Diffuse large B-cell lymphoma in the elderly: a review of potential difficulties.
Half of patients with diffuse large B-cell lymphoma (DLBCL) are more than 65 years old. These elderly patients frequently have other diseases, some of them severe, which may alter their ability to receive standard curative therapy. However, these associated diseases are heterogeneous and only a few contraindicate chemotherapy treatments. We reviewed all potential difficulties, such as the evaluation of comorbidities, the heterogeneous functional status of this population, and the consequences of the aging process that might be associated with treating these patients, and now propose solutions. As standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy may cure the majority of patients, it must always be the first proposed option. With this approach, elderly patients with DLBCL treated with a curative intent can reach a complete remission and have a similar outcome as younger patients. Reduced dose intensity must be applied for very elderly patients or those unfit for full-dose anthracycline. The critical question for a physician is why these patients cannot be treated with the standard regimen, namely R-CHOP.


Platelet-derived growth factor can activate purified primate, phorbol myristate acetate-primed eosinophils.
We are interested in the physiologic mechanisms of eosinophil activation because of the presumed participation of activated eosinophils in the inflammatory sequelae of asthma. Suspecting that other formed elements of the blood may contribute to such an activation, we examined the capacity of platelet-derived growth factor (PDGF), a product of activated platelets, to activate eosinophils. We found that highly purified monkey and human eosinophils, but not guinea pig eosinophils, were activated by PDGF (superoxide anion production) in a dose-dependent fashion. Moreover, this activation was further dependent on a prior 'priming' of the cells by a brief exposure to subthreshold concentrations of phorbol ester. The response was specific for the BB homodimer of PDGF suggesting it is receptor-dependent.


Conformational changes at mesophase transitions in a ferroelectric liquid crystal by comparative DFT computational and (13)C NMR study.
In this work, we report a detailed investigation on both the conformational and the orientational ordering properties of a ferroelectric liquid crystal mesogen, namely, M10/**, through the combination of high resolution solid state (13)C NMR and density functional theory (DFT) computational methods. The trends of the observed (13)C chemical shift in the blue, cholesteric, and ferroelectric SmC* phases of M10/** were analyzed in terms of conformational changes occurring in the flexible parts of the molecule. In particular, we focused on the aliphatic alpha methylenoxy carbons because of their high sensitivity to mesophase environment, as evidenced by experimental (13)C chemical shift anisotropy (CSA). DFT computation of the chemical shift tensors as a function of geometrical parameters, such as dihedral angles, put in evidence significant changes in the average conformation at the mesophase transitions. The conformations predicted by DFT have been validated by comparing the calculated (13)C chemical shifts with those experimentally observed for the alkoxylic carbons, whose relative orientation plays a key role in establishing the overall conformation of the molecule in each liquid crystalline phase. Furthermore, the orientational order parameters of the relevant flexible fragments were calculated and found to be in good agreement with those characterizing similar systems, thus validating our approach.


ATP stimulates signal recognition particle (SRP)/FtsY-supported protein integration in chloroplasts.
The signal recognition particle (SRP) and its receptor (FtsY in prokaryotes) are essential for cotranslational protein targeting to the endoplasmic reticulum in eukaryotes and the cytoplasmic membrane in prokaryotes. An SRP/FtsY-like protein targeting/integration pathway in chloroplasts mediates the posttranslational integration of the light-harvesting chlorophyll a/b-binding protein (LHCP) into thylakoid membranes. GTP, chloroplast SRP (cpSRP), and chloroplast FtsY (cpFtsY) are required for LHCP integration into thylakoid membranes. Here, we report the reconstitution of the LHCP integration reaction with purified recombinant proteins and salt-washed thylakoids. Our data demonstrate that cpSRP and cpFtsY are the only soluble protein components required for LHCP integration. In addition, our studies reveal that ATP, though not absolutely required, remarkably stimulates LHCP integration into salt-washed thylakoids. ATP stimulates LHCP integration by a mechanism independent of the thylakoidal pH gradient (DeltapH) and exerts no detectable effect on the formation of the soluble LHCP-cpSRP-targeting complex. Taken together, our results indicate the participation of a thylakoid ATP-binding protein in LHCP integration.


Endothelial barrier antigen-immunoreactivity is conversely associated with blood-brain barrier dysfunction after embolic stroke in rats.
While the concept of the Neurovascular Unit (NVU) is increasingly recognized for exploring mechanisms of tissue damage in ischemic stroke, immunohistochemical analyses are of interest to specifically visualize constituents like the endothelium. Changes in immunoreactivity have also been discussed to reflect functional aspects, e.g., the integrity of the blood-brain barrier (BBB). This study aimed to characterize the endothelial barrier antigen (EBA) as addressed by the antibody SMI-71 in a rat model of embolic stroke, considering FITC-albumin as BBB leakage marker and serum levels of BBB-associated matrix metalloproteinases (MMPs) to explore its functional significance. Five and 25 h after ischemia onset, regions with decreased BBB integrity exhibited a reduction in number and area of EBA-immunopositive vessels, while the stained area per vessel was not affected. Surprisingly, EBA content of remaining vessels tended to be increased in areas of BBB dysfunction. Analyses addressing this interrelation resulted in a significant and inverse correlation between the vessels' EBA content and degree of BBB permeability. In conclusion, these data provide evidence for a functional relationship between EBA-immunoreactivity and BBB dysfunction in experimental ischemic stroke. Further studies are required to explore the underlying mechanisms of altered EBA-immunoreactivity, which might help to identify novel neuroprotective strategies.


Critical windows of perinatal particulate matter (PM2.5) exposure and preadolescent kidney function.
Air pollution exposure, especially particulate matter ≤2.5 μm in diameter (PM2.5), is associated with poorer kidney function in adults and children. Perinatal exposure may occur during susceptible periods of nephron development. We used distributed lag nonlinear models (DLNMs) to examine time-varying associations between early life daily PM2.5 exposure (periconceptional through age 8 years) and kidney parameters in preadolescent children aged 8-10 years. Participants included 427 mother-child dyads enrolled in the PROGRESS birth cohort study based in Mexico City. Daily PM2.5 exposure was estimated at each participant's residence using a validated satellite-based spatio-temporal model. Kidney function parameters included estimated glomerular filtration rate (eGFR), serum cystatin C, and blood urea nitrogen (BUN). Models were adjusted for child's age, sex and body mass index (BMI) z-score, as well as maternal education, indoor smoking report and seasonality (prenatal models were additionally adjusted for average first year of life PM2.5 exposure). We also tested for sex-specific effects. Average perinatal PM2.5 was 22.7 μg/m3 and ranged 16.4-29.3 μg/m3. Early pregnancy PM2.5 exposures were associated with higher eGFR in preadolescence. Specifically, we found that PM2.5 exposure between weeks 1-18 of gestation was associated with increased preadolescent eGFR, whereas exposure in the first 14 months of life after birth were associated with decreased eGFR. Specifically, a 5 μg/m3 increase in PM2.5 during the detected prenatal window was associated with a cumulative increase in eGFR of 4.44 mL/min/1.732 (95%CI: 1.37, 7.52), and during the postnatal window we report a cumulative eGFR decrease of -10.36 mL/min/1.732 (95%CI: -17.68, -3.04). We identified perinatal windows of susceptibility to PM2.5 exposure with preadolescent kidney function parameters. Follow-up investigating PM2.5 exposure with peripubertal kidney function trajectories and risk of kidney disease in adulthood will be critical.


Evaluation of the Effect of Scleral Buckling on Anterior Segment and Refractive Changes Using Anterior Segment Optical Coherence Tomography.
To evaluate the changes of anterior segment and refractive parameters after scleral buckling (SB) surgery for uncomplicated rhegmatogenous retinal detachment (RRD) using anterior segment optical coherence tomography (AS-OCT). Thirty-six RRD eyes were consecutively enrolled. Analysis concerned the central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber volume (ACV), iris-trabecular contact (ITC), angel opening distance (AOD), angle recess area (ARA), trabecular-iris space area (TISA),trabecular iris angle (TIA) and refractive parameters, including average keratometry (AvgK), cylindrical power (CYL), regular astigmatism, asymmetry and high order irregularity (HOI) at baseline and 1 day, 1 month, 2 months, 6 months and 12 months postoperatively. AS-OCT was performed at RRD diagnosis and day 1, week 1, month 1 and month 6 after SB to evaluate the scleral buckling. A statistically significant postoperative CCT increase, ACD and ACV decrease were observed at 1 day and 1 month postoperatively. ITC analysis showed that the angle of the entire circumference narrowed at 1 month postoperatively. There was a significant decrease in all the angle parameters (AOD500/750, ARA500/750, TISA500/750, and ARA500/750) at 1 day and 1 month after SB surgery. However, all of the above parameters returned to the preoperative level at 12 months. Refractive parameters including AvgK, regular astigmatism, CYL, asymmetry, and HOI of anterior corneal surface and total corneal increased on the 1 day and 1 month after SB surgery and persisted even after 12 months follow-up. However, there was no significant difference in refractive parameters of posterior corneal surface during follow-up. The changes in the structure of anterior segments after SB surgery were almost returned to the preoperative levels at 12 months postoperatively. However, SB surgery has a long-term effect on refractive parameters throughout a 12-month follow-up.


Different Evolutionary Pathways Lead to Incomplete Convergence of Elongate Body Shapes in Carnivoran Mammals.
Although convergence is often recognized as a ubiquitous feature across the Tree of Life, whether the underlying traits also exhibit similar evolutionary pathways towards convergent forms puzzles biologists. In carnivoran mammals, "elongate," "slender," and "long" are often used to describe and even to categorize mustelids (martens, polecats, and weasels), herpestids (mongooses), viverrids (civets and genets), and other carnivorans together. But just how similar these carnivorans are and whether there is convergence in the morphological component that contribute to elongation has never been assessed. Here, I found that these qualitatively described elongate carnivorans exhibited incomplete convergence towards elongate bodies compared to other terrestrial carnivorans. In contrast, the morphological components underlying body shape variation do not exhibit convergence despite evidence that these components are more elongate in elongate carnivorans compared to nonelongate carnivorans. Furthermore, these components also exhibited shorter but different phylogenetic half-lives towards more elongate adaptive peaks, indicating that different selective pressures can create multiple pathways to elongation. Incorporating the fossil record will facilitate further investigation of whether body elongation evolved adaptively or if it is simply a retained ancestral trait.[Axial skeleton; body elongation; convergent evolution; macroevolution; phylogenetic comparative methods; thoracolumbar vertebrae.].


