Cerebral blood flow and cognitive function in HIV-infected men with sustained suppressed viremia on combination antiretroviral therapy.
To assess if HIV-infected patients on long-term successful combination antiretroviral therapy show cerebral blood flow (CBF) alterations in comparison with HIV-uninfected, otherwise similar controls. To explore whether such alterations are associated with HIV-associated cognitive impairment and to explore potential determinants of CBF alterations in HIV. Cross-sectional comparison of CBF in an observational cohort study. Clinical, cognitive and MRI data of 100 middle-aged aviremic HIV-infected men on combination antiretroviral therapy and 69 HIV-uninfected controls were collected and compared. From pseudocontinuous arterial spin labeling MRI data, CBF-maps were calculated. The associations of mean gray matter CBF with clinical and cognitive parameters were explored in regression models, followed by a spatial delineation in a voxel-based analysis. CBF was decreased in HIV-infected patients compared with HIV-uninfected controls (P = 0.02), adjusted for age, ecstasy use and waist circumference. Spatially distinct and independent effects of total gray matter volume and HIV-serostatus on CBF were found. Within the HIV-infected group, decreased CBF was associated with increased triglyceride levels (P = 0.005) and prior clinical AIDS (P = 0.03). No association between CBF and cognitive impairment was found. Decreased CBF was observed among HIV-infected patients, which was associated with both vascular risk factors as well as with measures of past immune deficiency. These results provide support for increased vascular disease in HIV-infected patients as represented by hemodynamic alteration, but without overt cognitive consequences within the current cohort of patients on long-term successful treatment.


Genomic screening identifies novel linkages and provides further evidence for a role of MYH9 in nonsyndromic cleft lip and palate.
Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth anomaly that requires prolonged multidisciplinary rehabilitation. Although variation in several genes has been identified as contributing to NSCLP, most of the genetic susceptibility loci have yet to be defined. To identify additional contributory genes, a high-throughput genomic scan was performed using the Illumina Linkage IVb Panel platform. We genotyped 6008 SNPs in nine non-Hispanic white NSCLP multiplex families and a single large African-American NSCLP multiplex family. Fourteen chromosomal regions were identified with LOD>1.5, including six regions not previously reported. Analysis of the data from the African-American and non-Hispanic white families revealed two likely chromosomal regions: 8q21.3-24.12 and 22q12.2-12.3 with LOD scores of 2.98 and 2.66, respectively. On the basis of biological function, syndecan 2 (SDC2) and growth differentiation factor 6 (GDF6) in 8q21.3-24.12 and myosin heavy-chain 9, non-muscle (MYH9) in 22q12.2-12.3 were selected as candidate genes. Association analyses from these genes yielded marginally significant P-values for SNPs in SDC2 and GDF6 (0.01<or=P<0.05). Evidence for an altered transmission was found for four MYH9 SNPs (P<0.01). SNP rs1002246 exhibited altered transmission by all analytic methods. However, analysis of two SNP MYH9 haplotypes did not identify a single high-risk haplotype. Our results confirm a previous report that 8q21.3-24.12 may harbor a clefting gene and identify 22q12.2-12.3 as a new candidate region that contains MYH9. Most importantly, we confirm the previous report of an association with MYH9.


Bendamustine for treatment of chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) often has an extended disease course. With a median age at diagnosis of 72 years, newer treatment options with less toxicity than standard nucleoside analogue-based regimens are needed. Historically, few therapy options are available once CLL has become refractory to nucleoside analogues. Bendamustine has emerged as a feasible therapy for older and less fit CLL patients, with clinical efficacy in previously untreated and refractory CLL. This paper reviews several of the pivotal clinical trials that established the clinical activity of bendamustine in previously untreated and relapsed/refractory CLL. The toxicity profile of bendamustine, primarily myelosuppression and infections, is reviewed and compared across different CLL populations. A review of the clinical data focuses on potential explanations for differences in response rates and duration of remission reported across studies and how this may impact the development of therapies for CLL. Bendamustine is a valuable new agent for the management of CLL. Ongoing clinical trials are comparing bendamustine with standard CLL regimens in untreated disease, and investigating bendamustine combinations with novel targeted therapies and monoclonal antibodies. These studies will help to define the optimal role for bendamustine in CLL management.


Investigating Outcomes of a Family Strengthening Intervention for Resettled Somali Bantu and Bhutanese Refugees: An Explanatory Sequential Mixed Methods Study.
Pre- and post-migration stressors can put resettled refugee children at risk of poor mental health outcomes. The Family Strengthening Intervention for Refugees (FSI-R) is a peer-delivered preventative home visiting program for resettled refugees that aims to draw upon families' strengths to foster improved family communication, positive parenting, and caregiver-child relationships, with the ultimate goal of reducing children's risk of mental health problems. Using an explanatory sequential mixed methods design, this study draws upon qualitative interviews with caregivers (n = 19) and children (n = 17) who participated in a pilot study of the FSI-R intervention in New England, as well as interventionists (n = 4), to unpack quantitative findings on mental health and family functioning from a randomized pilot study (n = 80 families). Most patterns observed in the quantitative data as published in the pilot trial were triangulated by qualitative data. Bhutanese caregivers and children noted that children were less shy or scared to speak up after participating in the FSI-R. Somali Bantu families spoke less about child mental health and underscored feasibility challenges like language barriers between caregivers and children. Interventionists suggested that families with higher levels of education were more open to implementing behavior change. In both groups, families appreciated the intervention and found it to be feasible and acceptable, but also desired additional help in addressing broader family and community needs such as jobs and literacy programs.


[Effect of amigluracil and levorin on membrane permeability and protein synthesis in Candida albicans protoplasts].
It was shown that amigluracyl, a water soluble derivative of methacyl which decreased the nephrotoxic effect of polyens activated the membrane permeability in Candida albicans for a mixture of 14C-amino acids but had no significant effect on protein synthesis in this microorganism. The level of inhibition of the membrane permeability in C. albicans for the amino acids and protein synthesis in the fungus by levorin did not practically depend on the presence of amigluracyl in the incubation medium. The minimum levorin concentration inhibiting the growth of Candida albicans in the presence or absence of levorin was 0.039 gamma/ml. Therefore, amigluracyl may be used in combination with polyenic antibiotics for the treatment of mycoses.


Clinical comparison of either small doses of fentanyl or remifentanil for blunting cardiovascular changes induced by tracheal intubation.
To compare in a prospective, randomized study the effects on cardiovascular changes after tracheal intubation produced by small doses of either remifentanil or fentanyl. With Ethical Committee approval, after intravenous midazolam premedication (0.05 mg.kg-1), 30 normotensive, ASA physical status I-II patients, without cardiovascular or respiratory diseases, and with a Mallampati score < 2, were randomly allocated to receive an intravenous bolus of either 3 micrograms.kg-1 fentanyl (n = 15) or 1 microgram.kg-1 remifentanil (n = 15) infused over 60 sec and followed by a 0.15 microgram.kg-1.min-1 continuous intravenous infusion. General anesthesia was then induced with propofol (2 mg.kg-1), followed by atracurium besilate (0.5 mg.kg-1) to facilitate tracheal intubation. Following intubation, the lungs were ventilated mechanically using a 60% nitrous oxide in oxygen mixture with a 1% inspired fraction of sevoflurane. Arterial blood pressure and heart rate were recorded before anesthesia induction (baseline), one minute after induction of anesthesia, immediately after tracheal intubation and every minute for the first five minutes after intubation. Systolic arterial blood pressure values were significantly higher in the Fentanyl than in the Remifentanil group patients from 2 to 5 min after tracheal intubation (p < 0.01), while no differences were observed between the two groups in either diastolic arterial blood pressure or heart rate values. Four patients in the Remifentanil group (26%) but only one patient in the Fentanyl group (7%) showed systolic blood pressure values < 90 mmHg during the study period (p = not significant); however, the observed decreases in systolic arterial blood pressure values were transient and did not require treatment for any subject. We conclude that in healthy normotensive patients, the control of cardiovascular responses to tracheal intubation obtained with a 1 microgram.kg-1 loading dose of remifentanil is more effective than that provided by a 3 micrograms.kg-1 bolus of fentanyl, with the advantage of no risks for postoperative respiratory depression.


