data collected in large outbreak investigations typically miss many transmission events, and some reported transmission events will be incorrect. Here the authors present robust likelihood-based methods that can be used to analyze outbreak data while explicitly accounting for both missing data and erroneous data. They apply this method to a school-based outbreak of pandemic influenza A(H1N1)v that occurred in London, United Kingdom, in April 2009. The authors show that the generation interval in this school-based population was 2.20 days and that the reproduction number declined coincident with school closure, from 1.33 secondary cases per primary case to 0.43 secondary cases per primary case. These results provide quantitative evidence for the change in influenza transmission that is to be expected from school closure.


Evaluation of a commercially available second-generation immunoglobulin G enzyme immunoassay for detection of Helicobacter pylori infection.
We evaluated a commercially available second-generation anti-H. pylori immunoglobulin G enzyme immunoassay (EIA) (Cobas Core Anti-Helicobacter pylori EIA; Roche S. A., Basel, Switzerland) for serodiagnosis of H. pylori infection. The results of the assay were assessed in relation to the results of bacterial culture, urease testing, and histological Giemsa stain of gastric biopsy specimens from 1,134 patients with a variety of symptoms relating to the upper gastrointestinal tract. H. pylori was detected in biopsy specimens from 660 (58.2%) patients: 6 had a normal mucosa, 123 had chronic gastritis only, and 531 were found to have chronic active gastritis by histology; endoscopy showed duodenal and gastric ulcers in 137 and 64 patients of the last two groups, respectively. The test was evaluated with different age and ethnic groups. The prevalence, sensitivity, specificity, and positive and negative predictive values were, respectively, (i) for Belgian patients between 18 and 40 years old, 34, 93, 95, 91, and 96%; (ii) for Belgian patients more than 40 years old, 53, 96, 91, 93, and 95%; and (iii) the Mediterranean patients more than 17 years old, 87, 94, 70, 95, and 64%. All sera showing discordant immunoassay results compared with the results of histology and culture of biopsy specimens, as well as those with borderline immunoassay results, were tested further by immunoblotting. Among the EIA results considered false negative, we demonstrated an absence of seroconversion in 14 of 19 patients tested by immunoblotting. Among the EIA results considered false positive, immunoblotting showed the presence of specific antibodies in 28 of 37 patients tested. Among the borderline results obtained in the first assay with 22 patients' sera, a second assay showed positive results in 10 patients (8 were positive by immunoblotting) and negative reactions in 10 patients (9 were negative by immunoblotting), whereas 2 remained borderline. These data indicate that sera showing borderline immunoassay results must be tested again. In conclusion, this commercially available second-generation EIA, which is easy and quick to perform, was found highly reliable for the serodiagnosis of H. pylori infection.


In vivo treatment sensitivity testing with positron emission tomography/computed tomography after one cycle of chemotherapy for Hodgkin lymphoma.
Negative [(18)F]fluorodeoxyglucose (FDG) -positron emission tomography (PET)/computed tomography (CT) after two cycles of chemotherapy indicates a favorable prognosis in Hodgkin lymphoma (HL). We hypothesized that the negative predictive value would be even higher in patients responding rapidly enough to be PET negative after one cycle. This prospective study aimed to assess the prognostic value of PET after one cycle of chemotherapy in HL and to assess the dynamics of FDG uptake after one cycle (PET1) and after two cycles (PET2). All PET scans were read by two blinded, independent reviewers in different countries, according to the Deauville five-point scale. The main end point was progression-free survival (PFS) after 2 years. A total of 126 patients were included, and all had PET1; 89 patients had both PET1 and PET2. The prognostic value of PET1 was statistically significant with respect to both PFS and overall survival. Two-year PFS for PET1-negative and PET1-positive patients was 94.1% and 40.8%, respectively. Among those with both PET1 and PET2, 2-year PFS was 98.3% and 38.5% for PET1-negative and PET1-positive patients and 90.2% and 23.1% for PET2-negative and PET2-positive patients, respectively. No PET1-negative patient was PET2 positive. PET after one cycle of chemotherapy is highly prognostic in HL. No other prognostic tool identifies a group of patients with HL with a more favorable outcome than those patients with a negative PET1. In the absence of precise pretherapeutic predictive markers, PET1 is the best method for response-adapted strategies designed to select patients for less intensive treatment.


Epigenetic remodeling during arsenical-induced malignant transformation.
Humans are exposed to arsenicals through many routes with the most common being in drinking water. Exposure to arsenic has been associated with an increase in the incidence of cancer of the skin, lung and bladder. Although the relationship between exposure and carcinogenesis is well documented, the mechanisms by which arsenic participates in tumorigenesis are not fully elucidated. We evaluated the potential epigenetic component of arsenical action by assessing the histone acetylation state of 13 000 human gene promoters in a cell line model of arsenical-mediated malignant transformation. We show changes in histone H3 acetylation occur during arsenical-induced malignant transformation that are linked to the expression state of the associated gene. DNA hypermethylation was detected in hypoacetylated promoters in the select cases analyzed. These epigenetic changes occurred frequently in the same promoters whether the selection was performed with arsenite [As(III)] or with monomethylarsonous acid, suggesting that these promoters were targeted in a non-random fashion, and probably occur in regions important in arsenical-induced malignant transformation. Taken together, these data suggest that arsenicals may participate in tumorigenesis by altering the epigenetic terrain of select genes.


Temporal gene expression variation associated with eyespot size plasticity in Bicyclus anynana.
Seasonal polyphenism demonstrates an organism's ability to respond to predictable environmental variation with alternative phenotypes, each presumably better suited to its respective environment. However, the molecular mechanisms linking environmental variation to alternative phenotypes via shifts in development remain relatively unknown. Here we investigate temporal gene expression variation in the seasonally polyphenic butterfly Bicyclus anynana. This species shows drastic changes in eyespot size depending on the temperature experienced during larval development. The wet season form (larvae reared over 24°C) has large ventral wing eyespots while the dry season form (larvae reared under 19°C) has much smaller eyespots. We compared the expression of three proteins, Notch, Engrailed, and Distal-less, in the future eyespot centers of the two forms to determine if eyespot size variation is associated with heterochronic shifts in the onset of their expression. For two of these proteins, Notch and Engrailed, expression in eyespot centers occurred earlier in dry season than in wet season larvae, while Distal-less showed no temporal difference between the two forms. These results suggest that differences between dry and wet season adult wings could be due to a delay in the onset of expression of these eyespot-associated genes. Early in eyespot development, Notch and Engrailed may be functioning as repressors rather than activators of the eyespot gene network. Alternatively, temporal variation in the onset of early expressed genes between forms may have no functional consequences to eyespot size regulation and may indicate the presence of an 'hourglass' model of development in butterfly eyespots.