NAD(P)H oxidases in rat basilar arterial endothelial cells.
Reactive oxygen species (ROS) may play a critical role in the regulation of vascular tone and development of vascular diseases, such as stroke. NAD(P)H oxidase is a major source of ROS in vascular cells, including endothelial cells. It has been considered that Nox2 and Nox4 are exclusively expressed among Nox homologues in the endothelial cells of noncerebral blood vessels. However, the precise molecular identity of the NAD(P)H oxidase in the endothelial cells of the cerebral arteries is not fully understood. We examined the expression of Nox homologues and their activation mechanism in the endothelial cells of the cerebral arteries. We isolated and cultured basilar artery endothelial cells (BAECs) of Sprague-Dawley rats. Expression of NAD(P)H oxidase was examined by reverse-transcription-polymerase chain reaction (RT-PCR) and immunohistological staining. RT-PCR disclosed abundant expression of Nox4 with marginal Nox2 in BAEC. In addition, Nox1 was expressed highly both at mRNA and protein levels in BAECs. Immunohistological staining also showed the prominent expression of Nox1 in the endothelial cells of the basilar artery. With respect to the cytosolic components of NAD(P)H oxidases, BAECs expressed p67phox and, to a lesser extent, p47phox, Noxo1, and Noxa1. Both NADH and NADPH induced superoxide production of the BAEC membranes. The phagocyte-type cytosolic components, p47phox and p67phox, significantly enhanced the NADH-induced superoxide production of the BAEC membranes, whereas the components failed to increase the NADPH-induced superoxide production. Nox1 is highly expressed in the endothelial cells of the cerebral arteries along with Nox2 and Nox4, and the endothelial NAD(P)H oxidase of the cerebral arteries may have a unique activation mechanism by the phagocyte-type cytosolic components.


The development and pilot randomised controlled trial of a group education programme for promoting walking in people with intermittent claudication.
The aim of this study was to develop and pilot a group education programme for promoting walking in people with intermittent claudication. Patient focus groups (n=24) and literature reviews were conducted to inform the development of the education programme, which involves a three-hour group-based education workshop and follow-up telephone support. A pilot study was subsequently conducted in which 23 new patients (Rutherford category 1-3) were randomly assigned to usual care (control) or usual care plus the education programme. Outcomes were assessed at baseline and six weeks including daily steps (tri-axial accelerometer), walking capacity (six-minute walk test and Gardner treadmill test), and quality of life (Intermittent Claudication Questionnaire [ICQ]). Exit interviews were conducted to assess the acceptability and usefulness of the programme. Compared with controls, the intervention group had superior walking capacity and quality of life at six weeks. Mean differences in six-minute walk distance, treadmill maximum walking distance and ICQ score were 44.9 m (95% confidence interval [CI], 6.9 to 82.9), 173 m (95% CI, 23 to 322), and -10.6 (95% CI, -18.9 to -2.3), respectively. The daily step count did not differ between groups. The exit interviews indicated that participants valued attending the programme, that it gave them a greater understanding of their condition, and that they had been walking more for exercise since attending. The results suggest that the education programme is feasible, acceptable, and potentially useful for improving walking capacity and quality of life. A fully-powered trial exploring clinical and cost effectiveness is needed. ISRCTN06733130 (http://www.controlled-trials.com).


Nouvelles drogues de « rave-parties » : ketamine et prolintane.
"Rave parties", all-night dance parties based on "techno" music, represent an increasing phenomenon in France. "Rave drugs" refers to a wide variety of drugs used by the young participants owing to their hallucinogenic or stimulant effects. Uncertainties about the sources of these substances, the possible contaminants and the multiplicity of the associations make it difficult to evaluate the toxic consequences that might be expected in this particular context. This report presents toxicological cases documented by analytical findings in which two pharmacological agents abused in "rave parties" in South-West of France were found. The day following a party, a 17 year-old girl showed a confused state with drowsiness and hallucinations. She confessed having consumed a white powder sold as "ecstasy", that sample analysis identified as pure ketamine. Ketamine is an anaesthetic agent primarily used in veterinary medicine and paediatrics. This drug seems to be abused, mainly by the intranasal route, owing to its hallucinogen effects. Its used in "rave-party" appears to be marked by unsuspected consumption. All long another party, a large quantity of orange tablets were sold and abused by several participants. Analysis performed on some fragments of these tablets revealed the presence of prolintane and ascorbic acid. Prolintane, an amphetamine-related substance, is a central nervous system stimulant. This compound is "freely" available in Spain in combination with several vitamins, under the form of tablets with orange coating named "Katovit" and sold at low price: 1.93 €/20 tablets (200 mg of prolintane).


Metacognitive Reflection and Insight Therapy: A Recovery-Oriented Treatment Approach for Psychosis.
Recent research has suggested that recovery from psychosis is a complex process that involves recapturing a coherent sense of self and personal agency. This poses important challenges to existing treatment models. While current evidence-based practices are designed to ameliorate symptoms and skill deficits, they are less able to address issues of subjectivity and self-experience. In this paper, we present Metacognitive Insight and Reflection Therapy (MERIT), a treatment approach that is explicitly concerned with self-experience in psychosis. This approach uses the term metacognition to describe those cognitive processes that underpin self-experience and posits that addressing metacognitive deficits will aid persons diagnosed with psychosis in making sense of the challenges they face and deciding how to effectively manage them. This review will first explore the conceptualization of psychosis as the interruption of a life and how persons experience themselves, and then discuss in more depth the construct of metacognition. We will next examine the background, practices and evidence supporting MERIT. This will be followed by a discussion of how MERIT overlaps with other emerging treatments as well as how it differs. MERIT's capacity to engage patients who reject the idea that they have mental illness as well as cope with entrenched illness identities is highlighted. Finally, limitations and directions for future research are discussed.


Hypertension Canada's 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension.
Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force provides annually updated, evidence-based recommendations to guide the diagnosis, assessment, prevention, and treatment of hypertension. This year, we present 4 new recommendations, as well as revisions to 2 previous recommendations. In the diagnosis and assessment of hypertension, automated office blood pressure, taken without patient-health provider interaction, is now recommended as the preferred method of measuring in-office blood pressure. Also, although a serum lipid panel remains part of the routine laboratory testing for patients with hypertension, fasting and nonfasting collections are now considered acceptable. For individuals with secondary hypertension arising from primary hyperaldosteronism, adrenal vein sampling is recommended for those who are candidates for potential adrenalectomy. With respect to the treatment of hypertension, a new recommendation that has been added is for increasing dietary potassium to reduce blood pressure in those who are not at high risk for hyperkalemia. Furthermore, in selected high-risk patients, intensive blood pressure reduction to a target systolic blood pressure ≤ 120 mm Hg should be considered to decrease the risk of cardiovascular events. Finally, in hypertensive individuals with uncomplicated, stable angina pectoris, either a β-blocker or calcium channel blocker may be considered for initial therapy. The specific evidence and rationale underlying each of these recommendations are discussed. Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force will continue to provide annual updates.


Is power training or conventional resistance training better for function in elderly persons? A meta-analysis.
to determine the effects of power training with high movement velocity compared with conventional resistance training with low movement velocity for older community-dwelling people. systematic review of randomised controlled trials. the Cochrane Central Register of Controlled TRIALS, PubMed (Medline), EMBASE, CINAHL, PEDro and Scholar-Google. all randomised or quasi-randomised trials investigating power training with high movement velocity versus conventional resistance training with low movement velocity in elderly persons over the age of 60 years. The primary outcomes were measures of functional outcomes; secondary outcomes were balance, gait, strength, power, muscle volume and adverse effects. eleven trials were identified involving 377 subjects. The pooled effect size for the follow-up values of the functional outcomes was 0.32 in favour of the power training (95% CI 0.06 to 0.57) and 0.38 (95% CI -0.51 to 1.28) for the change value. The pooled effect from three studies for self-reported function was 0.16 in favour of power training (95% CI -0.17 to 0.49). power training is feasible for elderly persons and has a small advantage over strength training for functional outcomes. No firm conclusion can be made for safety.


Genetic diversity and antibiotic resistance in Shigella dysenteriae and Shigella boydii strains isolated from children aged <5 years in Egypt.
Diversity within Shigella dysenteriae (n=40) and Shigella boydii (n=30) isolates from children living in Egypt aged <5 years was investigated. Shigella-associated diarrhoea occurred mainly in summer months and in children aged <3 years, it commonly presented with vomiting and fever. Serotypes 7 (30%), 2 (28%), and 3 (23%) accounted for most of S. dysenteriae isolates; 50% of S. boydii isolates were serotype 2. S. dysenteriae and S. boydii isolates were often resistant to ampicillin, chloramphenicol and tetracycline (42%, 17%, respectively), although resistance varied among serotypes. Pulsed-field gel electrophoresis separated the isolates into distinct clusters correlating with species and serotype. Genetic differences in trimethoprim/sulfamethoxazole and β-lactam-encoding resistance genes were also evident. S. dysenteriae and S. boydii are genetically diverse pathogens in Egypt; the high level of multidrug resistance associated with both pathogens and resistance to the most available inexpensive antibiotics underlines the importance of continuing surveillance.