Renal mechanisms for suppression of renin secretion by atrial natriuretic factor.
The effects of synthetic atrial natriuretic factor on renin secretion were examined in anesthetized dogs with either a single filtering kidney or a single denervated nonfiltering kidney. In dogs with a single filtering kidney (Series 1, n = 6), a priming dose of atrial natriuretic factor (2 micrograms/kg, i.v.) followed by sustained intravenous infusions at doses of 200 and 400 ng/kg/min for 20 minutes each produced striking decrements (p less than 0.05) in renin secretion, from 1083 +/- 322 to 205 +/- 120 and 286 +/- 168 ng of angiotensin I per minute. This fall in renin secretion was associated with significant increases (p less than 0.05) in creatinine clearance, urine flow, sodium excretion, and the filtered load of sodium. Renal blood flow increased only transiently. In dogs with a single denervated nonfiltering kidney (Series 2, n = 6), infusion of atrial natriuretic factor at these doses also produced marked inhibition (p less than 0.05) of renin secretion, from 311 +/- 98 to 72 +/- 22 and 91 +/- 37 ng of angiotensin I per minute. Renal blood flow remained significantly elevated (p less than 0.05) throughout the infusion, in contrast to renal blood flow in Series I. Similar results were obtained in a third series of dogs (n = 6) with a single denervated nonfiltering kidney, during sustained intrarenal arterial infusions of atrial natriuretic factor. These results suggest that an increase in the sodium load delivered to the macula suppression of renin secretion by atrial natriuretic factor is mediated through its interactions with the two intrarenal receptor mechanisms, the renal vascular receptor and the macula densa.(ABSTRACT TRUNCATED AT 250 WORDS)


Taking off into the wind: Unemployment risk and state-Dependent government spending multipliers.
We propose a model with involuntary unemployment, incomplete markets, and nominal rigidity, in which the effects of government spending are state-dependent. An increase in government purchases raises aggregate demand, tightens the labor market and reduces unemployment. This in turn lowers unemployment risk and thus precautionary saving, leading to a larger response of private consumption than in a model with perfect insurance. The output multiplier is further amplified through a composition effect, as the fraction of high-consumption households in total population increases in response to the spending shock. These features, along with the matching frictions in the labor market, generate significantly larger multipliers in recessions than in expansions. As the pool of job seekers is larger during downturns than during expansions, the concavity of the job-finding probability with respect to market tightness implies that an increase in government spending reduces unemployment risk more in the former case than in the latter, giving rise to countercyclical multipliers.


The Lateral suppressor (Ls) gene of tomato encodes a new member of the VHIID protein family.
The ability of the shoot apical meristem to multiply and distribute its meristematic potential through the formation of axillary meristems is essential for the diversity of forms and growth habits of higher plants. In the lateral suppressor mutant of tomato the initiation of axillary meristems is prevented, thus offering the unique opportunity to study the molecular mechanisms underlying this important function of the shoot apical meristem. We report here the isolation of the Lateral suppressor gene by positional cloning and show that the mutant phenotype is caused by a complete loss of function of a new member of the VHIID family of plant regulatory proteins.


Haemolytic uraemic syndrome: therapeutic effect of plasma infusion.
The therapeutic effect of plasma infusion was evaluated in 10 children and seven adults with haemolytic uraemic syndrome. All but one patient responded to this treatment with rapid disappearance of haematological abnormalities. The patient who apparently failed to respond to plasma infusion obtained complete remission of the disease after plasmapheresis. Although 15 of the 17 patients were anuric or oliguric on admission, renal function recovered completely in eight children and two adults. Seven patients showed residual chronic renal failure and two required long-term maintenance haemodialysis. Treatment with plasma was also successful in patients with relapses or recurrent episodes. Plasma infusion is a promising therapeutic approach for the haemolytic uraemic syndrome and deserves further study in clinical trials.


Detection limit enhancement of fluorescent heterogeneities in turbid media by dual-interfering excitation.
We report on a quantitative comparison between the single-source and the dual-interfering-source configurations for the detection of fluorescent heterogeneities embedded in a piecewise highly scattering homogeneous fluorescent background. The study is based on simulations with analytical solutions of the frequency-domain fluorescent diffuse photon density waves and practical signal-to-noise ratio considerations. Results show that dual-interfering sources outperform single-source techniques for the detection of heterogeneities in terms of fluorophore concentration and lifetime contrast. To detect the same inhomogeneity, less concentration and lifetime contrast is required with dual-interfering sources.


Cost-effectiveness of lumbar fusion and nonsurgical treatment for chronic low back pain in the Swedish Lumbar Spine Study: a multicenter, randomized, controlled trial from the Swedish Lumbar Spine Study Group.
A cost-effectiveness study was performed from the societal and health care perspectives. To evaluate the costs-effectiveness of lumbar fusion for chronic low back pain (CLBP) during a 2-year follow-up. A full economic evaluation comparing costs related to treatment effects in patients with CLBP is lacking. A total of 284 of 294 patients with CLBP for at least 2 years were randomized to either lumbar fusion or a nonsurgical control group. Costs for the health care sector (direct costs), and costs associated with production losses (indirect costs) were calculated. Societal total costs were identified as the sum of direct and indirect costs. Treatment effects were measured using patient global assessment of improvement, back pain (VAS), functional disability (Owestry), and return to work. The societal total cost per patient (standard deviations) in the surgical group was significantly higher than in the nonsurgical group: Swedish kroner (SEK) 704,000 (254,000) vs. SEK 636,000 (208,000). The cost per patient for the health care sector was significantly higher for the surgical group, SEK 123,000 (60,100) vs. 65,200 (38,400) for the control group. All treatment effects were significantly better after surgery. The incremental cost-effectiveness ratio (ICER), illustrating the extra cost per extra effect unit gained by using fusion instead of nonsurgical treatment, were for improvement: SEK 2,600 (600-5,900), for back pain: SEK 5,200 (1,100-11,500), for Oswestry: SEK 11,300 (1,200-48,000), and for return to work: SEK 4,100 (100-21,400). For both the society and the health care sectors, the 2-year costs for lumbar fusion was significantly higher compared with nonsurgical treatment but all treatment effects were significantly in favor of surgery. The probability of lumbar fusion being cost-effective increased with the value put on extra effect units gained by using surgery.


Understanding medical travel from a source country perspective: a cross sectional study of the experiences of medical travelers from the Maldives.
The resolution adopted in 2006 by the World Health Organization on international trade and health urges Member States to understand the implications of international trade and trade agreements for health and to address any challenges arising through policies and regulations. The government of Maldives is an importer of health services (with outgoing medical travelers), through offering a comprehensive universal health care package for its people that includes subsidized treatment abroad for services unavailable in the country. By the end of the first year of the scheme approximately US$11.6 m had been spent by the government of Maldives to treat patients abroad. In this study, affordability, continuity and quality of this care were assessed from the perspective of the medical traveler to provide recommendations for safer and more cost effective medical travel policy. Despite universal health care, a substantial proportion of Maldivian travelers have not accessed the government subsidy, and a third reported not having sufficient funds for the treatment episode abroad. Among the five most visited hospitals in this study, none were JCI accredited at the time of the study period and only three from India had undergone the National Accreditation Board for Hospitals (NABH) in India. Satisfaction with treatment received was high amongst travelers but concern for the continuity of care was very high, and more than a third of the patients had experienced complications arising from the treatment overseas. Source countries can use their bargaining power in the trade of health services to offer a more comprehensive package for medical travelers. Source countries with largely public funded health systems need to ensure that medical travel is truly affordable and universal, with measures for quality control such as the use of accredited foreign hospitals to make it safer and to impose measures that ensure the continuity of care for travelers.


Drug Repositioning Screen on a New Primary Cell Line Identifies Potent Therapeutics for Glioblastoma.
Glioblastoma is a malignant brain cancer with limited treatment options and high mortality rate. While established glioblastoma cell line models provide valuable information, they ultimately lose most primary characteristics of tumors under long-term serum culture conditions. Therefore, established cell lines do not necessarily recapitulate genetic and morphological characteristics of real tumors. In this study, in line with the growing interest in using primary cell line models derived from patient tissue, we generated a primary glioblastoma cell line, KUGBM8 and characterized its genetic alterations, long term growth ability, tumor formation capacity and its response to Temozolomide, the front-line chemotherapy utilized clinically. In addition, we performed a drug repurposing screen on the KUGBM8 cell line to identify FDA-approved agents that can be incorporated into glioblastoma treatment regimen and identified Topotecan as a lead drug among 1,200 drugs. We showed Topotecan can induce cell death in KUGBM8 and other primary cell lines and cooperate with Temozolomide in low dosage combinations. Together, our study provides a new primary cell line model that can be suitable for both in vitro and in vivo studies and suggests that Topotecan can offer promise as a therapeutic approach for glioblastoma.