Barley transcriptome analyses upon interaction with different aphid species identify thionins contributing to resistance.
Aphids are phloem-feeding insects that cause yield loss on a wide range of crops, including cereals such as barley. Whilst most aphid species are limited to one or few host species, some are able to reproduce on many plants belonging to different families. Interestingly, aphid probing behaviour can be observed on both host and non-host species, indicating that interactions take place at the molecular level that may impact host range. Here, we aimed to gain insight into the interaction of barley with aphid species differing in their ability to infest this crop by analysing transcriptional responses. Firstly, we determined colonization efficiency, settlement and probing behaviour for the aphid species Rhopalosiphum padi, Myzus persicae and Myzus cerasi, which defined host, poor-host and non-host interactions, respectively. Analyses of barley transcriptional responses revealed gene sets differentially regulated upon the different barley-aphid interactions and showed that the poor-host interaction with M. persicae resulted in the strongest regulation of genes. Interestingly, we identified several thionin genes strongly up-regulated upon interaction with M. persicae, and to a lesser extent upon R. padi interaction. Ectopic expression of two of these genes in Nicotiana benthamiana reduced host susceptibility to M. persicae, indicating that thionins contribute to defences against aphids.


Using a simple diary for management of nausea and vomiting during chemotherapy.
To help clinical staff make effective adjustments to patients' antiemetic therapy, the authors gave patients a nausea and vomiting diary to record their experiences. Use of the diary strengthened patients' sense of security, as well as trust between staff and patients, in addition to increasing the staff's sensitivity to cultural differences in their approach to cancer and chemotherapy. Most patients responded favorably to the opportunity to express their fears and anxieties in diary format.


Using Electronic Health Records and Clinical Decision Support to Provide Return-to-Work Guidance for Primary Care Practitioners for Patients With Low Back Pain.
The aim of this study was to describe the process by which a group of subject matter experts in the area of return to work developed a resource tool to provide clinical decision support (CDS) for primary care clinicians. A common musculoskeletal disorder, low back pain (LBP), was selected, pertinent literature reviewed, and specific recommendations for action in the clinical setting developed. Primary care practitioners (PCPs) are routinely expected to create work activity prescriptions. The knowledge base for a CDS tool that could be embedded in electronic health records has been developed. Improved clinical support should help prevent and manage work limitations associated with LBP not caused by work. The proposed decision support should reduce administrative burden and stimulate PCPs to explore the role of occupation and its demands on patients.


Acceptance of the extracare program by Beta interferon-treated patients with multiple sclerosis: results of the explore study.
To gain full benefit from disease-modifying therapies such as interferon β-1b, patients with multiple sclerosis (MS) need to adhere to treatment in the long term. Treatment adherence requires high patient satisfaction with treatment and care. Our aim was to evaluate the satisfaction of patients with MS receiving interferon β-1b Extavia with the patient care program Extracare. Efficacy and safety of treatment were evaluated as secondary objectives. In this prospective, noninterventional 1-year study, data on the satisfaction of 174 patients with MS with Extracare were obtained by questionnaires. Disability and symptom severity as well as patients' reported activity limitations, quality of life, and fatigue were recorded. We observed high levels of patients' satisfaction with MS nurses, telephonic care, and information provided by Extracare (values ≤ 1.53 on a Likert scale ranging from 1 [very good] to 6 [insufficient]). Patient reported quality of life (Patient Reported Indices for MS QoL) improved from 11.82 ± 11.36 at baseline to 9.74 ± 10.94 at the end of the study (p = .02), whereas clinical parameters of disease progression remained unchanged. Rate of adverse events was as expected. This study provides the basis for further improvements of care programs to increase treatment adherence of patients with MS.


Persistence and compliance with pazopanib in patients with advanced renal cell carcinoma within a U.S. administrative claims database.
Pazopanib is an oral tyrosine kinase inhibitor with demonstrated efficacy and tolerability in patients with advanced renal cell carcinoma (RCC). To examine pazopanib persistence and compliance (adherence) and other drug utilization patterns in both treatment-naïve (first-line) patients and those previously treated with RCC therapy in the real-world setting. Key factors affecting persistence and compliance were also explored. This was a retrospective claims analysis using the Truven Health MarketScan Databases to cover claims activity from October 2007 through March 2012. Patients with advanced RCC aged ≥ 18 years who had received pazopanib with 180 days of follow-up were included. Bivariate comparisons of results from first-line and previously treated patients with RCC were conducted. Pazopanib persistence was measured using (a) estimated level of persistence with therapy (ELPT; i.e., the percentage of patients remaining on therapy at 30, 60, and 90 days [patients were censored at 180 days]); (b) time to discontinuation (i.e., duration of therapy); and (c) proportion of days covered (PDC; i.e., the ratio of [total days drug available minus days' supply of last prescription] to [last prescription date minus first prescription date]). Compliance was measured by medication possession ratio (MPR; i.e., the ratio of [total days' supply minus days' supply of last prescription] to [last prescription date minus first prescription date]). Other drug utilization measures included days' supply, time to initiation, time to switching, and dose-related measures. Random forest models were used to explore key factors of pazopanib persistence and compliance. A total of 143 patients met all inclusion criteria; 43.3% were treated with pazopanib first line (first-line cohort), and 56.6% had ≥ 1 prior lines of therapy (previously treated cohort). The mean (± standard deviation [SD]) age of patients was 62.9 (± 10.3) years, and 71.3% of them were males. Continuous pazopanib therapy for up to 90 days was observed in greater than 50% of patients in both cohorts. In the first-line cohort, ELPT at 30, 60, and 90 days was 98.39%, 70.97%, and 56.45%, respectively; the mean (± SD) number of days to discontinuation was 112.2 (± 62.8); the mean (± SD) PDC was 84.7% (± 16.7%); and the mean (± SD) MPR was 85.2% (± 16.9%). Similar results were observed in the previously treated population: ELPT at 30, 60, and 90 days was 98.77%, 75.31%, and 58.02%, respectively; the mean (± SD) number of days to discontinuation was 118.7 (± 61.4); the mean (± SD) PDC was 87.8% (± 13.5%); and the mean (± SD) MPR was 90.1% (± 13.9%). Differences between the 2 cohorts were not statistically significant. More than 90% of patients in both cohorts had at least a 30-day supply of therapy (91.9% of first-line versus 90.2% of previously treated; P = 0.153). The mean (± SD) time from metastatic diagnosis to start of pazopanib therapy was 104.7 (± 199.3) days in the first-line cohort and 360.9 (± 187.0) days in previously treated patients (P = 0.001). Forty-six patients switched to another therapy: 17 patients in the first-line cohort and 29 patients in the previously treated cohort; the mean (± SD) time to switching therapy from each cohort was 94.7 (± 41.4) days and 87.8 (± 49.6) days (P = 0.146), respectively. Statistically significant differences were observed for the starting and ending doses between the 2 cohorts. The average daily dosage of pazopanib was greater than 700 mg in both cohorts (P = 0.055), with a maximum dose of 800 mg. Random forest models demonstrated that younger age and higher comorbidity predicted both higher persistence and compliance. In this observational study, greater than 50% of patients with advanced RCC were on pazopanib for almost 4 months, with the majority of both cohorts achieving high persistence and high compliance. Additionally, younger age and higher comorbidity index were the strongest predictors of both greater persistence and compliance. Further studies with larger cohorts and longer follow-up are needed to validate these findings.