Use of Cervical Disk Arthroplasty to Treat Noncontiguous Cervical Disk Herniations.
Cervical disk arthroplasty is now a widely accepted alternative to anterior cervical interbody fusion, which is known to reduce normal cervical motion and increase the incidence of adjacent segment disease. Although multiple studies report the use of cervical disk arthroplasty to treat multilevel cervical disease, this is the first report in the literature detailing the placement of multiple, noncontiguous artificial disks. We describe a 41-year-old male who presented with myelopathy and left upper extremity radiculopathy resulting from 2 cervical disk herniations separated by a normal intervening level. He underwent an anterior cervical diskectomy and placement of an artificial disk prosthesis at cervical (C) 4-5 and C6-7 while leaving C5-6 intact. This approach serves to preserve cervical motion, spinal stability, and lordosis across all 3 levels, thus demonstrating that it is a viable alternative to a multilevel anterior cervical interbody fusion.


Projections of the caudate nucleus in the cat.
Circumscribed lesions of the caudate nucleus were made in four cats and two kittens. A third kitten was lesioned in the Middle Forebrain Bundle (MFB). Cats were sacrificed 8 days after the lesion and perfused intraventricularly with 10 per cent Formalin. Kittens were sacrificed 3 days after the lesion. Coronal frozen sections of the brains were made and studied under the light microscope with the Fink and Heimer staining method. Degeneration was observed in the contralateral caudate nucleus, in the homo and contralateral putamen, in the globus pallidum and in the accumbens. The substantia nigra was intensely involved as well as the red nucleus and the mesencephalic reticular formation. Patches of degeneration were also found in the superior colliculus and in the thalamus. As a preliminary conclusion we think that the projection of the caudate reaches all those structures by the middle forebrain bundle. The degeneration of the contralateral areas could be explained through a path of the anterior commissure.


The GRONORUN study: is a graded training program for novice runners effective in preventing running related injuries? Design of a Randomized Controlled Trial.
Running is a popular form of recreational exercise. Beside the positive effects of running on health and fitness, the risk of a running related injury has to be considered. The incidence of injuries in runners is high and varies from 30-79%. However, few intervention studies on prevention of running related injuries have been performed and none of these studies involved novice runners. GRONORUN (Groningen Novice Running) is a two armed randomized controlled trial, comparing the effects of two different training programs for novice runners on the incidence of running related injuries. Participants are novice runners, who want to train for a four mile running event. The control group will train according a standard 8 week training program. The intervention group will use a more gradual, 13 week training program which is based on "the ten percent training rule". During the thirteen week follow up participants register information on running and RRI's in an internet based running log. The primary outcome measure is RRI. An injury is defined as a musculoskeletal ailment of the lower extremity or back, causing a restriction of running for at least one week. The GRONORUN trial is the first randomized controlled trial to study a preventive intervention in novice runners. Many different training programs for novice runners are offered, but none are evidence based.


Comparative Analysis of Transposable Elements in Strawberry Genomes of Different Ploidy Levels.
Transposable elements (TEs) make up a large portion of plant genomes and play a vital role in genome structure, function, and evolution. Cultivated strawberry (Fragaria x ananassa) is one of the most important fruit crops, and its octoploid genome was formed through several rounds of genome duplications from diploid ancestors. Here, we built a pan-genome TE library for the Fragaria genus using ten published strawberry genomes at different ploidy levels, including seven diploids, one tetraploid, and two octoploids, and performed comparative analysis of TE content in these genomes. The TEs comprise 51.83% (F. viridis) to 60.07% (F. nilgerrensis) of the genomes. Long terminal repeat retrotransposons (LTR-RTs) are the predominant TE type in the Fragaria genomes (20.16% to 34.94%), particularly in F. iinumae (34.94%). Estimating TE content and LTR-RT insertion times revealed that species-specific TEs have shaped each strawberry genome. Additionally, the copy number of different LTR-RT families inserted in the last one million years reflects the genetic distance between Fragaria species. Comparing cultivated strawberry subgenomes to extant diploid ancestors showed that F. vesca and F. iinumae are likely the diploid ancestors of the cultivated strawberry, but not F. viridis. These findings provide new insights into the TE variations in the strawberry genomes and their roles in strawberry genome evolution.


Unsupervised Online Learning With Multiple Postsynaptic Neurons Based on Spike-Timing-Dependent Plasticity Using a Thin-Film Transistor-Type NOR Flash Memory Array.
We present a two-layer fully connected neuromorphic system based on a thin-film transistor (TFT)-type NOR flash memory array with multiple postsynaptic (POST) neurons. Unsupervised online learning by spike-timing-dependent plasticity (STDP) on the binary MNIST handwritten datasets is implemented, and its recognition result is determined by measuring firing rate of POST neurons. Using a proposed learning scheme, we investigate the impact of the number of POST neurons in terms of recognition rate. In this neuromorphic system, lateral inhibition function and homeostatic property are exploited for competitive learning of multiple POST neurons. The simulation results demonstrate unsupervised online learning of the full black-and-white MNIST handwritten digits by STDP, which indicates the performance of pattern recognition and classification without preprocessing of input patterns.


[Psychophysiologic disorders in patients with functional disorders of upper sections of the gastrointestinal tract and with gastroesophageal reflux disease].
The features of the psychovegetative status in patients with functional disorders of the esophagus and stomach (FD) and gastroesophageal reflux disease (GERD) are investigated. The methods included clinical, instrumental and psychometric examination. The patients of both groups had similar vegetative abnormalities and a tendency towards the growth of depression and anxiety parameters, did not differ in psychosocial factors, and had a wide range of psychovegetative abnormalities (PA). Lump in the throat, heartburn, epigastralgia (p < 0.01), depression, actual anxiety, alexitymia and vegetative disorders decreased in both groups (p < 0.05) after treatment with citalopram (20 mg per day) during 2 months. So PA are revealed in patients with FD and GERD, and citalopram reduces psychovegetative and GIT disorders.


Moral distress: levels, coping and preferred interventions in critical care and transitional care nurses.
To examine the level and frequency of moral distress in staff nurses working in two types of units in an acute care hospital and to gather information for future interventions addressing moral distress. In 2008, the American Association of Critical Care Nurses published a Position Statement on Moral Distress. Nurses working in units where critically ill patients are admitted may encounter distressing situations. Moral distress is the painful feelings and/or psychological disequilibrium that may occur when taking care of patients. An exploratory, descriptive design study was used to identify the type and frequency of moral distress experienced by nurses. The setting was an acute care hospital in which the subjects were sampled from two groups of nurses based on their unit assignment. A descriptive, questionnaire study was used. Nurses completed the 38-item moral distress scale, a coping questionnaire, and indicated their preferred methods for institutional support in managing distressing situations. A convenience sample of staff nurses was approached to complete the moral distress questionnaire. Overall, the nurses reported low levels of moral distress. Situations creating the highest levels of moral distress were those related to futile care. A significance between group differences was found in the physician practice dimension. Specific resources were identified to help guide future interventions to recognise and manage moral distress. Nurses reported lower levels and frequency of moral distress in these units but their open-ended responses appeared to indicate moral distress. Nurses identified specific resources that they would find helpful to alleviate moral distress. There are numerous studies that identify the situations and the impact of moral distress, but not many studies explore treatments and interventions for moral distress. This study attempted to identify nurse preferences for lessening the impact of moral distress.


Comparison Between Multisite Injection and Single Rotator Interval Injection of Corticosteroid in Primary Frozen Shoulder (Adhesive Capsulitis): A Randomized Controlled Trial.
Steroid injection is a commonly used conservative treatment for primary frozen shoulder (PFS), but the optimal injection site remains undetermined. We conducted a prospective randomized controlled trial of multisite combined injection (MCI) vs single rotator interval injection (SRI). A randomized double-blinded controlled trial. Center for Joint Surgery, Department of Orthopaedic Surgery, the Second Affiliated Hospital of Chongqing Medical University. Sixty-four patients with PFS were randomly assigned to 2 groups. The experimental group received MCI in the rotator interval, intraarticular, and subacromial bursa; the control group received an SRI. Both groups were injected with one mL of 40 mg triamcinolone acetonide and 4 mL of 2% lidocaine. The injection process was completed under ultrasound guidance. Follow-up points were 4, 8, and 12 weeks postinjection. The outcome measures included the Visual Analog Scale (VAS) score, the American Shoulder and Elbow Surgeons (ASES) score, the Constant-Murley Shoulder (CMS) score, passive range of motion of the shoulder, and patient satisfaction rating. Thirty patients in the MCI group and 29 patients in the SRI group were included in the data analysis. All the outcomes in the 2 groups were significantly better postinjection than preinjection. The MCI group had a lower VAS score than the SRI group at 4 weeks (3.1 ± 1.2 vs 4.3 ± 1.6) and 8 weeks (2.2 ± 1.2 vs. 3.4 ± 1.2) (P < 0.05). Compared with the SRI group, the MCI group had a significant improvement in flexion and abduction (P < 0.01). Additionally, the ASES and CMS scores in the MCI group were better than those in the SRI group at 4, 8 and 12 weeks (P < 0.01). Limitations include the sample size of this study is small and a that it was conducted at a single-center. Both MCI and SRI effectively alleviated pain and restored range of motion in patients with PFS. However, the MCI group had obviously lower early pain scores, better flexion and abduction, and better function scores than the SRI group; no additional adverse events were observed.


Effects of pH and urea on the conformational properties of subtilisin DY.
Subtilisin DY is very resistant to the denaturing action of urea: the conformational properties are not affected up to 4.5 M-urea, and even in the presence of 8 M-urea there is only a slow loss of ordered structure and caseinolytic activity. C.d. and fluorescence-emission studies also show that this proteinase is stable in the 5.5-10.0 pH range, whereas below pH 5.5 a sharp denaturation occurs that is complete at pH 4.5. Protein denaturation leads to a change of the emission quantum yield; in particular, in the native protein, indole fluorescence is quenched by some amino groups. Moreover, subtilisin DY possesses two classes of tyrosine residues: one class of exposed residues titrates normally, with pKapp. = 10.24, whereas one class of partially buried or hydrogen-bonded residues ionizes with pKapp. = 11.58. In general, such conformational properties resemble those of other subtilisins. However, some differences occur: e.g., subtilisin DY is less stable at acidic pH values and its tyrosine residues are more accessible to the solvent. Such differences are probably due to small variations of the three-dimensional structure; e.g., subtilisin DY has a slightly lower alpha-helix content.