Real-life assessment of the multidimensional nature of dyspnoea in COPD outpatients.
Dyspnoea is a prominent symptom of chronic obstructive pulmonary disease (COPD). Recent multidimensional dyspnoea questionnaires like the Multidimensional Dyspnea Profile (MDP) individualise the sensory and affective dimensions of dyspnoea. We tested the MDP in COPD outpatients based on the hypothesis that the importance of the affective dimension of dyspnoea would vary according to clinical characteristics.A multicentre, prospective, observational, real-life study was conducted in 276 patients. MDP data were compared across various categories of patients (modified Medical Research Council (mMRC) dyspnoea score, COPD Assessment Test (CAT) score, Global Initiative for Chronic Obstructive Lung Disease (GOLD) airflow obstruction categories, GOLD "ABCD" categories, and Hospital Anxiety and Depression Scale (HADS)). Univariate and multivariate regressions were conducted to explore factors influencing the affective dimension of dyspnoea. Cluster analysis was conducted to create homogeneous patient profiles.The MDP identified a more marked affective dimension of dyspnoea with more severe mMRC, CAT, 12-item Short-Form Health Survey mental component, airflow obstruction and HADS. Multivariate analysis identified airflow obstruction, depressive symptoms and physical activity as determinants of the affective dimension of dyspnoea. Patients clustered into an "elderly, ex-smoker, severe disease, no rehabilitation" group exhibited the most marked affective dimension of dyspnoea.An affective/emotional dimension of dyspnoea can be identified in routine clinical practice. It can contribute to the phenotypic description of patients. Studies are needed to determine whether targeted therapeutic interventions can be designed and whether they are useful.


Genetics of non-syndromic and syndromic oculocutaneous albinism in human and mouse.
Oculocutaneous albinism (OCA) is the most frequent presentation of albinism, a heterogeneous rare genetic condition generally associated with variable alterations in pigmentation and with a profound visual impairment. There are non-syndromic and syndromic types of OCA, depending on whether the gene product affected impairs essentially the function of melanosomes or, in addition, that of other lysosome-related organelles (LROs), respectively. Syndromic OCA can be more severe and associated with additional systemic consequences, beyond pigmentation and vision alterations. In addition to OCA, albinism can also be presented without obvious skin and hair pigmentation alterations, in ocular albinism (OA), and a related genetic condition known as foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA). In this review, we will focus only in the genetics of skin pigmentation in OCA, both in human and mouse, updating our current knowledge on this subject.


Evaluating online and tangible interfaces for engaging stakeholders in forecasting and control of biological invasions.
Ecological forecasts will be best suited to inform intervention strategies if they are accessible to a diversity of decision-makers. Researchers are developing intuitive forecasting interfaces to guide stakeholders through the development of intervention strategies and visualization of results. Yet, few studies to date have evaluated how user interface design facilitates the coordinated, cross-boundary management required for controlling biological invasions. We used a participatory approach to develop complementary tangible and online interfaces for collaboratively forecasting biological invasions and devising control strategies. A diverse group of stakeholders evaluated both systems in the real-world context of controlling sudden oak death, an emerging forest disease killing millions of trees in California and Oregon. Our findings suggest that while both interfaces encouraged adaptive experimentation, tangible interfaces are particularly well suited to support collaborative decision-making. Reflecting on the strengths of both systems, we suggest workbench-style interfaces that support simultaneous interactions and dynamic geospatial visualizations.


A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Tolerability, and Safety of Celecoxib Oral Solution (ELYXYB) in Acute Treatment of Episodic Migraine with or without Aura.
Safe, effective, oral therapies are needed for acute treatment of migraine. This clinical trial assessed the efficacy, tolerability, and safety of celecoxib oral solution (ELYXYB) in a single migraine attack associated with moderate-to-severe pain. This was a phase III, randomized (1:1), double-blind, placebo-controlled trial, conducted at 41 US centers from December 2016 to October 2017. Adults with episodic migraine (with or without aura) for ≥1 year were treated with a single 4.8 mL dose of 120-mg celecoxib oral solution or placebo. Co-primary endpoints were the proportion of patients who were pain-free and free from the most bothersome migraine symptom (MBS) at 2 hours post-dose. The MBS was identified at screening from among nausea, photophobia, or phonophobia. Six hundred thirty-one patients were randomized (celecoxib oral solution, n=316; placebo, n=315; mean age 41 years, range 18-75; 84.3% female). One study site met prespecified outlier criteria (defined as a treatment effect estimate that was at least twice as large as all other sites) and was excluded from efficacy analyses. This site had a mean 2-hour pain freedom placebo response rate of 75% vs a combined mean of 23.5% for all other sites. In subsequent analysis, 2-hour post-dose pain freedom response rates were significantly higher in the celecoxib oral solution group vs placebo (32.8%, [27.2%, 38.8%]) vs 23.5%, [18.5%, 29.2%]; P=0.020). For 2-hour post-dose MBS freedom, response rates were significantly higher in the celecoxib oral solution group vs placebo (58.1% [51.4%, 64.5%] vs 43.9% [37.2%, 50.7%]; P=0.003). A total of 10.7% (31/289) of patients treated with celecoxib oral solution and 9.9% (28/283) of placebo-treated patients reported a treatment-emergent adverse event (TEAE). Study drug-related TEAEs were reported by 7.3% (21/289) and 7.4% (21/283) of celecoxib oral solution and placebo patients, respectively; the most common were nausea (celecoxib oral solution: 1.4% [4/289] vs placebo: 1.8% [5/283]) and dysgeusia (celecoxib oral solution: 1.7% [5/289] vs placebo: 1.1% [3/283]). No serious TEAEs, deaths, or drug-related TEAEs leading to withdrawal were reported. Celecoxib oral solution is a safe, effective COX-2-selective nonsteroidal anti-inflammatory drug for the treatment of acute migraine. In this analysis, celecoxib oral solution was significantly more effective than placebo and was also associated with a low rate of gastric TEAEs. Celecoxib oral solution may provide a convenient, alternate option to currently available treatments. ClinicalTrials.gov Identifier: NCT03009019; registered January 4, 2017; retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03009019.


Measurement of gamma+b+X and gamma+c+X Production Cross Sections in pp[over ] Collisions at sqrt[s]=1.96 TeV.
First measurements of the differential cross sections d;{3}sigma/(dp_{T};{gamma}dy;{gamma}dy;{jet}) for the inclusive production of a photon in association with a heavy quark (b, c) jet are presented, covering photon transverse momenta 30<p_{T};{gamma}<150 GeV, photon rapidities |y;{gamma}|<1.0, jet rapidities |y;{jet}|<0.8, and jet transverse momenta p_{T};{jet}>15 GeV. The results are based on an integrated luminosity of 1 fb;{-1} in pp[over ] collisions at sqrt[s]=1.96 TeV recorded with the D0 detector at the Fermilab Tevatron Collider. The results are compared with next-to-leading order perturbative QCD predictions.


[Improvement of the surgical treatment results of patients with an acute ileus].
The results of surgical treatment of 339 patients with an acute ileus (AI) were analyzed. Severe disorders of water-electrolytic, protein metabolism and immune status in 62 patients were revealed. Method of treatment of functional postoperative AI with application of serotonin adipinate was proposed.