HVGH: Unsupervised Segmentation for High-Dimensional Time Series Using Deep Neural Compression and Statistical Generative Model.
Humans perceive continuous high-dimensional information by dividing it into meaningful segments, such as words and units of motion. We believe that such unsupervised segmentation is also important for robots to learn topics such as language and motion. To this end, we previously proposed a hierarchical Dirichlet process-Gaussian process-hidden semi-Markov model (HDP-GP-HSMM). However, an important drawback of this model is that it cannot divide high-dimensional time-series data. Furthermore, low-dimensional features must be extracted in advance. Segmentation largely depends on the design of features, and it is difficult to design effective features, especially in the case of high-dimensional data. To overcome this problem, this study proposes a hierarchical Dirichlet process-variational autoencoder-Gaussian process-hidden semi-Markov model (HVGH). The parameters of the proposed HVGH are estimated through a mutual learning loop of the variational autoencoder and our previously proposed HDP-GP-HSMM. Hence, HVGH can extract features from high-dimensional time-series data while simultaneously dividing it into segments in an unsupervised manner. In an experiment, we used various motion-capture data to demonstrate that our proposed model estimates the correct number of classes and more accurate segments than baseline methods. Moreover, we show that the proposed method can learn latent space suitable for segmentation.


Screening asymptomatic subjects for subclinical atherosclerosis: can we, does it matter, and should we?
Unheralded vaso-occlusive cardiovascular events (myocardial infarction, sudden death, and stroke) are common manifestations of atherothrombotic vascular disease, and accurate identification of individuals at risk of such events is highly desirable. Risk factor assessment and management have been the cornerstones of preventive strategies but are constrained by less than desirable accuracy and less than optimal compliance, respectively. In selected populations, noninvasive imaging using carotid ultrasound and/or coronary calcium score can incrementally refine risk assessment and may allow for improved adherence and better matching of preventive interventions to the magnitude of risk. Further refinements in the future may also be possible with novel biomarkers and measures of plaque phenotype.


Proteus: a random forest classifier to predict disorder-to-order transitioning binding regions in intrinsically disordered proteins.
The focus of the computational structural biology community has taken a dramatic shift over the past one-and-a-half decades from the classical protein structure prediction problem to the possible understanding of intrinsically disordered proteins (IDP) or proteins containing regions of disorder (IDPR). The current interest lies in the unraveling of a disorder-to-order transitioning code embedded in the amino acid sequences of IDPs/IDPRs. Disordered proteins are characterized by an enormous amount of structural plasticity which makes them promiscuous in binding to different partners, multi-functional in cellular activity and atypical in folding energy landscapes resembling partially folded molten globules. Also, their involvement in several deadly human diseases (e.g. cancer, cardiovascular and neurodegenerative diseases) makes them attractive drug targets, and important for a biochemical understanding of the disease(s). The study of the structural ensemble of IDPs is rather difficult, in particular for transient interactions. When bound to a structured partner, an IDPR adapts an ordered conformation in the complex. The residues that undergo this disorder-to-order transition are called protean residues, generally found in short contiguous stretches and the first step in understanding the modus operandi of an IDP/IDPR would be to predict these residues. There are a few available methods which predict these protean segments from their amino acid sequences; however, their performance reported in the literature leaves clear room for improvement. With this background, the current study presents 'Proteus', a random forest classifier that predicts the likelihood of a residue undergoing a disorder-to-order transition upon binding to a potential partner protein. The prediction is based on features that can be calculated using the amino acid sequence alone. Proteus compares favorably with existing methods predicting twice as many true positives as the second best method (55 vs. 27%) with a much higher precision on an independent data set. The current study also sheds some light on a possible 'disorder-to-order' transitioning consensus, untangled, yet embedded in the amino acid sequence of IDPs. Some guidelines have also been suggested for proceeding with a real-life structural modeling involving an IDPR using Proteus.


Priority setting in general practice: health priorities of older patients differ from treatment priorities of their physicians.
To ascertain health priorities of older patients and treatment priorities of their general practitioners (GP) on the basis of a geriatric assessment and to determine the agreement between these priorities. The study included a sample of 9 general practitioners in Hannover, Germany, and a stratified sample of 35 patients (2-5 patients per practice, 18 female, average age 77.7 years). Patients were given a geriatric assessment using the Standardized Assessment for Elderly Patients in Primary Care (STEP) to gain an overview of their health and everyday problems. On the basis of these results, patients and their physicians independently rated the importance of each problem disclosed by the assessment. Whereas patients assessed the importance for their everyday lives, physicians assessed the importance for patients' medical care and patients' everyday lives. Each patient had a mean ± standard deviation of 18 ± 9.2 health problems. Thirty five patients disclosed a total of 634 problems; 537 (85%) were rated by patients and physicians. Of these 537 problems, 332 (62%) were rated by patients and 334 (62%) by physicians as important for patients' everyday lives. In addition, 294 (55%) were rated by physicians as important for patients' medical care. Although these proportions of important problems were similar between patients and physicians, there was little overlap in the specific problems that each group considered important. The chance-corrected agreement (Cohen κ) between patients and physicians on the importance of problems for patients' lives was low (κ=0.23). Likewise, patients and physicians disagreed on the problems that physicians considered important for patients' medical care (κ=0.18, P<0.001 for each). The low agreement on health and treatment priorities between patients and physicians necessitates better communication between the two parties to strengthen mutual understanding.