Opinions of lung cancer clinicians on shared decision making in early-stage non-small-cell lung cancer.
To investigate the opinions of lung cancer clinicians concerning shared decision making (SDM) in early-stage non-small-cell lung cancer patients. A survey was conducted among Dutch cardiothoracic surgeons and lung surgeons, pulmonologists and radiation oncologists. The opinions of clinicians on the involvement of patients in treatment decision making was assessed using a 1-5 Likert-type scale. Through open questions, we queried barriers to and drivers of SDM in clinical practice. Clinicians were asked to review 7 hypothetical cases and indicate which treatment strategy they would choose using a 1-7 Likert-type scale. Twenty-six percent of surgeons, 20% of pulmonologists and 12% of radiation oncologists indicated that they always engage in SDM (16% missing; P-value = 0.10). Most respondents stated that, ideally, doctors and patients should decide together (surgeons 52%, pulmonologists 67% and radiation oncologists 35%; P-value = 0.005). Thirty percent of surgeons, 27% of pulmonologists and 44% of radiation oncologists indicated that doctors are not properly trained to implement SDM in clinical practice (P-value = 0.37). SDM may not always be feasible due to low patient education level and minimal knowledge about lung cancer. Wide variations in the clinicians' lung cancer treatment preferences were observed in the responses to the hypothetical cases. In current clinical decision making in lung cancer treatment, a majority of clinicians agree that it is important to involve lung cancer patients in treatment decision making but that time constraints and the inability of some patients to make a weighted decision are important barriers. The observed variation in lung cancer treatment preferences among clinicians suggests that for most patients both surgery and radiotherapy are suitable options, and it underlines the sensitive nature of treatment choices in early-stage non-small-cell lung cancer.


Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics.
Relatively little is known about the viral factors contributing to the lethality of the 1918 pandemic, although its unparalleled virulence was likely due in part to the newly discovered PB1-F2 protein. This protein, while unnecessary for replication, increases apoptosis in monocytes, alters viral polymerase activity in vitro, enhances inflammation and increases secondary pneumonia in vivo. However, the effects the PB1-F2 protein have in vivo remain unclear. To address the mechanisms involved, we intranasally infected groups of mice with either influenza A virus PR8 or a genetically engineered virus that expresses the 1918 PB1-F2 protein on a PR8 background, PR8-PB1-F2(1918). Mice inoculated with PR8 had viral concentrations peaking at 72 hours, while those infected with PR8-PB1-F2(1918) reached peak concentrations earlier, 48 hours. Mice given PR8-PB1-F2(1918) also showed a faster decline in viral loads. We fit a mathematical model to these data to estimate parameter values. The model supports a higher viral production rate per cell and a higher infected cell death rate with the PR8-PB1-F2(1918) virus. We discuss the implications these mechanisms have during an infection with a virus expressing a virulent PB1-F2 on the possibility of a pandemic and on the importance of antiviral treatments.


Selective loss of polymorphic mating types is associated with rapid phenotypic evolution during morphic speciation.
Polymorphism may play an important role in speciation because new species could originate from the distinctive morphs observed in polymorphic populations. However, much remains to be understood about the process by which morphs found new species. To detail the steps of this mode of speciation, we studied the geographic variation and evolutionary history of a throat color polymorphism that distinguishes the "rock-paper-scissors" mating strategies of the side-blotched lizard, Uta stansburiana. We found that the polymorphism is geographically widespread and has been maintained for millions of years. However, there are many populations with reduced numbers of throat color morphs. Phylogenetic reconstruction showed that the polymorphism is ancestral, but it has been independently lost eight times, often giving rise to morphologically distinct subspecies/species. Changes to the polymorphism likely involved selection because the allele for one particular male strategy, the "sneaker" morph, has been lost in all cases. Polymorphism loss was associated with accelerated evolution of male size, female size, and sexual dimorphism, which suggests that polymorphism loss can promote rapid divergence among populations and aid species formation.


Narrow and wide field amacrine cells fire action potentials in response to depolarization and light stimulation.
Action potentials in amacrine cells are important for lateral propagation of signals across the inner retina, but it is unclear how many subclasses of amacrine cells contain voltage-gated sodium channels or can fire action potentials. This study investigated the ability of amacrine cells with narrow ( <200 microm) and wide (>200 microm) dendritic fields to fire action potentials in response to depolarizing current injections and light stimulation. The pattern of action potentials evoked by current injections revealed two distinct classes of amacrine cells; those that responded with a single action potential (single-spiking cells) and those that responded with repetitive action potentials (repetitive-spiking cells). Repetitive-spiking cells differed from single-spiking cells in several regards: Repetitive-spiking cells were more often wide field cells, while single-spiking cells were more often narrow field cells. Repetitive-spiking cells had larger action potential amplitudes, larger peak voltage-gated NaV currents lower action potential thresholds, and needed less current to induce action potentials. However, there was no difference in the input resistance, holding current or time constant of these two classes of cells. The intrinsic capacity to fire action potentials was mirrored in responses to light stimulation; single-spiking amacrine cells infrequently fired action potentials to light steps, while repetitive-spiking amacrine cells frequently fired numerous action potentials. These results indicate that there are two physiologically distinct classes of amacrine cells based on the intrinsic capacity to fire action potentials.


Elimination of Acrolein by Disodium 5'-Guanylate or Disodium 5'-Inosinate at High Temperature and Its Application in Roasted Pork Patty.
Acrolein (ACR) is a highly active, simple unsaturated aldehyde found in various high-temperature processed foods. Its long-term accumulation in the human body increases the risk of chronic diseases. Animal and plant foodstuffs are rich in disodium 5'-guanylate (GMP) and disodium 5'-inosinate (IMP), which are authorized flavor enhancers. Herein, we used liquid chromatography with tandem mass spectrometry to explore the reaction-active kinetics and pathway of the interaction between GMP/IMP and ACR and validated it in roasted pork patties. Our results suggested that GMP and IMP could efficiently eliminate ACR by forming ACR adducts (GMP-ACR, IMP-ACR). In addition, IMP exhibited a higher reaction rate, whereas GMP had a good trapping capacity at a later stage. As carriers of GMP and IMP, dried mushrooms and shrimp exhibited an effective ACR-trapping ability in the ACR model and roasted pork patty individually and in combination. Adding 10% of dried mushroom or shrimp alone or 5% of dried mushroom and shrimp in combination eliminated up to 53.9%, 55.8%, and 55.2% ACR in a roasted pork patty, respectively. This study proposed a novel strategy to eliminate the generation of ACR in roasted pork patties by adding foodstuffs rich in GMP and IMP.


Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes.
Several options exist for surgical management of essential tremor (ET), including radiofrequency lesioning, deep brain stimulation and γ knife radiosurgery of the ventralis intermedius nucleus of the thalamus. Recently, magnetic resonance-guided focused ultrasound (MRgFUS) has been developed as a less-invasive surgical tool aimed to precisely generate focal thermal lesions in the brain. Patients underwent tremor evaluation and neuroimaging study at baseline and up to 6 months after MRgFUS. Tremor severity and functional impairment were assessed at baseline and then at 1 week, 1 month, 3 months and 6 months after treatment. Adverse effects were also sought and ascertained by directed questions, neuroimaging results and neurological examination. The current feasibility study attempted MRgFUS thalamotomy in 11 patients with medication-resistant ET. Among them, eight patients completed treatment with MRgFUS, whereas three patients could not complete the treatment because of insufficient temperature. All patients who completed treatment with MRgFUS showed immediate and sustained improvements in tremors lasting for the 6-month follow-up period. Skull volume and maximum temperature rise were linearly correlated (linear regression, p=0.003). Other than one patient who had mild and delayed postoperative balance, no patient developed significant postsurgical complications; about half of the patients had bouts of dizziness during the MRgFUS. Our results demonstrate that MRgFUS thalamotomy is a safe, effective and less-invasive surgical method for treating medication-refractory ET. However, several issues must be resolved before clinical application of MRgFUS, including optimal patient selection and management of patients during treatment.


Heat trapping in a nano-layered microenvironment: estimation of temperature by thermal sensing molecules.
We have previously found reversible photo-induced expansion and contraction of organic/inorganic clay hybrids, and even sliding of niobate nano-sheets at the macroscopic level of organic/inorganic niobate hybrids, induced by the molecular photo-isomerization of the polyfluoroalkylated azobenzene derivative (C3F-Azo-C6H) intercalated within the interlayer, which is viewed as an artificial muscle model unit. Based on systematic investigations of the steady state photo-isomerization and transient behavior of the reaction, we comprehended that the phenomena is caused by trapping of excess energy liberated during the isomerization, as well as the relaxation processes upon excitation of azobenzene chromophores in the interlayers of the hybrid. In this paper, quantitative estimation of transient 'heat' trapped in various microenvironments has been studied by each co-intercalation of temperature sensing dye molecules - rhodamine B (RhB) or tris(bipyridine)ruthenium(ii) chloride (Rubpy) with C3F-Azo-C6H within clay (SSA) nano-layers. The amount of dye molecules co-intercalated was kept to trace amounts that did not alter the bi-layered structure of the hybrid. The temperature of the microenvironment surrounding the probe molecules was estimated from the emission lifetime analysis. The evidently reduced emission lifetimes in C3F-Azo-C6H/SSA and C3H-Azo-C6H/SSA hybrids in the film state, indicated the elevation of temperature of the microenvironment upon excitation of the chromophores, which demonstrated our previous hypothesis rationalizing that the high reactivity of isomerization in the hybrid film state is caused by heat trapping via multi-step dissipation of the excess energy. With the hybrid of a hydrocarbon analogue (C3H-Azo-C6H), a distinct difference in temperature gradient was found to show the crucial role of the perfluoroalkyl chain of the surfactant that traps the excess energy to retard its dissipation leading to three-dimensional morphological motion.