In-Silico Screening of Ligand Based Pharmacophore, Database Mining and Molecular Docking on 2, 5-Diaminopyrimidines Azapurines as Potential Inhibitors of Glycogen Synthase Kinase-3β.
Glycogen synthase kinase-3β plays a significant role in the regulation of various pathological pathways relating to the Central Nervous System (CNS). Dysregulation of Glycogen synthase kinase 3 (GSK-3) activity gives rise to numerous neuroinflammation and neurodegenerative related disorders that affect the whole central nervous system. By the sequential application of in-silico tools, efforts have been attempted to design the novel GSK-3β inhibitors. Owing to the potential role of GSK-3β in nervous disorders, we have attempted to develop the quantitative four featured pharmacophore model comprising two Hydrogen Bond Acceptors (HBA), one Ring Aromatic (RA), and one Hydrophobe (HY), which were further affirmed by costfunction analysis, rm2 matrices, internal and external test set validation and Guner-Henry (GH) scoring analysis. Validated pharmacophoric model was used for virtual screening and out of 345 compounds, two potential virtual hits were finalized that were on the basis of fit value, estimated activity and Lipinski's violation. The chosen compounds were subjected to dock within the active site of GSK-3β. Four essential features, i.e., two Hydrogen Bond Acceptors (HBA), one Ring Aromatic (RA), and one Hydrophobe (HY), were subjected to build the pharmacophoric model and showed good correlation coefficient, RMSD and cost difference values of 0.91, 0.94 and 42.9 respectively and further model was validated employing cost-function analysis, rm2-matrices, internal and external test set prediction with r2 value of 0.77 and 0.84. Docked conformations showed potential interactions in between the features of the identified hits (NCI 4296, NCI 3034) and the amino acids present in the active site. In line with the overhead discussion, and through our stepwise computational approaches, we have identified novel, structurally diverse glycogen synthase kinase inhibitors.


Pattern of Stress-Induced Hyperglycemia according to Type of Diabetes: A Predator Stress Model.
We aimed to quantify stress-induced hyperglycemia and differentiate the glucose response between normal animals and those with diabetes. We also examined the pattern in glucose fluctuation induced by stress according to type of diabetes. To load psychological stress on animal models, we used a predator stress model by exposing rats to a cat for 60 minutes and measured glucose level from the beginning to the end of the test to monitor glucose fluctuation. We induced type 1 diabetes model (T1D) for ten Sprague-Dawley rats using streptozotocin and used five Otsuka Long-Evans Tokushima Fatty rats as obese type 2 diabetes model (OT2D) and 10 Goto-Kakizaki rats as nonobese type 2 diabetes model (NOT2D). We performed the stress loading test in both the normal and diabetic states and compared patterns of glucose fluctuation among the three models. We classified the pattern of glucose fluctuation into A, B, and C types according to speed of change in glucose level. Increase in glucose, total amount of hyperglycemic exposure, time of stress-induced hyperglycemia, and speed of glucose increase were significantly increased in all models compared to the normal state. While the early increase in glucose after exposure to stress was higher in T1D and NOT2D, it was slower in OT2D. The rate of speed of the decrease in glucose level was highest in NOT2D and lowest in OT2D. The diabetic state was more vulnerable to stress compared to the normal state in all models, and the pattern of glucose fluctuation differed among the three types of diabetes. The study provides basic evidence for stress-induced hyperglycemia patterns and characteristics used for the management of diabetes patients.


Using Health Care Professionals' Perspectives to Refine a Clinical Decision Support Implementation Strategy for Increasing the Prescribing of HIV Preexposure Prophylaxis (PrEP) in Alabama.
Pre-exposure prophylaxis (PrEP) is underused in the southern United States (US), a region with high HIV incidence. Clinical decision support (CDS) tools could increase PrEP prescriptions. We explored barriers to PrEP delivery and views of CDS tools to identify refinements for implementation strategies for PrEP prescribing and PrEP CDS tools. We conducted focus groups with health care providers from two federally qualified health centers in Alabama and analyzed the results using rapid qualitative methods. Barriers to PrEP included providers' lack of training in PrEP, competing priorities and time constraints during clinical visits, concerns about side effects, and intensive workload. We identified refinements to the planned implementation strategies to address the barriers, including training all clinic staff in PrEP and having CDS PrEP alerts in electronic health records sent to all staff. Development and deployment of CDS tools in collaboration with providers has potential to increase PrEP prescribing in high-priority jurisdictions.


Using variability to guide dimensional weighting: associative mechanisms in early word learning.
At 14 months, children appear to struggle to apply their fairly well-developed speech perception abilities to learning similar sounding words (e.g., bih/dih; Stager & Werker, 1997). However, variability in nonphonetic aspects of the training stimuli seems to aid word learning at this age. Extant theories of early word learning cannot account for this benefit of variability. We offer a simple explanation for this range of effects based on associative learning. Simulations suggest that if infants encode both noncontrastive information (e.g., cues to speaker voice) and meaningful linguistic cues (e.g., place of articulation or voicing), then associative learning mechanisms predict these variability effects in early word learning. Crucially, this means that despite the importance of task variables in predicting performance, this body of work shows that phonological categories are still developing at this age, and that the structure of noninformative cues has critical influences on word learning abilities.


The trans-membrane protein p25 forms highly specialized domains that regulate membrane composition and dynamics.
Trans-membrane proteins of the p24 family are abundant, oligomeric proteins predominantly found in cis-Golgi membranes. They are not easily studied in vivo and their functions are controversial. We found that p25 can be targeted to the plasma membrane after inactivation of its canonical KKXX motif (KK to SS, p25SS), and that p25SS causes the co-transport of other p24 proteins beyond the Golgi complex, indicating that wild-type p25 plays a crucial role in retaining p24 proteins in cis-Golgi membranes. We then made use of these observations to study the intrinsic properties of these proteins, when present in a different membrane context. At the cell surface, the p25SS mutant segregates away from both the transferrin receptor and markers of lipid rafts, which are enriched in cholesterol and glycosphingolipids. This suggests that p25SS localizes to, or contributes to form, specialized membrane domains, presumably corresponding to oligomers of p25SS and other p24 proteins. Once at the cell surface, p25SS is endocytosed, together with other p24 proteins, and eventually accumulates in late endosomes, where it remains confined to well-defined membrane regions visible by electron microscopy. We find that this p25SS accumulation causes a concomitant accumulation of cholesterol in late endosomes, and an inhibition of their motility - two processes that are functionally linked. Yet, the p25SS-rich regions themselves seem to exclude not only Lamp1 but also accumulated cholesterol. One may envision that p25SS accumulation, by excluding cholesterol from oligomers, eventually overloads neighboring late endosomal membranes with cholesterol beyond their capacity (see Discussion). In any case, our data show that p25 and presumably other p24 proteins are endowed with the intrinsic capacity to form highly specialized domains that control membrane composition and dynamics. We propose that p25 and other p24 proteins control the fidelity of membrane transport by maintaining cholesterol-poor membranes in the Golgi complex.


Viral vaccines for the prevention of childhood pneumonia in developing nations: priorities and prospects.
In concert with bacteria, respiratory viruses play a major role in the high rates of acute lower respiratory infection (ALRI) experienced in developing nations. Respiratory syncytial virus, parainfluenza and influenza viruses, and the adenoviruses are the predominant viral causes of ALRI in both developed and developing regions. In this review, the epidemiologic data from developing nations for these viral infections are summarized and the current status of viral vaccines for prevention of ALRI are described. Among the questions to be addressed before these vaccines are used in developing nations are (1) the age-specific rates of infection and disease, (2) the effect of high-dose early exposure to these viruses, and (3) the effect of malnutrition on the immunogenicity of the vaccines. Prospective family studies and other community-based approaches will be required in the acquisition of these data.


Patterns and bilateral coordination of scaphognathite rhythms in the lobster Homarus americanus.
The bilateral patterns of forward and reversed scaphognathite (SG) pumping are described for the American lobster. During forward pumping the two SGs usually function synchronously, but may also function independently. The nine muscles of one SG are arranged into four functional groups which are sequentially active during forward pumping. During reversed beats, motor neurones to one group of muscles are inactive while bursts to another are either delayed or missing. Reversal beats do not appear to alter the phasing of the central oscillators that generate the basic SG rhythm. Phase analysis of bilateral SG beating demonstrates two types of relationship: phase coupling or phase drifting with a tendency to couple. An animal may remain in one state for long periods of time or may alternate between states. Coupling can occur at more than one phase indicating phase multistability. The coupled state may remain constant at markedly different frequencies of beating, indicating phase rather than latency coupling between SGs. During the drifting state each SG tends to assume its "intrinsic" rate of oscillation. The drift state reflects the inherent asymmetry of the two SG systems. The influence of several parameters of sensory stimulation on phase and frequency of SG beating are analyzed.