Performance characteristics of NuVal and the Overall Nutritional Quality Index (ONQI).
Improving diets has considerable potential to improve health, but progress in this area has been limited, and advice to increase fruit and vegetable intake has largely gone unheeded. Our objective was to test the performance characteristics of the Overall Nutritional Quality Index (ONQI), a tool designed to help improve dietary patterns one well-informed choice at a time. The ONQI was developed by a multidisciplinary group of nutrition and public health scientists independent of food industry interests and is the basis for the NuVal Nutritional Guidance System. Dietary guidelines, existing nutritional scoring systems, and other pertinent scientific literature were reviewed. An algorithm incorporating >30 entries that represent both micro- and macronutrient properties of foods, as well as weighting coefficients representing epidemiologic associations between nutrients and health outcomes, was developed and subjected to consumer research and testing of performance characteristics. ONQI and expert panel rankings correlated highly (R = 0.92, P < 0.001). In consumer testing, approximately 80% of >800 study participants indicated that the ONQI would influence their purchase intent. ONQI scoring distinguished the more-healthful DASH (Dietary Approaches to Stop Hypertension) diet (mean score: 46) from the typical American diet according to the National Health and Nutrition Examination Survey (NHANES) 2003-2006 (mean score: 26.5; P < 0.01). In linear regression analysis of the NHANES 2003-2006 populations (n = 15,900), the NuVal system was significantly associated with the Healthy Eating Index 2005 (P < 0.0001). Recently generated data from ongoing studies indicate favorable effects on purchase patterns and significant correlation with health outcomes in large cohorts of men and women followed for decades. NuVal offers universally applicable nutrition guidance that is independent of food industry interests and is supported by consumer research and scientific evaluation of its performance characteristics.


Release of K+ and H+ from poly U in aqueous solution upon gamma and electron irradiation. Rate of strand break formation in poly U.
Conductivity changes were found which followed the reaction of radiolytically generated OH radicals with the potassium salt of polyuridylic acid (poly U) in aqueous solution. After 60Co-gamma-irradiation the observed increase of conductivity at pH = 6.8 was shown to consist of the liberation of K+ ions from the stock of K+ ions electrostatically bound to the polyanion. The initial G(K+) is 36 and hence 6 times higher than the G value of OH radicals in N2O saturated solutions. At a poly U concentration of 60 mg l-1 half of the ion release occurred at 12 J kg-1 and nearly all ions are released at 40 J kg-1. The liberation of K+ is explained to be a consequence of the formation of chain breaks leading to an increase of the degree of dissociation. The rate of the ion release was studied under pulse radiolysis conditions. Because of the high G-value of counterion liberation and the use of conductivity as analytical quantity the method is very sensitive. With 6 mg l-1 poly U the rate could be measured even at a dose per pulse of 0.25 J kg-1. The kinetics of the ion release can be described in terms of two parallel first order reactions of comparable contribution with an average rate constant of 0.8 s-1 at 20 degrees C, 60 mg l-1 poly U and pH = 6.8 with a small contribution of slower components. In more acidic solutions, besides K+ ions H+ are also liberated since at low pH values bound K+ is replaced by H+. The rate of the ion release was found to increase with increasing replacement of K+ by H+ (kobs = 100 s-1 at pH = 3.4, 60 mg l-1 poly U and T = 18 degrees C). With potassium ion free polyuridylic acid the corresponding rate constant amounted to 220 s-1, nearly independent of pH. From the temperature dependence activation parameters for the ion release were derived (Ea = 57 kJ mol-1, A = 1.0 X 10(10) s-1 at pH = 6.8). Addition of p-benzoquinone at pH = 3.7 and dithiothreitol (DTT) at pH 6.8 were found to decrease the size of the conductivity changes and to increase the rate. The results show that p-benzoquinone and DTT react with poly U radicals and that these reactions prevent chain breaks and ion liberation. It is concluded that the rate determining step of the conductivity increase is the formation of strand breaks by a cleavage of poly U radicals and that this reaction is pH dependent. The pH dependence and the observed value for the activation energy was found to be in agreement with the behaviour of a model system for the earlier postulated C-4' mechanism for strand break formation of polynucleotides and DNA.


Research of Nanomaterials as Electrodes for Electrochemical Energy Storage.
This paper has experimentally proved that hydrogen accumulates in large quantities in metal-ceramic and pocket electrodes of alkaline batteries during their operation. Hydrogen accumulates in the electrodes in an atomic form. After the release of hydrogen from the electrodes, a powerful exothermic reaction of atomic hydrogen recombination with a large energy release occurs. This exothermic reaction is the cause of thermal runaway in alkaline batteries. For the KSL-15 battery, the gravimetric capacity of sintered nickel matrix of the oxide-nickel electrode, as hydrogen storage, is 20.2 wt%, and cadmium electrode is 11.5 wt%. The stored energy density in the metal-ceramic matrix of the oxide-nickel electrode of the battery KSL-15 is 44 kJ/g, and in the cadmium electrode it is 25 kJ/g. The similar values for the KPL-14 battery are as follows. The gravimetric capacity of the active substance of the pocket oxide-nickel electrode, as a hydrogen storage, is 22 wt%, and the cadmium electrode is 16.9 wt%. The density of the stored energy in the active substance oxide-nickel electrode is 48 kJ/g, and in the active substance of the cadmium electrode it is 36.8 kJ/g. The obtained results of the accumulation of hydrogen energy in the electrodes by the electrochemical method are three times higher than any previously obtained results using the traditional thermochemical method.


Adherence to Antiretroviral Therapy and Associated Factors among People Living with HIV/AIDS in Hara Town and Its Surroundings, North-Eastern Ethiopia: A Cross-Sectional Study.
Adherence is the most important factor in determining Antiretroviral Therapy (ART) treatment success and long-term viral suppression. Nonadherence to ART led to the human Immunodeficiency Virus (HIV) related morbidity and mortality. Moreover, it intensifies the risk of the emerging drug resistant HIV strains. This study aimed to assess the level of ART adherence and to identify its predictive associated factors among people living with HIV/AIDS in Hara Town and its surroundings, North-Eastern Ethiopia. An institutional facility based cross-sectional study was conducted from April-May 2017. A total of 454 individuals were on ART follow-up in the selected ART-clinic, and only 418 patients were recruited. Bivariate and multivariate logistic regression analyses were carried out to identify associated factors. Odds ratio and 95% Confidence Interval (CI) were calculated to determine the level of significance. The level of ART adherence in the study setting was 300 (71.8%). Participants who had not disclosed their HIV status to their families were 88% less likely to adhere to their ART medication than those who had disclosed their HIV status ((Odds ratio (OR): 0.12, 95%CI:0.05-0.58; p<0.001). On the other hand, participants who had not encountered drug side effects were 2.69 times more likely to adhere to their ART medication than those who had ever encountered drug side effects (OR: 2.69, 95%CI:1.27-5.05; p<0.001). A very low level of ART adherence was shown in the study population. It was below the recommended good adherence standard. Therefore, patients should get adequate and comprehensive ART adherence counselling before initiation ART treatment and during the follow-up time.