Posterior Reversible Encephalopathy Syndrome: Three Ethiopian Hypertensive Patients Presented with Recurrent Seizure: Case Series and Literature Review.
Posterior Reversible Encephalopathy Syndrome (PRES) is a potentially reversible neurological disorder of acute to subacute onset characterized by headache, nausea and vomiting, visual disturbance, seizure and altered mental status. Neuroimaging findings are characteristic, which allow early diagnosis in the appropriate clinical setting and enable to institute appropriate therapy timely. We report 3 adult patients with a history of hypertension presented with recurrent episode of seizure and altered mentation. While all the 3 patients were preliminarily diagnosed with Ischemic stroke, they were subsequently diagnosed with posterior reversible encephalopathy syndrome after neuroimaging revealed the typical features of the syndrome. They were started on antihypertensive and anticonvulsant drugs. On follow-up examination after 3-4 weeks, the patients showed marked clinical and neuro-imaging improvements. Posterior reversible encephalopathy syndrome is a rare condition. The presenting clinical symptoms are non-specific and may mimic other neurological disorders. Therefore, early recognition of classic radiographic features is vital to the diagnosis. Timely diagnosis and treatment of this syndrome is important as the treatment outcome is mostly favorable.


Music Therapy Is Effective during Sleep in Preterm Infants.
Recent research found evidence supporting music therapy for preterm infants to stabilize vital signs and possibly promote neurodevelopment. Even though preterm infants spend a considerable amount of time sleeping, the effectiveness of music therapy during sleep has not been studied. The aim of this study was to investigate the effect of music therapy on preterm infants' vital signs with respect to the state of wakefulness. The first 20 consecutive infants born with <32 weeks' gestational age (GA) from the intervention group of an ongoing randomized controlled trial received live music therapy twice a week until hospital discharge. The heart rate, respiratory rate, oxygen saturation, and state of wakefulness were recorded before and after therapy. We observed significantly lower heart and respiratory rates and higher oxygen saturation after live music therapy sessions in general (mean differences -4.9 beats per min; -7.0 breaths per min and +1.5%, respectively). When music therapy was applied during sleep, respiratory rates significantly lowered by 8.8 breaths per min and oxygen saturation increased by 1.6%, whereas in the awake state the vital parameters did not significantly change (heart rate -5.2 beats per min; respiratory rate +0.6 breaths per min and oxygen saturation +1.0%). Music therapy stabilized the respiratory rates and oxygen saturations in sleeping preterm infants.


Specimen pooling for efficient use of biospecimens in studies of time to a common event.
For case-control studies that rely on expensive assays for biomarkers, specimen pooling offers a cost-effective and efficient way to estimate individual-level odds ratios. Pooling helps to conserve irreplaceable biospecimens for the future, mitigates limit-of-detection problems, and enables inclusion of individuals who have limited available volumes of biospecimen. Pooling can also allow the study of a panel of biomarkers under a fixed assay budget. Here, we extend this method for application to discrete-time survival studies. Assuming a proportional odds logistic model for risk of a common outcome, we propose a design strategy that forms pooling sets within those experiencing the outcome at the same event time. We show that the proposed design enables a cost-effective analysis to assess the association of a biomarker with the outcome. Because the standard likelihood is slightly misspecified for the proposed pooling strategy under a nonnull biomarker effect, the proposed approach produces slightly biased estimates of exposure odds ratios. We explore the extent of this bias via simulations and illustrate the method by revisiting a data set relating polychlorinated biphenyls and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene to time to pregnancy.


Validation study on new isothermal container for hot ready to eat food in catering establishments: Preliminary results.
The production methods, in particular the cook-serve method, applied in high production catering establishments, even if inserted in a correct spatial design, it is affected by time-temperature flows characterized by inadequate designed moments during which critical points can be observed. The aim of this study was to evaluate, at a preliminary stage, how the new technologies can support the supply chain and production processes in catering establishments. To this end, a specific passive and active heat storage system was tested: "Polibox Smart Heater®" (PX SH), which makes an isothermal expanded polypropylene container an advanced maintainer for ready to eat food. The experimental design was divided into four different experiments, during which the functionality of the isothermal containers was evaluated, and thermal-tightness tests were carried out. The results showed that the PX SH containers, containing a heat accumulator, are temperature maintainers, which guarantee thermal stability (>65°C), according to the current standard (UNI EN 12571:1999). In conclusion, the production chain of catering establishments should use innovative technologies such as PX SH, in order to benefit from performance consistent with the safety, hygiene and sensory criteria.


A quantitative analysis of sources of changes in government expenditures on health, 2000 to 2015: what can we learn from experience to date?
Background: Achieving universal health coverage (UHC) requires increased domestic financing of health by low-income countries (LICs) and middle-income countries (MICs). It is critical to understand how much governments have devoted to health from domestic sources and how much growth might be realistic over time. Methods: Using data from WHO's Global Health Expenditure Database, we examined how the composition of current health expenditure changed by financing source and the sources of growth in health expenditures from 2000-2015 across different income groups. We disaggregated how much growth in government expenditures on health from domestic sources was due to economic growth, growth in government spending as a share of GDP, and reallocations in government expenditures towards health. Results: Lower MICs (LMICs) and upper MICs (UMICs), as a group, saw a significant reduction in out-of-pocket expenditures and a significant growth in government expenditures on health from domestic sources as a share of current health expenditures over the period. This trend indicates likely progress in the pathway to UHC. For LICs, these trends were more muted. Growth in government expenditure on health from domestic sources was driven primarily by economic growth in LICs, LMICs, and UMICs. Growth in government expenditure on health due to increased government spending as a share of GDP was high in UMICs. For the high-income country group, where economic growth was relatively slower and government spending was already high with strong tax bases, the largest driver of growth in government expenditure on health from domestic sources was reallocation of the government budget towards health. Conclusions: Dialogue on domestic resource mobilization needs to emphasize overall economic growth and growth in the government spending as a share of GDP as well as the share of health in the government budget.


Macula densa stimulation of renin is reversed by selective inhibition of neuronal nitric oxide synthase.
The neuronal isoform of nitric oxide synthase (nNOS) exists in the renal cortex predominantly in the macula densa, suggesting that nitric oxide (NO) derived from the macula densa plays a role in feedback regulation of renin in response to altered sodium metabolism. To determine if nNOS is a critical component in renin stimulation induced by dietary sodium restriction, rats received either normal sodium or a sodium-restricted diet (0.03%) for 7 days and subsequently were or were not treated with the selective inhibitor of nNOS 7-nitroindazole (7-NI) either acutely (50 mg/kg body wt ip) on the final day or chronically (20 mg/kg body wt ip 2 x/day) over the final 5 days. On the last day, rats were anesthetized with Inactin and fitted with arterial and renal venous catheters to collect blood and monitor blood pressure (BP) and a flow probe to measure renal blood flow (RBF). BP (105 vs. 108 mmHg) was similar in normal and low-sodium dietary groups, respectively, whereas RBF tended to be higher in the sodium-restricted group (6.5 +/- 0.3 vs. 7.6 +/- 0.4 ml.min-1.g kidney wt-1). Both renal venous renin (RR) and renin secretion rate (RSR) were elevated approximately fourfold by sodium restriction [RR = 5.8 +/- 0.8 vs. 20.5 +/- 2.7 ng angiotensin (ANG) I.ml-1.h-1; P < 0.001; RSR = 3.0 +/- 0.9 vs. 13.1 +/- 4.1 ng ANG I.h-1.min-1; P < 0.025]. Acute 7-NI did not change BP, RR, or RSR, but reduced RBF in sodium-restricted rats by 8% (P < 0.05). Chronic 7-NI had no effect on renin in rats on a normal diet, but reduced RR by one-half in the sodium-restricted group (to 9.9 +/- 1.6 ng ANG I-ml-1.h-1; P < 0.001) and reduced RSR to normal (diet) levels (to 3.9 +/- 1.4 ng ANG I.h-1.min-1; P < 0.05). Although selective NOS inhibition by 7-NI did not affect BP, RBF, or renin in control rats on a normal diet, chronic 7-NI reversed the stimulation of renin induced by dietary sodium restriction. These data suggest that nNOS-derived NO plays an important role in the macula densa during feedback stimulation of renin induced by dietary sodium restriction.


Seasonal patterns for entomological measures of risk for exposure to Culex vectors and West Nile virus in relation to human disease cases in northeastern Colorado.
We examined seasonal patterns for entomological measures of risk for exposure to Culex vectors and West Nile virus (family Flaviviridae, genus Flavivirus, WNV) in relation to human WNV disease cases in a five-county area of northeastern Colorado during 2006-2007. Studies along habitat/elevation gradients in 2006 showed that the seasonal activity period is shortened and peak numbers occur later in the summer for Culex tarsalis Coquillett females in foothills-montane areas >1600 m compared with plains areas <1600 m in Colorado's Front Range. Studies in the plains of northeastern Colorado in 2007 showed that seasonal patterns of abundance for Cx. tarsalis and Culex pipiens L. females differed in that Cx. tarsalis reached peak abundance in early July (mean of 328.9 females per trap night for 18 plains sites), whereas the peak for Cx. pipiens did not occur until late August (mean of 16.4 females per trap night). During June-September in 2007, which was a year of intense WNV activity in Colorado with 578 reported WNV disease cases, we recorded WNV-infected Cx. tarsalis females from 16 of 18 sites in the plains. WNV infection rates in Cx. tarsalis females increased gradually from late June to peak in mid-August (overall maximum likelihood estimate for WNV infection rate of 8.29 per 1000 females for the plains sites in mid-August). No WNV-infected Culex mosquitoes were recorded from sites >1600 m. The vector index for abundance of WNV-infected Cx. tarsalis females for the plains sites combined exceeded 0.50 from mid-July to mid-August, with at least one site exceeding 1.00 from early July to late August. Finally, we found that abundance of Cx. tarsalis females and the vector index for infected females were strongly associated with weekly numbers of WNV disease cases with onset 4-7 wk later (female abundance) or 1-2 wk later (vector index).