Impact of e-cigarette and cigarette prices on youth and young adult e-cigarette and cigarette behaviour: evidence from a national longitudinal cohort.
Understanding the impact of prices for tobacco and nicotine products is critical for creating policies to prevent use among young people. This study examines the impact of electronic cigarette (e-cigarette) and cigarette prices on current e-cigarette and cigarette use among youth and young adults. Data were from a national probability-based sample aged 15-21 collected in 2014 and followed every 6 months for 2.5 years through 2016. We conducted separate conditional likelihood logistic regression models with past 30-day e-cigarette use and past 30-day cigarette use outcomes on the sample of individuals who participated in at least two survey waves (n=11 578) with linked Nielsen market-level price data for rechargeable e-cigarettes and cigarettes. Models controlled for time-varying variables at the individual and state policy levels, and fixed effects at the individual, wave and market levels. Higher cigarette prices were associated with increased past 30-day e-cigarette use, indicating e-cigarettes may serve as a substitute for cigarettes. We did not find a statistically significant relationship between rechargeable e-cigarette prices and past 30-day e-cigarette use; neither did we find a significant relationship between rechargeable e-cigarette prices and past 30-day cigarette smoking. This is the first study to examine e-cigarette and cigarette prices on e-cigarette and cigarette behaviour longitudinally among young people. Findings suggest the need for better measuring the costs associated with e-cigarette use among this population, as well as a careful assessment of price and tax policies that takes into account cross-product impact to sufficiently discourage e-cigarette and cigarette use among young people.


Transmission risk of two chikungunya lineages by invasive mosquito vectors from Florida and the Dominican Republic.
Between 2014 and 2016 more than 3,800 imported human cases of chikungunya fever in Florida highlight the high risk for local transmission. To examine the potential for sustained local transmission of chikungunya virus (CHIKV) in Florida we tested whether local populations of Aedes aegypti and Aedes albopictus show differences in susceptibility to infection and transmission to two emergent lineages of CHIKV, Indian Ocean (IOC) and Asian genotypes (AC) in laboratory experiments. All examined populations of Ae. aegypti and Ae. albopictus mosquitoes displayed susceptibility to infection, rapid viral dissemination into the hemocoel, and transmission for both emergent lineages of CHIKV. Aedes albopictus had higher disseminated infection and transmission of IOC sooner after ingesting CHIKV infected blood than Ae. aegypti. Aedes aegypti had higher disseminated infection and transmission later during infection with AC than Ae. albopictus. Viral dissemination and transmission of AC declined during the extrinsic incubation period, suggesting that transmission risk declines with length of infection. Interestingly, the reduction in transmission of AC was less in Ae. aegypti than Ae. albopictus, suggesting that older Ae. aegypti females are relatively more competent vectors than similar aged Ae. albopictus females. Aedes aegypti originating from the Dominican Republic had viral dissemination and transmission rates for IOC and AC strains that were lower than for Florida vectors. We identified small-scale geographic variation in vector competence among Ae. aegypti and Ae. albopictus that may contribute to regional differences in risk of CHIKV transmission in Florida.


Evolution of surgical techniques for the treatment of angular and torsional deviation in DDH: 20 years experience.
The anatomical abnormalities associated with developmental dysplasia of the hip (DDH) increase the complexity of hip arthroplasty. In addition, previous femoral osteotomy can deform the proximal femur. Noncemented cups and stems are specifically designed for dysplasia to recover the true acetabular region in Crowe grade IV and sometimes Crowe grade III; additional surgical procedures are required. The purpose of the study was to analyse the surgical procedure and then the reconstructive options in DDH. From 1984 until now, total arthroplasty has been performed, on dysplastic hips, in 2,101 patients for 2,308 hips (207 patients bilateral 9% rate). All the procedures were performed by the senior authors (LS, GG) at the same hospital specialised in elective hip surgery. More than 80% of patients came from Northern Italy. The average age was 51 (range 32-83), 565 cases had involved a previous femoral osteotomy. Out of these 2,308 cases, 128 cases needed treatment for corrections of femoral side deformity; 64 cases were subjected to a greater trochanter osteotomy. In 12 cases, proximal femur shortening was involved. In 9 cases, rotational abnormality and shortening were controlled with a distal femur osteotomy. Fifty-five cases were treated by a shortening subtrochanteric osteotomy that allows corrections of any deformity. Only noncemented stems were used. Long-term results in these patients are consistently inferior (70% survival rate at 15 years) compared to those in the non-DDH population (97.7% survival at 15 years). On the femoral side, early failures are the reflection of a learning curve and are due to insufficient fixation of the osteotomy. The more promising outcomes are those involving a shortening subtrochanteric osteotomy.


A high-throughput screening assay for determining cellular levels of total tau protein.
The microtubule-associated protein (MAP) tau has been implicated in the pathology of numerous neurodegenerative diseases. In the past decade, the hyperphosphorylated and aggregated states of tau protein have been important targets in the drug discovery field for the potential treatment of Alzheimer's disease. Although several compounds have been reported to reduce the hyperphosphorylated state of tau or impact the stabilization of tau, their therapeutic activities are remain to be validated. Recently, reduction of total cellular tau protein has emerged as an alternate intervention point for drug development and a potential treatment of tauopathies. We have developed and optimized homogenous assays, using the AlphaLISA and HTRF assay technologies, for the quantification of total cellular tau protein levels in the SH-SY5Y neuroblastoma cell line. The signal-to-basal ratios were 375 and 5.3, and the Z' factors were 0.67 and 0.60 for the AlphaLISA and HTRF tau assays, respectively. The clear advantages of these homogeneous tau assays over conventional total tau assays, such as ELISA and Western blot, are the elimination of plate wash steps and miniaturization of the assay into 1536-well plate format for the ultra-high-throughput screening of large compound libraries.


Gel-carbon nanotube materials: the relationship between nanotube network connectivity and conductivity.
The electrical resistance of carbon nanotube networks (NNs) prepared from combinations of gellan gum, xanthan gum, Triton X-100, SWNT and MWNT is reported. It is demonstrated that the NN conductivity can be obtained by analysing the resistance of two overlapping NN as a function of their overlap distance. Unexpectedly, the connectivity between two overlapping NN was found to scale with the electrical conductivity over 4 orders of magnitude. Insights into the dependence of inter-NN contact on applied pressure were obtained.


Anesthesia for synchronous liver and kidney transplantation in a child: A case report.
Synchronous liver and kidney transplantation (SLK) is considered a treatment of choice for an end-stage liver disease patient with irreversible kidney disease. Several perioperative renal supportive treatments, especially continuous renal replacement therapy (CRRT), have contributed to the effective control of hypervolemia and electrolytes and acid-base disturbances leading to high success rate in adults. However, anesthesia for SLK in children is frequently difficult since the CRRT is seldom available because of difficulty in securing large venous lines. In addition, conventional techniques such as venovenous bypass and side-clamping of the inferior vena cava are less applicable in small children causing difficult volume control. Herein, we report a case of SLK in a child with glycogen storage disease type I with a review of literature.


The GADD45, ZBRK1 and BRCA1 pathway: quantitative analysis of mRNA expression in colon carcinomas.
GADD45 is a growth arrest-associated gene that is induced in response to DNA damage. This gene is a target for coordinate regulation by both ZBRK1 and BRCA1. A sequence within intron 3 of GADD45 supports specific assembly of the ZBRK1/BRCA1 complex. In this study, the relationships between GADD45, ZBRK1, and BRCA1 expression were investigated in colon carcinomas. mRNA expression of these three genes was analysed in 116 colon carcinomas by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Genetic and epigenetic changes that could alter expression of these genes were studied. Possible relationships between expression levels of GADD45, ZBRK1, and BRCA1, and a series of clinicopathological parameters classically associated with poor prognosis, were also examined. ZBRK1 showed a tendency towards underexpression, while GADD45 and BRCA1 were generally overexpressed. A direct relationship between these three genes was observed, with the exception of BRCA1 expression levels, similar to normal tissues, which showed a tendency to be associated with low levels of GADD45 mRNA. Concomitantly altered expression of ZBRK1 and BRCA1 was associated with GADD45 mRNA expression. Promoter hypermethylation was not observed in GADD45 or BRCA1, and no mutations in GADD45 or ZBRK1 were found in regions involved in the interaction between the GADD45 gene and the ZBRK1 and BRCA1 proteins. No clinicopathological parameter was correlated with altered GADD45 or ZBRK1 expression but there was a statistically significant relationship between BRCA1 levels and the sex of patients. In conclusion, these results suggest that this pathway, involved in the response to DNA damage, is deregulated in colon carcinomas, and concomitantly altered expression of ZBRK1 and BRCA1 has an additive effect on GADD45 regulation. This is the first study in human carcinomas to analyse the relationships between expression of GADD45, ZBRK1, and BRCA1 mRNA.