A model of risk and mental state shifts during social interaction.
Cooperation and competition between human players in repeated microeconomic games offer a window onto social phenomena such as the establishment, breakdown and repair of trust. However, although a suitable starting point for the quantitative analysis of such games exists, namely the Interactive Partially Observable Markov Decision Process (I-POMDP), computational considerations and structural limitations have limited its application, and left unmodelled critical features of behavior in a canonical trust task. Here, we provide the first analysis of two central phenomena: a form of social risk-aversion exhibited by the player who is in control of the interaction in the game; and irritation or anger, potentially exhibited by both players. Irritation arises when partners apparently defect, and it potentially causes a precipitate breakdown in cooperation. Failing to model one's partner's propensity for it leads to substantial economic inefficiency. We illustrate these behaviours using evidence drawn from the play of large cohorts of healthy volunteers and patients. We show that for both cohorts, a particular subtype of player is largely responsible for the breakdown of trust, a finding which sheds new light on borderline personality disorder.


The genetic architecture of intracerebral hemorrhage.
Intracerebral hemorrhage (ICH), the acute manifestation of a common progressive cerebrovascular disease of the elderly, is the most fatal and least treatable form of stroke. There is a desperate need for ICH-specific therapeutics and effective primary prevention strategies, a need that is certain to grow with the aging of the population. Data point to a sizable genetic component to ICH susceptibility. Identification of ICH-related genes therefore holds promise for identifying novel biological targets for ICH prevention. This review focuses on evidence for a genetic contribution to ICH, delineates approaches to genetic studies of ICH, and explores foundations for their future applications. ICH occurs both sporadically and as part of familial syndromes. Monogenic disorders associated with ICH or microscopic bleeding, such as hereditary cerebral amyloid angiopathy, CADASIL, and collagen type IV A1-associated vasculopathy, demonstrate the potent effect of rare mutations. Dissecting the more complex genetics of sporadic ICH, however, will likely require defining multiple common DNA variants with weaker effects. Advances in high-throughput genotyping technology, computational and analytic methodologies, and large-scale collaborative efforts have already led to the identification of new genetic risk factors for dozens of common diseases. Such whole-genome association studies are being undertaken in sporadic ICH. Investigations of genetic risk factors for sporadic ICH have thus far been limited to candidate gene polymorphisms. Genome-wide association studies currently hold the greatest hope for robust discovery of ICH genes, which can generate novel insights into ICH biology and strategies for prevention.


VATS for congenital lobar emphysema: a case report.
Congenital lobar emphysema (CLE) is a rare congenital lung disease consisting in overinflation of a pulmonary lobe. Adult onset of CLE is therefore unusual, often presented with mild symptoms. The authors report a very uncommon case of congenital segmental emphysema diagnosed in a 21-year-old non-smoking man because of recurrent right pneumothorax. Indication to pulmonary resection was established according to functional limitation, radiological findings of right upper lobe segmental emphysema with corresponding bronchial agenesia, scintigraphic result of extremely reduced ventilation and perfusion of lung emphysematous area and recurrency of pneumothorax. The intervention was carried out by 3-portal video-assisted thoracic surgery (VATS) using single-lung ventilation leading to determine precisely how much lung to resect thanks to the obvious and clear-cut distinction between functioning and non functioning parenchyma of the upper lobe. A stapler wedge resection by VATS was thus obtained, that, as far as the author's knowledge, it is the first case of endoscopic parenchymal sparing resection in CLE. Even though congenital lobar emphysema is rare, clinical awareness of this condition is important for early diagnosis and effective surgical treatment that in this case led to favourable The VATS procedure seems to be an advantageous approach.


Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial.
Sudden unexpected death frequently occurs in chronic heart failure. The importance of acute coronary events in triggering sudden death (SD) is unclear. We evaluated at autopsy the prevalence of acute coronary findings (coronary thrombus, ruptured plaque, or myocardial infarction [MI]) and their relation to SD. Autopsy results in 171 patients in the randomized ATLAS trial were reviewed. The prevalence of acute coronary findings was 33%: in 54% of patients with significant coronary artery disease (CAD) who died suddenly, 32% who died of myocardial failure, but in non-CAD patients, they were present in only 5% and 10% respectively. The percentage of patients classified as dying of MI was 28% in the autopsy group versus 4% in the nonautopsied group (P<0.0001). Of the autopsied group with acute MI, 97% (31 of 32 patients) with SD and 40% (6 of 15 patients) with myocardial failure did not have the MI diagnosed during life. When undiagnosed MI was classified as "sudden unexpected" or "myocardial failure" from clinical information only, the distribution of death causes was similar in the autopsy and nonautopsied groups. Acute coronary findings are frequent and usually not clinically diagnosed in heart failure patients with CAD, particularly in those dying suddenly, suggesting the importance of acute coronary events as a trigger for SD in this setting.


Barriers to Self-Management in Depressed Women With Type 2 Diabetes.
Purpose To describe the impact of family functioning on the self-management of type 2 diabetes (T2DM) and depression in a subsample of women who completed a randomized clinical trial using vitamin D3 (5000 or 50,000 IUs weekly) for depression treatment. Background Women are at higher risk for increased severity of T2DM when experiencing depression. Methods Narrative inquiry was used. A semi-structured interview was conducted to understand helpful strategies and barriers in managing T2DM and depression. In addition, women were asked their meaning of family quality of life (FQOL). Results Twenty-one women participated after completion of the six-month final visit in the randomized clinical trial. The mean age was 55.2 years. Participants were 24% Hispanic, 48% African-American, and 52% Caucasian. The major themes generated related to family issues that impacted their self-management, yet participants did not want to "bring fault" to their families. Three themes emerged: (a) experience of family hardships-"it's been hard for me," (b) lack of disclosure to family about being depressed-"no point in talking to them," and (c) the need for connectedness with family and others-"the way it used to be… close as a family." Conclusion Family-centered approaches could address barriers to self-management. A "family lens" for practice and research may improve health outcomes.