Diagnostic Accuracy and Clinical Implications of Translabial Ultrasound for the Assessment of Levator Ani Defects and Levator Ani Biometry in Women With Pelvic Organ Prolapse: A Systematic Review.
The aim of this study was to assess the diagnostic accuracy and clinical implications of translabial 3-dimensional (3D) ultrasound for the assessment of levator ani defects and biometry in women with pelvic organ prolapse (POP). We performed a systematic literature search through computerized databases including MEDLINE (via PubMed), EMBASE (via OvidSP), and the Cochrane Library using both medical subject headings and text terms from January 1, 2003, to December 25, 2015.We included articles that reported on POP status and diagnostic accuracy measurements with translabial 3D ultrasound or transperineal ultrasound for the detection of levator ani defects or for measuring pelvic floor biometry, that is, levator ani hiatus, or reported on the clinical relevance of using translabial 3D ultrasound for levator ani defects or measuring pelvic floor biometry in women with POP. Thirty-one articles were selected in accordance with parts of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines that can be applied to studies of diagnostic accuracy. Twenty-two articles (71%) are coauthored by 1 expert in this field. Detecting levator ani defects with translabial 3D ultrasound compared with magnetic resonance imaging showed a moderate to good agreement, whereas measuring hiatal biometry on translabial 3D ultrasound compared with magnetic resonance imaging showed a moderate to very good agreement.The interobserver agreement for diagnosing levator ani defects and measuring the levator hiatal area showed a moderate to very good agreement. Furthermore, levator ani defects increase the risk of cystocele and uterine prolapse, and levator ani defects are associated with recurrent POP.Finally, a larger hiatus was associated with POP and recurrent POP. Translabial 3D ultrasound is reproducible for diagnosing levator ani defects and ballooning hiatus. Both levator ani defects and a larger hiatal area are, in a selected population of patients with pelvic floor dysfunction, associated with POP and recurrent POP. More research is needed concerning external validation because most data in this article are coauthored by 1 expert in this field.


A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.
To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.


Modelling the persistence of mosquito vectors of malaria in Burkina Faso.
Populations of the Anopheles gambiae complex are found during the rainy season throughout West Africa, even in arid areas with long dry seasons during which mosquitoes appear to be absent. Several hypotheses have been proposed to explain this apparent paradox, including aestivation, dispersal between neighbouring settlements, and long distance migration using high-altitude wind currents. An individual-based, spatially explicit model of mosquito populations was developed for a region of West Africa centred on, and including all of, Burkina Faso. Populations associated with human settlements were linked by dispersal and the model incorporated geospatial data on the distribution of settlements, water bodies and rainfall. Local dispersal (at rates consistent with experimental data) was necessary to explain observed patterns of rainy season populations across all of the simulation area, but by itself failed to account for the presence of populations in the arid North (the Sahel). The presence of rare dry-season larval sites could explain these northern populations, but seems inconsistent with field surveys. Aestivation by female mosquitoes explained rainy-season populations in all but the very sparsest and driest areas of human habitation, while long-distance migration based on annual wind patterns could account for all observed populations. Modelling studies such as this can help assess the potential validity of different hypotheses and suggest priority areas for experimental study. In particular, the results highlight a shortage of empirical research on mosquito dispersal between neighbouring settlements, which may be critically important to the continued presence of many mosquito populations in West Africa. Further research that establishes the extent to which mosquitoes aestivate, and migrate using high altitude winds, is also much needed to understand Sahelian mosquito populations.


The presence of Helicobacter pylori in dental plaque of children and their parents: is it related to their periodontal status and oral hygiene?
To investigate the possible presence of H. pylori in subgingival dental plaque of children with upper gastrointestinal symptoms, as well as of their parents' and to detect any association between the presence of H. pylori and oral hygiene together with the periodontal status of children and their parents. The study comprised of 35 children with upper gastrointestinal symptoms, aged 4 to 14 years and 45 family members (mothers and/or fathers). Gastric biopsies were collected from all children for CLO-test, histology and culture. Serology was used to assess the H. pylori infection status of their parents. Before endoscopy, subgingival dental plaque from children and their parents were collected from 4 healthy and 4 diseased sites, and the clinical indices (gingival index, plaque index, bleeding on probing, pocket depth, loss of clinical attachment) after plaque collection were recorded. The Chi-square test was performed to investigate possible differences between children and their parents and logistic regression analysis was used to evaluate the association of parental infection status with that of children. 15 out of 35 children (42.86%) were found H. pylori-positive. In 6 out of the 15 infected children (40%) H. pylori was also identified in their subgingival plaque samples, as well as in one among the 20 non infected children. The presence of H. pylori in dental plaque was significantly associated with its presence in the gastric antrum (p=0.0274). H. pylori was identified in the dental plaque of 7 mothers corresponding to children with positive PCR in their dental plaque and of 4 fathers (one corresponding with his child found H. pylori positive in dental plaque). Children who had H. pylori identified in their dental plaque belonged to families with members also having H. pylori in dental plaque. No significant relationship between periodontal clinical parameters and detection of H. pylori in dental plaque in both children and their parents was found. However, the presence of H. pylori in the subgingival plaque samples was significantly correlated with the parental diseased sites (p=0.02). H. pylori was detected in subgingival dental plaque of children and their families, possibly acting as a "reservoir" contributing to the intra-familial spread. Efficient oral hygiene and healthy periodontal status could reduce this transmission.


[Diagnostic pitfalls of pseudo-foster kennedy syndrome - a case report].
To the outpatient facility of the Department of Ophthalmology, Faculty Hospital Brno, Czech Republic, E.U., was in June 2013 referred a 24 years old man with the suspicion of Foster Kennedy syndrome. On the fundus examinations, the findings were in correlation with the symptoms of this syndrome: slightly pale optic disc of the right eye and edema with the anterior extension of the optic nerve head of the left eye. The perimetric examination revealed bilateral visual fields defects, mainly in the nasal parts of the visual fields which is not typical for this syndrome. The native magnetic resonance imaging (MRI) examination was negative. Due to the suspicion of pathologic finding in the visual pathway area, the blood levels of pituitary gland hormones were examined and revealed elevated prolactin levels. In the indicated MRI examination with contrast, in the revised reading, a suspicious microadenoma of the pituitary gland was detected. Due to the atypical changes in the perimetric examinations, other possible causes of visual fields defects as coincidence of multiple, each other independent pathologies (neuritis or neuropathy of the optic nerve, neuromyelitis optica (Devic disease), Lebers hereditary optic neuritis (LHON) etc.) to exclude or to confirm the Pseudo-Foster Kennedy syndrome were taken into account. The patient is regularly followed up at our outpatient facility as well as at the outpatient facility of the Department of Neurosurgery, where, until now, the follow up only was recommended. The diagnosis of this case was, until now, set as Pseudo- Foster Kennedy syndrome, with unclarified cause of the clinical findings.


Herbivory elicits changes in green leaf volatile production via jasmonate signaling and the circadian clock.
The timing of plant volatile emissions is important for a robust indirect defense response. Green leaf volatiles (GLVs) are emitted by plants upon damage but can be suppressed by herbivore-associated elicitors, and the abundance and composition of GLVs vary depending on the timing of herbivore attack. We show that the GLV biosynthetic enzyme HYDROPEROXIDE LYASE (HPL) is transcriptionally regulated by the circadian clock in Nicotiana attenuata. In accordance with transcript abundance of NaHPL, GLV aldehyde pools in intact leaves peaked at night and at subjective night under diurnal and continuous light conditions, respectively. Moreover, although the basal abundance of NaHPL transcripts is upregulated by jasmonate (JA) signaling, JA does not regulate the reduction of NaHPL transcript abundance in damaged leaves by simulated herbivore treatment. Unexpectedly, the plant circadian clock was strongly altered when Manduca sexta larvae fed on N. attenuata, and this was also independent of JA signaling. Lastly, the temporal dynamics of NaHPL transcripts and total GLV emissions were strongly altered by M. sexta larval feeding. Our data suggest that the temporal dynamics of emitted GLV blends result from a combination of damage, JA signaling, herbivore-associated elicitors, and the plant circadian clock.


The irritable colon.
The irritable colon syndrome is a very common disorder with no serious sequelae. The cause is unknown but low dietary bulk and psychological factors are believed important. Sufferers may experience various combinations of diarrhea, constipation and abdominal pain. The mechanisms are obscure but abnormal colon motility has been amply demonstrated. Serious organic diseases such as colitis and carcinoma of the colon must be firmly excluded. Treatment consists of sympathetic explanation and reassurance, increased dietary bulk and occasional judicious use of antispasmodic agents.


Developmental expression of three prmt genes in Xenopus.
Protein arginine methyltransferases (PRMTs) are involved in many cellular processes via the arginine methylation of histone or non-histone proteins. We examined the expression patterns of prmt4, prmt7, and prmt9 during embryogenesis in Xenopus using whole-mount in situ hybridization and quantitative reverse transcription polymerase chain reaction (RT-PCR). Xenopus prmt4 and prmt7 were expressed in the neural crest, brain, and spinal cord, and also detected in the eye, branchial arches, and heart at the tailbud stage. Specific prmt9 signals were not detected in Xenopus embryos until the late tailbud stage when weak expression was observed in the branchial arches. Quantitative RT-PCR indicated that the expressions of prmt4 and prmt7 were up-regulated during the neurula stage, whereas prmt9 maintained its low expression until the late tailbud stage, consistent with the whole-mount in situ hybridization results. Thus, the developmental expression patterns of these three prmt genes in Xenopus embryos provide a basis for further functional study of such genes.