Thin-film lithium niobate-on-insulator waveguides fabricated on silicon wafer by room-temperature bonding method with silicon nanoadhesive layer.
Lithium niobate-on-insulator (LNOI) waveguides fabricated on a silicon wafer using a room-temperature bonding method have potential application as Si-based high-density photonic integrated circuits. A surface-activated bonding method using a Si nanoadhesive layer was found to produce a strong bond between LN and SiO2/Si at room temperature, which is sufficient to withstand both the wafer-thinning (LN thickness <5 μm) and surface micromachining processes used to form the strongly confined waveguides. In addition, the bond quality and optical propagation characteristics of the resulting LNOI waveguides were investigated, and the applicability of this bonding method to low-loss LNOI waveguide fabrication is discussed. The propagation loss for the ridged waveguide was approximately 2 dB/cm at a wavelength of 1550 nm, which was sufficiently low for the device application. The results of the present study will be of significant use in the development of fabrication techniques for waveguides with any bonded materials using this room-temperature bonding method, and not only LN core/SiO2 cladding waveguides.


Effectiveness verification of an educational program about hearing protection for noise-exposed workers.
To verify the effectiveness of an educational action in the form of training, emphasizing the importance of hearing protection for workers exposed to occupational noise. The study included 78 male individuals. All participants answered a questionnaire before they were submitted to audiological evaluation. For the second application of the questionnaire, participants were randomly divided into two groups: Research Group, constituted by 44 subjects that received educational training before the second questionnaire application, and Control Group, comprising 34 individuals that answered the questionnaire before the educational training. Training was based on material with graphic images and text, in the form of conversation. The topics covered included: the importance of hearing, noise effects on health, importance of preventing hearing loss and using hearing protection, conservation and cleaning of hearing protectors, levels of noise in the workplace and noise attenuation provided by hearing protectors. The questionnaire contained 14 multiple choice questions that addressed the same themes explored in the educational training. There was a significant increase of correct responses in the second application of the questionnaire, only in the Research Group, in all comparisons. Educational action performed with workers exposed to occupational noise are effective, and the questionnaire is a stable and viable tool to evaluate the effectiveness of educational programs.


SDF-1α/CXCR4 Axis Mediates The Migration of Mesenchymal Stem Cells to The Hypoxic-Ischemic Brain Lesion in A Rat Model.
Transplantation of mesenchymal stem cells (MSCs) can promote functional recovery of the brain after hypoxic-ischemic brain damage (HIBD). However, the mechanism regulating MSC migration to a hypoxic-ischemic lesion is poorly understood. Interaction between stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXC chemokine receptor 4 (CXCR4) is crucial for homing and migration of multiple stem cell types. In this study, we investigate the potential role of SDF-1α/CXCR4 axis in mediating MSC migration in an HIBD model. In this experimental study, we first established the animal model of HIBD using the neonatal rat. Bone marrow MSCs were cultured and labeled with 5-bromo-21-deoxyuridine (BrdU) after which 6×10(6) cells were intravenously injected into the rat. BrdU positive MSCs in the hippocampus were detected by immunohistochemical analyses. The expression of hypoxia-inducible factor-1α (HIF-1α) and SDF-1α in the hippocampus of hypoxic-ischemic rats was detected by Western blotting. To investigate the role of hypoxia and SDF-1α on migration of MSCs in vitro, MSCs isolated from normal rats were cultured in a hypoxic environment (PO2=1%). Migration of MSCs was detected by the transwell assay. The expression of CXCR4 was tested using Western blotting and flow cytometry. BrdU-labeled MSCs were found in the rat brain, which suggested that transplanted MSCs migrated to the site of the hypoxic-ischemic brain tissue. HIF-1α and SDF-1α significantly increased in the hippocampal formations of HIBD rats in a time-dependent manner. They peaked on day 7 and were stably expressed until day 21. Migration of MSCs in vitro was promoted by SDF-1α under hypoxia and inhibited by the CXCR4 inhibitor AMD3100. The expression of CXCR4 on MSCs was elevated by hypoxia stimulation as well as microdosage treatment of SDF-1α. This observation illustrates that SDF-1α/CXCR4 axis mediate the migration of MSCs to a hypoxic-ischemic brain lesion in a rat model.


Consequences of proceeding with surgery after resuscitation from intra-operative anaphylaxis.
Intra-operative acute hypersensitivity reactions require a decision to be made regarding whether to proceed with or abandon the planned surgical procedure once the patient has stabilised. Using retrospective case controls, we examined all cases (223) of proven acute hypersensitivity reactions from 2005 to 2014 in Western Australia, in which the syndrome was recognised by the treating clinician before or during surgery, to determine whether recovery outcomes were adversely affected by proceeding with the planned procedure. Surgery proceeded in 104 patients (47%) and was abandoned in 119 (53%). The severity of acute hypersensitivity reactions was Société Française d'Anesthésie et de Réanimation grade 1 or 2 in 56 patients (25%), grade 3 in 128 (56%) and grade 4 in 39 (17%). Abandoning surgery was more common in patients with increasing severity of hypersensitivity. The rate of major hypersensitivity-related complications for all patients was zero for grade 1 and 2 reactions, 4.7% for grade 3 and 12.8% for grade 4. There were no deaths. Patients in whom surgery was completed were not observed to have a higher frequency of major hypersensitivity-related complications when compared with cases of similar severity in whom surgery was abandoned. For patients admitted to the intensive care unit, proceeding with surgery was not associated with an increased duration of mechanical ventilation of the lungs. Our results suggest that, once initial resuscitation has been achieved and if resuscitative efforts can be re-instituted if required, continuing with planned surgery in grade 1, 2 and 3 immediate hypersensitivity was not associated with poorer outcomes. After grade 3 reactions, there was a significant incidence of complications attributable to acute hypersensitivity regardless of whether surgery proceeded or was abandoned. Surgery was frequently abandoned in grade 4 immediate hypersensitivity and was associated with a high rate of complications.


Exercise for dysmenorrhoea.
Dysmenorrhoea is characterised by cramping lower abdominal pain that may radiate to the lower back and upper thighs and is commonly associated with nausea, headache, fatigue and diarrhoea. Physical exercise has been suggested as a non-medical approach to the management of these symptoms. To assess the evidence for the effectiveness of exercise in the treatment of dysmenorrhoea. A search was conducted using the methodology of the Menstrual Disorders and Subfertility Group (August 2009). CENTRAL (The Cochrane Library), MEDLINE, EMBASE, AMED and PsycINFO electronic databases were searched. Handsearching of relevant bibliographies and reference lists was also conducted. Randomised controlled trials comparing exercise with a control or no intervention in women with dysmenorrhoea. Trials were independently selected and data extracted by two review authors. Four potential trials were identified of which one was included in the review. The available data could only be included as a narrative description. There appeared to be some evidence from the trial that exercise reduced the Moos' Menstrual Distress Questionnaire (MDQ) score during the menstrual phase (P < 0.05) and resulted in a sustained decrease in symptoms over the three observed cycles (P < 0.05). The results of this review are limited to a single randomised trial of limited quality and with a small sample size. The data should be interpreted with caution and further research is required to investigate the hypothesis that exercise reduces the symptoms associated with dysmenorrhoea.


Nanoparticles as a Solution for Eliminating the Risk of Mycotoxins.
Mycotoxins are toxic secondary metabolites produced by certain filamentous fungi. The occurrence of mycotoxins in food and feed causes negative health impacts on both humans and animals. Clay binders, yeast cell walls, or antioxidant additives are the most widely used products for mycotoxin elimination to reduce their impact. Although conventional methods are constantly improving, current research trends are looking for innovative solutions. Nanotechnology approaches seem to be a promising, effective, and low-cost way to minimize the health effects of mycotoxins. This review aims to shed light on the critical knowledge gap in mycotoxin elimination by nanotechnology. There are three main strategies: mold inhibition, mycotoxin adsorption, and reducing the toxic effect via nanoparticles. One of the most promising methods is the use of carbon-based nanomaterials. Graphene has been shown to have a huge surface and high binding capacity for mycotoxins. Attention has also been drawn to polymeric nanoparticles; they could substitute adsorbents or enclose any substance, which would improve the health status of the organism. In light of these findings, this review gives new insights into possible future research that might overcome challenges associated with nanotechnology utilization for mycotoxin elimination from agricultural products.