Prospective, randomized, multicenter comparison of laser-facilitated balloon angioplasty versus stand-alone balloon angioplasty in patients with obstructive coronary artery disease. The Laser Angioplasty Versus Angioplasty (LAVA) Trial Investigators.
The goal of this study was to examine the relative safety and efficacy of laser-facilitated percutaneous transluminal coronary angioplasty (PTCA) versus "stand-alone" PTCA. Plaque debulking with lasing before PTCA may result in improved lumen dimensions and decreased rates of periprocedural ischemic complications, thus improving short- and long-term outcomes after percutaneous intervention. The mid-infrared holmium:yttrium-aluminum-garnet (YAG) laser has been shown to be effective in a variety of plaque subtypes and may be particularly useful in high risk acute ischemic syndromes. A total of 215 patients (mean [+/-SD] age 61 +/- 12 years) with 244 lesions were prospectively randomized at 14 clinical centers to laser versus stand-alone PTCA. After laser treatment, all patients underwent PTCA; 148 patients (69%) had unstable angina. The procedural success rate without major catheterization laboratory complications was similar in patients assigned to laser treatment or PTCA alone (96.6% vs. 96.9%, p = 0.88), as was the in-hospital clinical success rate (89.7% vs. 93.9%, p = 0.27). There was no difference in postprocedural diameter stenosis after laser treatment compared with PTCA (18.3% +/- 13.6% vs. 19.5% +/- 15.1%, p = 0.50). However, use of the laser, versus PTCA alone, did result in significantly more major and minor procedural complications (18.0% vs. 3.1%, p = 0.0004), myocardial infarctions (4.3% vs. 0%, p = 0.04) and total in-hospital major adverse events (103% vs. 4.1%, p = 0.08). At a mean follow-up time of 11.2 +/- 7.7 months, there were no differences in late or event-free survival in patients assigned to laser treatment versus PTCA alone. Compared with stand-alone PTCA, laser-facilitated PTCA results in a more complicated hospital course, without immediate or long-term benefits.


Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis.
Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.


A Comparison of Measured Airborne and Self-Reported Secondhand Smoke Exposure in the MADRES Pregnancy Cohort Study.
Secondhand smoke (SHS) exposure during pregnancy is linked to adverse birth outcomes, such as low birth weight and preterm birth. While questionnaires are commonly used to assess SHS exposure, their ability to capture true exposure can vary, making it difficult for researchers to harmonize SHS measures. This study aimed to compare self-reported SHS exposure with measurements of airborne SHS in personal samples of pregnant women. SHS was measured on 48-hour integrated personal PM2.5 Teflon filters collected from 204 pregnant women, and self-reported SHS exposure measures were obtained via questionnaires. Descriptive statistics were calculated for airborne SHS measures, and analysis of variance tests assessed group differences in airborne SHS concentrations by self-reported SHS exposure. Participants were 81% Hispanic, with a mean (SD) age of 28.2 (6.0) years. Geometric mean (SD) personal airborne SHS concentrations were 0.14 (9.41) µg/m3. Participants reporting lower education have significantly higher airborne SHS exposure (p=0.015). Mean airborne SHS concentrations were greater in those reporting longer duration with windows open in the home. There was no association between airborne SHS and self-reported SHS exposure; however, asking about the number of smokers nearby in the 48-hour monitoring period was most correlated with measured airborne SHS (Two+ smokers: 0.30µg/m3 vs. One: 0.12µg/m3 and Zero: 0.15µg/m3; p=0.230). Self-reported SHS exposure was not associated with measured airborne SHS in personal PM2.5 samples. This suggests exposure misclassification using SHS questionnaires and the need for harmonized and validated questions to characterize this exposure in health studies. This study adds to the growing body of evidence that measurement error is a major concern in pregnancy research, particularly in studies that rely on self-report questionnaires to measure secondhand smoke (SHS) exposure. The study introduces an alternative method of SHS exposure assessment using objective optical measurements, which can help improve the accuracy of exposure assessment. The findings emphasize the importance of using harmonized and validated SHS questionnaires in pregnancy health research to avoid biased effect estimates. This study can inform future research, practice, and policy development to reduce SHS exposure and its adverse health effects.


Vasopressors for the Treatment and Prophylaxis of Spinal Induced Hypotension during Caesarean Section.
Vasopressors have currently become the mainstay therapy for the management of spinal-induced hypotension (SIH) as the major mechanism of hypotension after spinal anaesthesia is the loss of arteriolar tone produced by sympathetic block. Vasopressors for the prophylaxis and treatment of SIH have been the subject of a significant amount of research, yet remain an attractive and important clinical problem. This review will highlight controversies and recent research on the use of vasopressors for both prophylaxis and treatment of SIH. For decades, ephedrine was considered to be the best vasopressor for the management of maternal hypotension. However, its use has been reported to be associated with a 5-fold increased risk of foetal acidosis than phenylephrine. At present, phenylephrine is the vasopressor of choice for preventing and treating SIH at caesarean section. However, its use is often associated with a decreased heart rate and low cardiac output state owing to the lack of β-mimetic activity. Norepinephrine has been introduced as an alternative vasopressor for preventing and treating SIH because of its additional β-mimetic activity. However before its routine clinical use, a further series of studies are needed to establish its efficacy and safety for both the mother and foetus.


Animal Models of Pulmonary Hypertension: Matching Disease Mechanisms to Etiology of the Human Disease.
Recently a great deal of progress has been made in our understanding of pulmonary hypertension (PH). Research from the past 30 years has resulted in newer treatments that provide symptomatic improvements and delayed disease progression. Unfortunately, the cure for patients with this lethal syndrome remains stubbornly elusive. With the relative explosion of scientific literature regarding PH, confusion has arisen regarding animal models of the disease and their correlation to the human condition. This short review uniquely focuses on the clear and present need to better correlate mechanistic insights from existing and emerging animal models of PH to specific etiologies and histopathologies of human PH. A better understanding of the pathologic processes in various animal models and how they relate to the human disease should accelerate the development of newer and more efficacious therapies.


Asymmetric transfer of CO2 across a broken sea surface.
Most estimates of the climatically-important transfer of atmospheric gases into, and out of, the ocean assume that the ocean surface is unbroken by breaking waves. However the trapping of bubbles of atmospheric gases in the ocean by breaking waves introduces an asymmetry in this flux. This asymmetry occurs as a bias towards injecting gas into the ocean where it dissolves, and against the evasion/exsolution of previously-dissolved gas coming out of solution from the oceans and eventually reaching the atmosphere. Here we use at-sea measurements and modelling of the bubble clouds beneath the ocean surface to show that the numbers of large bubbles found metres below the sea surface in high winds are sufficient to drive a large and asymmetric flux of carbon dioxide. Our results imply a much larger asymmetry for carbon dioxide than previously proposed. This asymmetry contradicts an assumption inherent in most existing estimates of ocean-atmosphere gas transfer. The geochemical and climate implications include an enhanced invasion of carbon dioxide into the stormy temperate and polar seas.