Antigenic regions of African swine fever virus phosphoprotein P30.
African swine fever (ASF) is one of the most complex and lethally haemorrhagic viral diseases of swine, affecting all breeds and ages of pigs. In the absence of ASF vaccines, reliable laboratory diagnosis and restricted biosecurity are critical for disease prevention and control. A detection of ASF-specific antibodies in an unvaccinated pig is a good marker for the diagnosis of ASF. The immunoperoxidase test (IPT) is a sensitive test for detecting ASF virus (ASFV) antibodies. However, due to the complexity of the procedure, the IPT is only suitable to be used as a confirmatory test. The ASFV p30 protein-based enzyme-linked immunosorbent assay (ELISA) is widely used for ASFV antibody screening, but the sensitivity is not comparable to the IPT. It is essential to have a better understanding of the antigenic properties of ASFV p30 to improve p30-based serologic tests. In this study, we developed a panel of 21 monoclonal antibodies (mAbs) against ASFV p30. With 14 out of the 21 mAbs, we defined 4 antigenic regions that contain at least 4 linear epitopes. Nine of the 14 mAbs mapped to antigenic regions 3 and 4 reacted with p30 in all serologic methods tested in this study, such as indirect immunofluorescence assay (IFA), ELISA and Western blot. The antigenic regions 3 and 4 are highly conserved and immunodominant in host antibody response. These mAbs and the defined p30 antigenic regions 3 and 4 provide valuable tools for the development and improvement of ASF serologic assays.


Enhanced in vitro model of the CSF dynamics.
Fluid dynamics of the craniospinal system are complex and still not completely understood. In vivo flow and pressure measurements of the cerebrospinal fluid (CSF) are limited. Whereas in silico modeling can be an adequate pathway for parameter studies, in vitro modeling of the craniospinal system is essential for testing and evaluation of therapeutic measures associated with innovative implants relating to, for example, normal pressure hydrocephalus and other fluid disorders. Previously-reported in vitro models focused on the investigation of only one hypothesis of the fluid dynamics rather than developing a modular set-up to allow changes in focus of the investigation. The aim of this study is to present an enhanced and validated in vitro model of the CSF system which enables the future embedding of implants, the validation of in silico models or phase-contrast magnetic resonance imaging (PC-MRI) measurements and a variety of sensitivity analyses regarding pathological behavior, such as reduced CSF compliances, higher resistances or altered blood dynamics. The in vitro model consists of a ventricular system which is connected via the aqueduct to the cranial and spinal subarachnoid spaces. Two compliance chambers are integrated to cushion the arteriovenous blood flow generated by a cam plate unit enabling the modeling of patient specific flow dynamics. The CSF dynamics are monitored using three cranial pressure sensors and a spinal ultrasound flow meter. Measurements of the in vitro spinal flow were compared to cervical flow data recorded with PC-MRI from nine healthy young volunteers, and pressure measurements were compared to the literature values reported for intracranial pressure (ICP) to validate the newly developed in vitro model. The maximum spinal CSF flow recorded in the in vitro simulation was 133.60 ml/min in the caudal direction and 68.01 ml/min in the cranial direction, whereas the PC-MRI flow data of the subjects showed 122.82 ml/min in the caudal and 77.86 ml/min in the cranial direction. In addition, the mean ICP (in vitro) was 12.68 mmHg and the pressure wave amplitude, 4.86 mmHg, which is in the physiological range. The in vitro pressure values were in the physiological range. The amplitudes of the flow results were in good agreement with PC-MRI data of young and healthy volunteers. However, the maximum cranial flow in the in vitro model occurred earlier than in the PC-MRI data, which might be due to a lack of an in vitro dynamic compliance. Implementing dynamic compliances and related sensitivity analyses are major aspects of our ongoing research.


Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide.
Inflammatory bowel disease (IBD) has been linked to a loss of tolerance towards the resident microflora. Therapeutic use of probiotics is known to be strain specific, but precise mechanisms remain unclear. The role of NOD2 signalling and the protective effect of Lactobacillus peptidoglycan (PGN) and derived muropeptides in experimental colitis were evaluated. The anti-inflammatory capacity of lactobacilli and derived bacterial compounds was evaluated using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model. The role of NOD2, MyD88 and interleukin 10 (IL-10) in this protection was studied using Nod2(-/-), MyD88(-/-) and Il10-deficient mice, while induction of regulatory dendritic cells (DCs) was monitored through the expansion of CD103(+) DCs in mesenteric lymph nodes or after adoptive transfer of bone marrow-derived DCs. The development of regulatory T cells was investigated by following the expansion of CD4(+)FoxP3(+) cells. High-performance liquid chromatography and mass spectrometry were used to analyse the PGN structural differences. The protective capacity of strain Lactobacillus salivarius Ls33 was correlated with a local IL-10 production and was abolished in Nod2-deficient mice. PGN purified from Ls33 rescued mice from colitis in an IL-10-dependent manner and favoured the development of CD103(+) DCs and CD4(+)Foxp3(+) regulatory T cells. In vitro Ls33 PGN induced IL-10-producing DCs able to achieve in vivo protection after adoptive transfer in a NOD2-dependent way. This protection was also correlated with an upregulation of the indoleamine 2,3-dioxygenase immunosuppressive pathway. The protective capacity was not obtained with PGN purified from a non-anti-inflammatory strain. Structural analysis of PGNs highlighted in Ls33 the presence of an additional muropeptide, M-tri-Lys. The synthesised ligand protected mice from colitis in a NOD2-dependent but MyD88-independent manner. The results indicated that PGN and derived muropeptides are active compounds in probiotic functionality and might represent a useful therapeutic strategy in IBD.


Nonproteolytic K29-Linked Ubiquitination of the PB2 Replication Protein of Influenza A Viruses by Proviral Cullin 4-Based E3 Ligases.
The multifunctional nature of viral proteins is essentially driven by posttranslational modifications (PTMs) and is key for the successful outcome of infection. For influenza A viruses (IAVs), a composite pattern of PTMs regulates the activity of viral proteins. However, almost none are known that target the PB2 replication protein, except for inducing its degradation. We show here that PB2 undergoes a nonproteolytic ubiquitination during infection. We identified E3 ubiquitin ligases catalyzing this ubiquitination as two multicomponent RING-E3 ligases based on cullin 4 (CRL4s), which are both contributing to the levels of ubiquitinated forms of PB2 in infected cells. The CRL4 E3 ligase activity is required for the normal progression of the viral cycle and for maximal virion production, indicating that the CRL4s mediate a ubiquitin signaling that promotes infection. The CRL4s are recruiting PB2 through an unconventional bimodal interaction with both the DDB1 adaptor and DCAF substrate receptors. While able to bind to PB2 when engaged in the viral polymerase complex, the CRL4 factors do not alter transcription and replication of the viral segments during infection. CRL4 ligases catalyze different patterns of lysine ubiquitination on PB2. Recombinant viruses mutated in the targeted lysines showed attenuated viral production, suggesting that CRL4-mediated ubiquitination of PB2 contributes to IAV infection. We identified K29-linked ubiquitin chains as main components of the nonproteolytic PB2 ubiquitination mediated by the CRL4s, providing the first example of the role of this atypical ubiquitin linkage in the regulation of a viral infection.IMPORTANCE Successful infection by influenza A virus, a pathogen of major public health importance, involves fine regulation of the multiple functions of the viral proteins, which often relies on post-translational modifications (PTMs). The PB2 protein of influenza A viruses is essential for viral replication and a key determinant of host range. While PTMs of PB2 inducing its degradation have been identified, here we show that PB2 undergoes a regulating PTM signaling detected during infection, based on an atypical K29-linked ubiquitination and mediated by two multicomponent E3 ubiquitin ligases. Recombinant viruses impaired for CRL4-mediated ubiquitination are attenuated, indicating that ubiquitination of PB2 is necessary for an optimal influenza A virus infection. The CRL4 E3 ligases are required for normal viral cycle progression and for maximal virion production. Consequently, they represent potential candidate host factors for antiviral targets.


Ram management for northeastern flocks.
The ram is an important member of the flock, particularly in smaller, intensively managed flocks such as are found in the Northeast. An infertile ram can spell reproductive and financial failure for the producer. A highly fertile ram can settle more ewes in a shorter time, produce more twins, and confer valuable traits on his offspring. These include wool type, rate of gain and higher sperm production and ovulation rates. Details of the breeding soundness examination, including semen evaluation are discussed. Ram management techniques appropriate for Northeastern sheep producers are presented.


Are stroke patients discharged sooner if in-patient rehabilitation services are provided seven v six days per week?
A comparison was made of 113 consecutive patients who suffered a cerebrovascular accident and were hospitalized at a rehabilitation inpatient unit by dividing them into two groups: one group received the traditional 6-day/wk treatment regimen, and another group received treatment during the entire week (7 days/wk). When the patients were asked whether they had a preference (which did not affect their group assignment), 82% preferred a 6-day/wk program and 18% preferred a 7-day/wk program. The length of inpatient stay for the 57 patients enrolled in the 6-day/wk program was 20.14 days; for the 56 patients enrolled in the 7-day/wk program, the average length of stay was 20.11 days. This represents no significant difference. The functional recoveries were evaluated in areas that can affect length of stay, including dressing, bladder control, ambulation, and problem-solving. Both groups demonstrated significant gains in each domain when the intake and discharge ratings were compared. However, these gains were not significantly different when the 6- and 7-day/wk groups were compared. The results of the study contained herein, therefore, suggest that a 6-day/wk program for patients who have suffered a cardiovascular accident is just as effective as a 7-day/wk program.


Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis.
Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge. Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate. MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate. Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior.