Measurement and manipulation of cytosolic pH in polarizing zygotes.
The role of cytosolic pH (pHc) in establishment and expression of developmental polarity was examined in zygotes of the brown alga Pelvetia. pHc was measured and manipulated at specific developmental stages during the first zygotic cell cycle. pHc was measured using pH-sensitive microelectrodes and by confocal ratio imaging of dextran-conjugated SNARF 1 (dc SNARF 1) loaded cells. The two techniques yielded very similar values of pHc in the cellular cortex, but ratio imaging was not effective in measuring endoplasmic pHc values. As zygotes formed a developmental axis, cortical pHc decreased abruptly by approximately 0.1 units, and a small but significant difference in pHc was detected at the thallus and rhizoid poles. The cortical cytosol was relatively acidic at the presumptive rhizoid pole. The magnitude of the pHc difference increased following initiation of rhizoid growth. pHc was manipulated by treating zygotes with membrane-permeant weak acids (propionic and benzoic acid) or bases (methylamine and procaine), which effectively clamp pHc to specific values in a concentration-dependent manner. pHc values in treated zygotes were measured for each concentration of acid or base, and a dose response curve was generated. Zygotes in which pHc had been clamped were examined for their ability to form a developmental axis and to initiate rhizoid outgrowth (germination). Both developmental processes were inhibited by relatively small (0.2-0.3 pH units) perturbations of pHc. The permissive ranges of pHc were slightly different, germination (permissive pHc range-pH 7.0 to 7.7) being more acid tolerant than axis formation (permissive pHc range-7.2 to 7.8).


Questioning your treatment of tachycardia.
These six questions may make it easier to guide your steps as critical minutes pass while treating your tachycardic patient. Ultimately, local protocols and the contents of your drug box may limit some of your choices, but good decisions can start the process. Adequate oxygenation, establishing IV lines and diagnosing specific rhythms are the first steps toward successful treatment of your next patient.


Sequence-defined vinyl sulfonamide click nucleic acids (VS-CNAs) and their assembly into dynamically responsive materials.
Synthetic DNA analogues are of great interest for their application in information storage, therapeutics, and nanostructured materials, yet are often limited in scalability. Vinyl sulfonamide click nucleic acids (VS-CNAs) have been developed to overcome this limitation using the highly efficient thiol-Michael 'click' reaction. Utilizing all four nucleobases, sequence-defined click nucleic acids (CNAs) were synthesized using a simple and scalabale solution-phase approach. Employing a polyethylene glycol (PEG) support, synthesis of the CNA sequence, GATTACA, was achieved in high yields. CNA crosslinked hydrogels were assembled using multiarm PEG-CNAs resulting in materials that dynamically respond to temperature, strain, and competitive sequences.


Mesenchymal stem/stromal cell therapy for inflammatory bowel disease: an updated review with maintenance of remission.
There is a need for novel therapies for inflammatory bowel diseases (IBDs) that are well tolerated and effective. Currently, mesenchymal stem/stromal cells (MSCs) are being investigated in clinical trials for treatment of IBD. In this review, we update the recently published studies with an emphasis on the long-term efficacy of MSC therapy for IBD. A cumulative body of data, including a recent phase III randomized controlled trial demonstrated excellent fistula healing in patients with refractory Crohn's perianal fistulae treated via local injections of MSCs and with a good safety profile. Follow-up studies suggest long-term efficacy of MSC therapy for complex perianal Crohn's disease fistulae; however, the efficacy decreases over time and may necessitate repeat treatment. Systemic (intravenous) therapy for luminal IBD offers a relatively well tolerated alternative but its efficacy remains unclear. Recent studies demonstrate that MSCs are well tolerated and have an excellent short-term efficacy for the management of refractory fistulizing perianal Crohn's disease. The current data suggest that its influence may 'wear off' over time. More data on larger number of patients with longer duration of follow-up in the setting of a randomized placebo controlled trial are needed to confirm these promising results. For luminal IBD, there is a need for more mechanistic studies in representative preclinical murine models, and the results of an ongoing phase III randomized controlled trial are eagerly awaited.


Singing in the moonlight: dawn song performance of a diurnal bird varies with lunar phase.
It is well established that the lunar cycle can affect the behaviour of nocturnal animals, but its potential to have a similar influence on diurnal species has received less research attention. Here, we demonstrate that the dawn song of a cooperative songbird, the white-browed sparrow weaver (Plocepasser mahali), varies with moon phase. When the moon was above the horizon at dawn, males began singing on average 10 min earlier, if there was a full moon compared with a new moon, resulting in a 67% mean increase in performance period and greater total song output. The lack of a difference between full and new moon dawns when the moon was below the horizon suggests that the observed effects were driven by light intensity, rather than driven by other factors associated with moon phase. Effects of the lunar cycle on twilight signalling behaviour have implications for both pure and applied animal communication research.


High-throughput identification of protein localization dependency networks.
Bacterial cells are highly organized with many protein complexes and DNA loci dynamically positioned to distinct subcellular sites over the course of a cell cycle. Such dynamic protein localization is essential for polar organelle development, establishment of asymmetry, and chromosome replication during the Caulobacter crescentus cell cycle. We used a fluorescence microscopy screen optimized for high-throughput to find strains with anomalous temporal or spatial protein localization patterns in transposon-generated mutant libraries. Automated image acquisition and analysis allowed us to identify genes that affect the localization of two polar cell cycle histidine kinases, PleC and DivJ, and the pole-specific pili protein CpaE, each tagged with a different fluorescent marker in a single strain. Four metrics characterizing the observed localization patterns of each of the three labeled proteins were extracted for hundreds of cell images from each of 854 mapped mutant strains. Using cluster analysis of the resulting set of 12-element vectors for each of these strains, we identified 52 strains with mutations that affected the localization pattern of the three tagged proteins. This information, combined with quantitative localization data from epitasis experiments, also identified all previously known proteins affecting such localization. These studies provide insights into factors affecting the PleC/DivJ localization network and into regulatory links between the localization of the pili assembly protein CpaE and the kinase localization pathway. Our high-throughput screening methodology can be adapted readily to any sequenced bacterial species, opening the potential for databases of localization regulatory networks across species, and investigation of localization network phylogenies.


Cu3 BiS3 : Two-Dimensional Coordination Induces Out-of-Plane Phonon Scattering Enabling Ultralow Thermal Conductivity.
The discovery of compounds with low thermal conductivity and the understanding of their microscopic mechanisms are of great challenges and scientific significance. Herein, we report a unique ternary sulfide compound, Cu3 BiS3 , in which all Cu atoms are coordinated within a two-dimensional [CuS3 ] triangle plane. This local coordination leads to efficient out-of-plane phonon scattering and an ultralow thermal conductivity. Through DFT phonon spectrum calculations and analyses, we reveal that the lowest vibration frequency decreases from 2 THz for high-dimensional [CuS4 ] tetrahedral coordinated Cu atoms in CuBiS2 (CN=4, with an average Cu-S bond length of 2.328 Å) to 1.5 THz for low-dimensional [CuS3 ] triangular coordinated Cu atoms in Cu3 BiS3 (CN=3, with a shorter Cu-S bond length of 2.285 Å). This is due to the out-of-plane thermal vibration of the Cu atoms in the latter. Consequently,Cu3 BiS3 exhibits one of the lowest values of κlat (0.32 W/m K) among its peer, with a 36 % reduction compared to CuBiS2 (0.50 W/m K). This groundbreaking discovery highlights the significant role of 2D local coordination in reducing thermal conductivity through characteristic out-of-plane phonon scattering, while also contributing to a large Grüneisen parameter (2.06) in Cu3 BiS3 .