SOX9 is a dose-dependent metastatic fate determinant in melanoma.
In this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma. Immunofluorescence, TCGA database and qPCR were used to analyze the correlation between the expression patterns and levels of SOX9, SOX10 and NEDD9 in melanoma patient samples. AlamarBlue, transwell invasion and colony formation assays in melanoma cell lines were conducted to investigate the epistatic relationship between SOX10 and NEDD9, as well as the effects of graded SOX9 expression levels. Lung metastasis was determined by tail vein injection assay. Live cell imaging was conducted to monitor dynamics of melanoma migratory behavior. RHOA and RAC1 activation assays measured the activity of Rho GTPases. High SOX9 expression was predominantly detected in patients with distant melanoma metastases whereas SOX10 was present in the different stages of melanoma. Both SOX9 and SOX10 exhibited distinct but overlapping expression patterns with metastatic marker NEDD9. Accordingly, SOX10 was required for NEDD9 expression, which partly mediated its oncogenic functions in melanoma cells. Compensatory upregulation of SOX9 expression in SOX10-inhibited melanoma cells reduced growth and migratory capacity, partly due to elevated expression of cyclin-dependent kinase inhibitor p21 and lack of NEDD9 induction. Conversely, opposite phenomenon was observed when SOX9 expression was further elevated to a range of high SOX9 expression levels in metastatic melanoma specimens, and that high levels of SOX9 can restore melanoma progression in the absence of SOX10 both in vitro and in vivo. In addition, overexpression of SOX9 can also promote invasiveness of the parental melanoma cells by modulating the expression of various matrix metalloproteinases. SOX10 or high SOX9 expression regulates melanoma mesenchymal migration through the NEDD9-mediated focal adhesion dynamics and Rho GTPase signaling. These results unravel NEDD9 as a common target for SOX10 or high SOX9 to partly mediate their oncogenic events, and most importantly, reconcile previous discrepancies that suboptimal level of SOX9 expression is anti-metastatic whereas high level of SOX9 is metastatic in a heterogeneous population of melanoma.


Effects of temperature and drought manipulations on seedlings of Scots pine provenances.
Rising temperatures and more frequent and severe climatic extremes as a consequence of climate change are expected to affect growth and distribution of tree species that are adapted to current local conditions. Species distribution models predict a considerable loss of habitats for Pinus sylvestris. These models do not consider possible intraspecific differences in response to drought and warming that could buffer those impacts. We tested 10 European provenances of P. sylvestris, from the southwestern to the central European part of the species distribution, for their response to warming and to drought using a factorial design. In this common-garden experiment the air surrounding plants was heated directly to prevent excessive soil heating, and drought manipulation, using a rain-out shelter, permitted almost natural radiation, including high light stress. Plant responses were assessed as changes in phenology, growth increment and biomass allocation. Seedlings of P. sylvestris revealed a plastic response to drought by increased taproot length and root-shoot ratios. Strongest phenotypic plasticity of root growth was found for southwestern provenances, indicating a specific drought adaptation at the cost of overall low growth of aboveground structures even under non-drought conditions. Warming had a minor effect on growth but advanced phenological development and had a contrasting effect on bud biomass and diameter increment, depending on water availability. The intraspecific variation of P. sylvestris provenances could buffer climate change impacts, although additional factors such as the adaptation to other climatic extremes have to be considered before assisted migration could become a management option.


Changing role of stem cell transplantation in follicular lymphoma.
Patients with advanced follicular lymphoma (FL) have numerous treatment options, including observation, radiotherapy, single-agent or combination chemotherapy, mAbs, and radioimmunoconjugates. These therapies can extend progression-free survival but none can provide a cure. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curable therapy for FL, with the field shifting more toward the use of reduced-intensity conditioning regimens because of the lower associated nonrelapse mortality compared with myeloablative regimens. However, GVHD and infection are still problematic in the allo-HSCT population. Autologous HSCT (auto-HSCT) confers high response rates and prolongs progression-free survival in relapsed patients who are chemosensitive, and an increasing amount of data suggest that auto-HSCT may be curative if offered to relapsed patients who are not heavily pretreated. Auto-HSCT has no role as consolidation therapy for patients in first remission based on the results from 3 large randomized trials. Novel conditioning regimens with radioimmunoconjugates have been used in both auto-HSCT and allo-HSCT regimens and results have shown efficacy even in chemorefractory patients. Therefore, with the exception of patients in first remission, the optimal timing for HSCT remains controversial. However, the outcomes seen after auto-HSCT and allo-HSCT continue to improve, and HSCT represents a treatment modality that should be considered in all FL patients, especially while their disease remains chemoresponsive.


EMERGE-A Data-Driven Medical Decision Making Aid.
EMERGE is an expert system designed as a medical decision making aid. It is machine-independent, and is implemented in standard Pascal. It has modest memory requirements, and can operate on a microcomputer. EMERGE is rule-based, and its initial application is the analysis of chest pain in the emergency room. The knowledge base is maintained separately from the consultation program. Thus the application area can be changed without any modification to the software. This paper describes the control structures and rule searching procedures used in EMERGE.


The importance of leadership style and psychosocial work environment to staff-assessed quality of care: implications for home help services.
Work in home help services is typically conducted by an assistant nurse or nursing aide in the home of an elderly person, and working conditions have been described as solitary with a high workload, little influence and lack of peer and leader support. Relations between leadership styles, psychosocial work environment and a number of positive and negative employee outcomes have been established in research, but the outcome in terms of quality of care has been addressed to a lesser extent. In the present study, we aimed to focus on working conditions in terms of leadership and the employee psychosocial work environment, and how these conditions are related to the quality of care. The hypothesis was that the relation between a transformational leadership style and quality of care is mediated through organisational and peer support, job control and workload. A cross-sectional survey design was used and a total of 469 questionnaires were distributed (March-April 2012) to assistant nurses in nine Swedish home help organisations, including six municipalities and one private organisation, representing both rural and urban areas (302 questionnaires were returned, yielding a 65% response rate). The results showed that our hypothesis was supported and, when indirect effects were also taken into consideration, there was no direct effect of leadership style on quality of care. The mediated model explained 51% of the variance in quality of care. These results indicate that leadership style is important not only to employee outcomes in home help services but is also indirectly related to quality of care as assessed by staff members.