Structure of outcome beliefs in condom use. The Project RESPECT Study Group.
To study the structure of beliefs about condom use outcomes, the authors derived and tested 4 psychosocial hypothetical models: (a) a 2-factor model of the personal and social outcomes of condom use; (b) a 2-factor model of the pros and cons of the behavior; (c) a 3-factor model (i.e., physical, self-evaluative, and social) of outcome expectancies; and (d) a thematic 4-factor model of the protection, self-concept, pleasure, and interaction implications of the behavior. All 4 models were studied with a confirmatory factor analysis approach in a multisite study of 4,638 participants, and the thematic solution was consistently the most plausible. Self-concept and pleasure were most strongly associated with attitudes toward using condoms, intentions to use condoms, and actual condom use, whereas protection and interaction generally had little influence.


Exploring Neural Efficiency in Multiple Sclerosis Patients during the Symbol Digit Modalities Test: A Functional Magnetic Resonance Imaging Study.
Reduced information-processing speed (IPS) is a primary cognitive deficit of multiple sclerosis (MS) patients. The neural efficiency hypothesis describes an inverse relationship between cognitive performance in a task and the amount of cognitive resources devoted to it. Previous studies have shown that the neural efficiency hypothesis provides an appropriate framework to explore cognitive dysfunction in neurological patients. The aim of this study was to explore the neural efficiency hypothesis regarding IPS capabilities in cognitively preserved MS patients. 16 MS patients and 17 healthy controls (HCs) were enrolled and neuropsychologically assessed. All participants also performed a functional magnetic resonance imaging (fMRI)-adapted version of the Symbol Digit Modalities Test (SDMT) at different interstimulus intervals (ISI: 1.5, 2, and 2.5 s). MS patients only displayed lower SDMT performance when the ISI was set at 1.5 s. However, MS patients' normal SDMT performance at larger ISIs was achieved at the cost of increased brain activation, hence revealing that they were less cognitively efficient than the HCs. Regression analyses confirmed this conclusion by showing an opposite relationship between SDMT performance and the amount of neural resources recruited in the HC and MS groups. Thus, while a positive relationship between both variables was observed in MS patients, this correlation was negative for the HC group. MS patients require more cognitive resources than HCs to achieve a normal SDMT performance, then revealing that they are less efficient regarding IPS capabilities.


Periodic properties of the histaminergic system of the mouse brain.
Brain histamine is involved in the regulation of the sleep-wake cycle and alertness. Despite the widespread use of the mouse as an experimental model, the periodic properties of major markers of the mouse histaminergic system have not been comprehensively characterized. We analysed the daily levels of histamine and its first metabolite, 1-methylhistamine, in different brain structures of C57BL/6J and CBA/J mouse strains, and the mRNA level and activity of histidine decarboxylase and histamine-N-methyltransferase in C57BL/6J mice. In the C57BL/6J strain, histamine release, assessed by in vivo microdialysis, underwent prominent periodic changes. The main period was 24 h peaking during the activity period. Additional 8 h periods were also observed. The release was highly positively correlated with active wakefulness, as shown by electroencephalography. In both mouse strains, tissue histamine levels remained steady for 24 h in all structures except for the hypothalamus of CBA/J mice, where 24-h periodicity was observed. Brain tissue 1-methylhistamine levels in both strains reached their maxima in the periods of activity. The mRNA level of histidine decarboxylase in the tuberomamillary nucleus and the activities of histidine decarboxylase and histamine-N-methyltransferase in the striatum and cortex did not show a 24-h rhythm, whereas in the hypothalamus the activities of both enzymes had a 12-h periodicity. These results show that the activities of histamine-metabolizing enzymes are not under simple direct circadian regulation. The complex and non-uniform temporal patterns of the histaminergic system of the mouse brain suggest that histamine is strongly involved in the maintenance of active wakefulness.


Stem Cells and Engineered Scaffolds for Regenerative Wound Healing.
The normal wound healing process involves a well-organized cascade of biological pathways and any failure in this process leads to wounds becoming chronic. Non-healing wounds are a burden on healthcare systems and set to increase with aging population and growing incidences of obesity and diabetes. Stem cell-based therapies have the potential to heal chronic wounds but have so far seen little success in the clinic. Current research has been focused on using polymeric biomaterial systems that can act as a niche for these stem cells to improve their survival and paracrine activity that would eventually promote wound healing. Furthermore, different modification strategies have been developed to improve stem cell survival and differentiation, ultimately promoting regenerative wound healing. This review focuses on advanced polymeric scaffolds that have been used to deliver stem cells and have been tested for their efficiency in preclinical animal models of wounds.


Combining CSs associated with the same or different USs.
In three experiments, hungry rats received appetitive training with four stimuli, A, B, X, and Y. In each Experiment, A and B were paired with one unconditioned stimulus (US; e.g. food pellets) whereas X and Y were paired with a second US (e.g. sucrose). Subsequently, rats responded more vigorously to combinations of stimuli associated with different USs (A-Y & X-B) than to combinations of stimuli associated with the same US (A-B & X-Y; Experiments 1, 2, & 3). This effect was observed when the stimuli were presented simultaneously and during the second elements of serial compounds (Experiments 2 & 3). Moreover, combining CSs associated with different USs resulted in a more marked CR than combining CSs that had each been paired with both US1 and US2 (Experiment 3). These results suggest that the sensory properties of appetitive reinforcers have an important influence on performance.


Genetic targeting and physiological features of VGLUT3+ amacrine cells.
Amacrine cells constitute a diverse class of interneurons that contribute to visual signal processing in the inner retina, but surprisingly, little is known about the physiology of most amacrine cell subtypes. Here, we have taken advantage of the sparse expression of vesicular glutamate transporter 3 (VGLUT3) in the mammalian retina to target the expression of yellow fluorescent protein (YFP) to a unique population of amacrine cells using a new transgenic mouse line. Electrophysiological recordings made from YFP-positive (VGLUT3+) amacrine cells provide the first functional data regarding the active membrane properties and synaptic connections of this recently identified cell type. We found that VGLUT3+ amacrine cells receive direct synaptic input from bipolar cells via both N-methyl-d-aspartate receptors (NMDARs) and non-NMDARs. Voltage-gated sodium channels amplified these excitatory inputs but repetitive spiking was never observed. VGLUT3+ amacrine cells responded transiently to both light increments (ON response) and decrements (OFF response); ON responses consisted exclusively of inhibitory inputs, while OFF responses comprised both excitatory and inhibitory components, although the inhibitory conductance was larger in amplitude and longer in time course. The physiological properties and anatomical features of the VGLUT3+ amacrine cells suggest that this bistratified interneuron may play a role in disinhibitory signaling and/or crossover inhibition between parallel pathways in the retina.


An open cluster-randomized, 18-month trial to compare the effectiveness of educational outreach visits with usual guideline dissemination to improve family physician prescribing.
The Portuguese National Health Directorate has issued clinical practice guidelines on prescription of anti-inflammatory drugs, acid suppressive therapy, and antiplatelets. However, their effectiveness in changing actual practice is unknown. The study will compare the effectiveness of educational outreach visits regarding the improvement of compliance with clinical guidelines in primary care against usual dissemination strategies. A cost-benefit analysis will also be conducted. We will carry out a parallel, open, superiority, randomized trial directed to primary care physicians. Physicians will be recruited and allocated at a cluster-level (primary care unit) by minimization. Data will be analyzed at the physician level. Primary care units will be eligible if they use electronic prescribing and have at least four physicians willing to participate. Physicians in intervention units will be offered individual educational outreach visits (one for each guideline) at their workplace during a six-month period. Physicians in the control group will be offered a single unrelated group training session. Primary outcomes will be the proportion of cyclooxygenase-2 inhibitors prescribed in the anti-inflammatory class, and the proportion of omeprazole in the proton pump inhibitors class at 18 months post-intervention. Prescription data will be collected from the regional pharmacy claims database. We estimated a sample size of 110 physicians in each group, corresponding to 19 clusters with a mean size of 6 physicians. Outcome collection and data analysis will be blinded to allocation, but due to the nature of the intervention, physicians and detailers cannot be blinded. This trial will attempt to address unresolved issues in the literature, namely, long term persistence of effect, the importance of sequential visits in an outreach program, and cost issues. If successful, this trial may be the cornerstone for deploying large scale educational outreach programs within the Portuguese National Health Service. ClinicalTrials.gov number NCT01984034.


Estimating relatedness and inbreeding using molecular markers and pedigrees: the effect of demographic history.
Estimates of inbreeding and relatedness are commonly calculated using molecular markers, although the accuracy of such estimates has been questioned. As a further complication, in many situations, such estimates are required in populations with reduced genetic diversity, which is likely to affect their accuracy. We investigated the correlation between microsatellite- and pedigree-based coefficients of inbreeding and relatedness in laboratory populations of Drosophila melanogaster that had passed through bottlenecks to manipulate their genetic diversity. We also used simulations to predict expected correlations between marker- and pedigree-based estimates and to investigate the influence of linkage between loci and null alleles. Our empirical data showed lower correlations between marker- and pedigree-based estimates in our control (nonbottleneck) population than were predicted by our simulations or those found in similar studies. Correlations were weaker in bottleneck populations, confirming that extreme reductions in diversity can compromise the ability of molecular estimates to detect recent inbreeding events. However, this result was highly dependent on the strength of the bottleneck and we did not observe or predict any reduction in correlations in our population that went through a relatively severe bottleneck of N = 10 for one generation. Our results are therefore encouraging, as molecular estimates appeared robust to quite severe reductions in genetic diversity. It should also be remembered that pedigree-based estimates may not capture realized identity-by-decent and that marker-based estimates may actually be more useful in certain situations.


[Mapping of the genetic locus determining the degree of natural resistance to erythromycin in Salmonella].
The locus which determines ordinary (natural--ery or) level of resistance to erythromycin in Salmonella has been mapped. According to the results of conjugation mating and the analysis of the properties' transfer gradient this region is localized next to his--locus, the gene order being; trp--his--eryor. However, no contransduction of eryor--locus with his--gene has been demonstrated. An assumption on a possible mechanism of alteration of natural level of erythromycin resistance in S. typhimurium mutants Er-4 and Es-1 (received earlier) has been made. This mechanism is connected with alterations in cell permeability.