The role of histidine-118 of inorganic pyrophosphatase from thermophilic bacterium PS-3.
Treatment of the inorganic pyrophosphatase from thermophilic bacterium PS-3 with diethyl pyrocarbonate resulted in the almost complete loss of its activity, which followed pseudo-first-order kinetics. The presence of Mg2+ prevented the inactivation. Enzyme inactivated with diethyl pyrocarbonate was re-activated by hydroxylamine. The inactivation parallelled the amount of modified histidine residue, and a plot of the activity remaining against the amount of modified histidine residue suggested that the modification of one of two histidine residues totally inactivated the enzyme. The site involved was found to be located in a single lysyl endopeptidase-digest peptide derived from the ethoxy[14C]carbonylated enzyme. Amino acid analysis and sequence analysis of the peptide revealed that it comprised residues 96-119 of the inorganic pyrophosphatase from thermophilic bacterium PS-3. These results, when compared with those reported for the Escherichia coli and yeast enzymes, imply that His-118 of the inorganic pyrophosphatase from thermophilic bacterium PS-3 is located near the Mg(2+)-binding site and thus affects the binding of Mg2+.


Does becaplermin (platelet-derived growth factor-BB) reverse detrimental effects of ischemia on colonic anastomosis?
The aim of this study was to evaluate the effects of becaplermin on normal and ischemic colon anastomoses. Forty adult male Wistar-Albino rats were divided into four equal groups of ten. All rats underwent standard left colon resection and end-to-end anastomosis. The groups were as follows: Group 1, normal anastomosis alone; Group 2, ischemic anastomosis alone; Group 3, normal anastomosis and becaplermin therapy; and Group 4, ischemic anastomosis and becaplermin therapy. All animals were killed on postoperative Day 4. Intra-abdominal adhesions were scored, and anastomotic healing was evaluated with both in situ bursting pressure and hydroxyproline levels. According to bursting pressure results, there was a significant difference between Group 2 and Group 4 (P < 0.05), but there was no statistically significant difference between Group 1 and Group 3 (P > 0.05). Hydroxyproline values revealed no statistically significant difference among any of the groups (P > 0.05). With regard to intra-abdominal adhesion scores, Group 3 had significantly lower values than Group 2 and Group 4 (P < 0.05). No statistically significant difference was observed between the other groups. Detrimental effects of ischemia on colonic anastomotic healing were reversed with becaplermin therapy. However, there was no such benefit on nonischemic anastomoses. Intra-abdominal application of this gel did not lead to an increase in intra-abdominal adhesion formation.


Navigating Alzheimer's Disease via Chronic Stress: The Role of Glucocorticoids.
Alzheimer's disease (AD) is a chronic intensifying incurable progressive disease leading to neurological deterioration manifested as impairment of memory and executive brain functioning affecting the physical ability like intellectual brilliance, common sense in patients. The recent therapeutic approach in Alzheimer's disease is only the symptomatic relief further emerging the need for therapeutic strategies to be targeted in managing the underlying silent killing progression of dreaded pathology. Therefore, the current research direction is focused on identifying the molecular mechanisms leading to the evolution of the understanding of the neuropathology of Alzheimer's disease. The resultant saturation in the area of current targets (amyloid β, τ Protein, oxidative stress etc.) has led the scientific community to rethink of the mechanistic neurodegenerative pathways and reprogram the current research directions. Although, the role of stress has been recognized for many years and contributing to the development of cognitive impairment, the area of stress has got the much-needed impetus recently and is being recognized as a modifiable menace for AD. Stress is an unavoidable human experience that can be resolved and normalized but chronic activation of stress pathways unsettle the physiological status. Chronic stress mediated activation of neuroendocrine stimulation is generally linked to a high risk of developing AD. Chronic stress-driven physiological dysregulation and hypercortisolemia intermingle at the neuronal level and leads to functional (hypometabolism, excitotoxicity, inflammation) and anatomical remodeling of the brain architecture (senile plaques, τ tangles, hippocampal atrophy, retraction of spines) ending with severe cognitive deterioration. The present review is an effort to collect the most pertinent evidence that support chronic stress as a realistic and modifiable therapeutic earmark for AD and to advocate glucocorticoid receptors as therapeutic interventions.


Ozone-Induced Oxidative Stress, Neutrophilic Airway Inflammation, and Glucocorticoid Resistance in Asthma.
Despite recent advances in using biologicals that target Th2 pathways, glucocorticoids form the mainstay of asthma treatment. Asthma morbidity and mortality remain high due to the wide variability of treatment responsiveness and complex clinical phenotypes driven by distinct underlying mechanisms. Emerging evidence suggests that inhalation of the toxic air pollutant, ozone, worsens asthma by impairing glucocorticoid responsiveness. This review discusses the role of oxidative stress in glucocorticoid resistance in asthma. The underlying mechanisms point to a central role of oxidative stress pathways. The primary data source for this review consisted of peer-reviewed publications on the impact of ozone on airway inflammation and glucocorticoid responsiveness indexed in PubMed. Our main search strategy focused on cross-referencing "asthma and glucocorticoid resistance" against "ozone, oxidative stress, alarmins, innate lymphoid, NK and γδ T cells, dendritic cells and alveolar type II epithelial cells, glucocorticoid receptor and transcription factors". Recent work was placed in the context from articles in the last 10 years and older seminal research papers and comprehensive reviews. We excluded papers that did not focus on respiratory injury in the setting of oxidative stress. The pathways discussed here have however wide clinical implications to pathologies associated with inflammation and oxidative stress and in which glucocorticoid treatment is essential.


The impact of multidimensional physical activity feedback on healthcare practitioners and patients.
Promotion of physical activity in primary care has had limited success. Wearable technology presents an opportunity to support healthcare practitioners (HCPs) in providing personalised feedback to their patients. To explore the differing thoughts and feelings of both HCPs and at-risk patients provided with personalised multidimensional physical activity feedback. Qualitative study with HCPs (n = 15) and patients at risk of cardiovascular disease or type 2 diabetes (n = 29), recruited from primary care. HCPs and patients wore a physical activity monitor for 7 days and were subsequently shown their personalised multidimensional feedback, including sedentary time, calorie burn, short (1-minute) or long (>10-minute) bouts of moderate-to-vigorous activity during semi-structured interviews. Transcripts were analysed thematically with comparisons made between individuals of high (n = 21) and low (n = 23) physical activity levels as to their cognitive-affective responses to their data. Personalised feedback elicited positive emotional responses for highly active participants and negative emotional responses for those with low activity. However, individuals with low activity demonstrated largely positive coping mechanisms. Some low active participants were in denial over feedback, but the majority valued it as an opportunity to think of ways to improve physical activity (cognitive reappraisal) and started forming action plans (problem-focused coping). Around half of all participants also sought to validate their feedback against peers. Personalised, visual feedback elicits immediate emotional and coping responses in participants of high and low physical activity levels. Further studies should explore whether multidimensional feedback could help practitioners explore diverse ways for lifestyle change with patients.