The cotranscriptional assembly of snoRNPs controls the biosynthesis of H/ACA snoRNAs in Saccharomyces cerevisiae.
The carboxy-terminal domain (CTD) of RNA polymerase II large subunit acts as a platform to assemble the RNA processing machinery in a controlled way throughout the transcription cycle. In yeast, recent findings revealed a physical connection between phospho-CTD, generated by the Ctk1p kinase, and protein factors having a function in small nucleolar RNA (snoRNA) biogenesis. The snoRNAs represent a large family of polymerase II noncoding transcripts that are associated with highly conserved polypeptides to form stable ribonucleoprotein particles (snoRNPs). In this work, we have studied the biogenesis of the snoRNPs belonging to the box H/ACA class. We report that the assembly factor Naf1p and the core components Cbf5p and Nhp2p are recruited on H/ACA snoRNA genes very early during transcription. We also show that the cotranscriptional recruitment of Naf1p and Cbf5p is Ctk1p dependent and that Ctk1p and Cbf5p are required for preventing the readthrough into the snoRNA downstream genes. All these data suggest that proper cotranscriptional snoRNP assembly controls 3'-end formation of snoRNAs and, consequently, the release of a functional particle.


Sleep and its disorders.
Sleep disorders are very prevalent in the general population and are associated with significant medical, psychological, and social disturbances. Insomnia is the most common. When chronic, it usually reflects psychological/behavioral disturbances. Most insomniacs can be evaluated in an office setting, and a multidimensional approach is recommended, including sleep hygiene measures, psychotherapy, and medication. The parasomnias, including sleepwalking, night terrors, and nightmares, have benign implications in childhood but often reflect psychopathology or significant stress in adolescents and adults and organicity in the elderly. Excessive daytime sleepiness is typically the most frequent complaint and often reflects organic dysfunction. Narcolepsy and idiopathic hypersomnia are chronic brain disorders with an onset at a young age, whereas sleep apnea is more common in middle age and is associated with obesity and cardiovascular problems. Therapeutic naps, medications, and supportive therapy are recommended for narcolepsy and hypersomnia; continuous positive airway pressure, weight loss, surgery, and oral devices are the common treatments for sleep apnea.


[Functional status and seasonal changes in white blood cells in submarine personnel in the Kola Polar region].
Evaluated was potentiality of the blood leukocyte count analysis proposed by L.H. Garkavi et al. (1985-1990) within the program of submariners health monitoring. Leukograms of 573 sailors on active service in a large nuclear submarines unit and 455 divers of a formation of ships removed from an active unit of nuclear submarines for utilization. Seasonal variations in the functional state of submariners were revealed. The most noticeable differences in these two large groups of sailors were associated with particular months. Results suggest, first of all, serious adaptive loads on the physiology of submariners on military service in the Kola polar. Burden of these loads varies with seasons and has some peculiar features which means that health-improving programs should be developed for each season and each specific group of submariners, and Garkavi's method should be standardized to be applicable to the Kola polar population.


Honey bee workers that are pollen stressed as larvae become poor foragers and waggle dancers as adults.
The negative effects on adult behavior of juvenile undernourishment are well documented in vertebrates, but relatively poorly understood in invertebrates. We examined the effects of larval nutritional stress on the foraging and recruitment behavior of an economically important model invertebrate, the honey bee (Apis mellifera). Pollen, which supplies essential nutrients to developing workers, can become limited in colonies because of seasonal dearths, loss of foraging habitat, or intensive management. However, the functional consequences of being reared by pollen-stressed nestmates remain unclear, despite growing concern that poor nutrition interacts with other stressors to exacerbate colony decline. We manipulated nurse bees' access to pollen and then assessed differences in weight, longevity, foraging activity, and waggle-dance behavior of the workers that they reared (who were co-fostered as adults). Pollen stress during larval development had far-reaching physical and behavioral effects on adult workers. Workers reared in pollen-stressed colonies were lighter and shorter lived than nestmates reared with adequate access to pollen. Proportionally fewer stressed workers were observed foraging and those who did forage started foraging sooner, foraged for fewer days, and were more likely to die after only a single day of foraging. Pollen-stressed workers were also less likely to waggle dance than their unstressed counterparts and, if they danced, the information they conveyed about the location of food was less precise. These performance deficits may escalate if long-term pollen limitation prevents stressed foragers from providing sufficiently for developing workers. Furthermore, the effects of brief pollen shortages reported here mirror the effects of other environmental stressors that limit worker access to nutrients, suggesting the likelihood of their synergistic interaction. Honey bees often experience the level of stress that we created, thus our findings underscore the importance of adequate nutrition for supporting worker performance and their potential contribution to colony productivity and quality pollination services.


Stop Searching under the Streetlight! A Primer and Practical Guide to the Diagnosis of Joint Pain and Inflammation.
It is impossible to achieve a diagnosis without a comprehensive list of possible diagnostic explanations for a certain symptom or syndrome. Joint complaints are very frequent in general practice, paediatrics, emergency medicine and naturally rheumatology and orthopaedics. The differential diagnosis of joint and surrounding tissue pain and inflammation is impressively challenging. Orthopaedic surgeons and rheumatologists deal with different aspects of this subject, while primary care physicians need to have a wider perspective that includes both orthopaedic and rheumatic disorders. The purpose of this paper is to provide a unified, comprehensive, clear and concise guide to this subject that will include both orthopaedic and rheumatic disorders and may serve the practitioner as basic reference for differential diagnosis. Short dictionary-style definitions would be given for each disorder in order to provide a 'bird's-eye view', rather than an in-depth description of many diseases. Medical students, residents and primary care physicians are the primary target audience, but we believe that even the experienced orthopaedic surgeon or rheumatologist may benefit from a systematic and well-organised method.


Measles Elimination: Identifying Susceptible Sub-Populations to Tailor Immunization Strategies.
Measles elimination has been identified as a public health priority in Europe for a long time but has not yet been achieved. The World Health Organization (WHO) recommends identification of susceptible sub-populations to target supplementary immunization activities. We used three different sources of information: retrospective samples investigated for measles IgG between 1997 and 2016, vaccine coverage data from the existing electronic registry for birth cohorts 2015 to 1999, and surveillance data from 2009 until 20 July 2019. We calculated susceptibility by birth cohort using seroprevalence data, adjusting vaccine coverage data with reported effectiveness (93% for the first and 97% for the second dose, respectively), and compared it with measles incidence data, aggregated by birth cohorts and districts. Susceptibility levels for persons 10-41 years (birth cohorts 2007-1976) were 10.4% and thus far above the recommended values of WHO (5%). Older birth cohorts were sufficiently protected. Districts with the highest susceptibility estimates corresponded with districts with the highest incidence rates. Birth cohorts with susceptibility levels > 10% showed a 4.7 increased relative risk of having had more than one measles case. We conclude that retrospective serosurveys are a cheap and useful approach in identifying susceptible sub-populations, especially for older birth cohorts whose coverage data remain scarce.


Chromosomal localization of the 5-HT1F receptor gene: no evidence for involvement in response to sumatriptan in migraine patients.
The 5-HT1F receptor, which is present in both human vascular and neuronal tissue, may mediate the therapeutic effect and/or side-effects of sumatriptan. We investigated the chromosomal localization of the 5-HT1F receptor gene and the relation between eventually existing polymorphisms and the clinical response to sumatriptan in migraine patients. The 5-HT1F receptor gene was localized using a monochromosomal mapping panel, followed by a radiation-reduced hybrid mapping and fluorescent in situ hybridization. The results of these techniques show that the 5-HT1F receptor gene is localized at 3p12. We investigated the presence of polymorphisms by single strand conformation polymorphism analysis in 14 migraine patients who consistently responded well to sumatriptan, 12 patients who consistently experienced recurrence of the headache after initial relief, 12 patients with no response to sumatriptan, and in 13 patients who consistently experienced chest symptoms after use of sumatriptan. No polymorphisms were detected in any of the patients. We therefore conclude that genetic diversity of the 5-HT1F receptor gene is most probably not responsible for the variable clinical response to sumatriptan.


How to Make Outpatient Healthcare Data in Germany Available for Research in the Dynamic Course of Digital Transformation.
There is increasing interest on re-use of outpatient healthcare data for research, as most medical diagnosis and treatment is provided in the ambulatory sector. One of the early projects to bring primary data from German ambulatory care into clinical research technically, organizationally and in compliance with legal demands has been the RADAR project, that is based on a broad consent and has used the then available practice information system's interfaces to extract and transfer data to a research repository. In course of the digital transformation of the German healthcare system, former standards are abandoned and new interoperability standards, interfaces and regulations on secondary use of patient data are defined, however with slow adoption by Health-IT systems. Therefore, it is of importance for all initiatives that aim at using ambulatory healthcare data for research, how to access this data in an efficient and effective way. Currently defined healthcare standards are compared regarding coverage of data relevant for research as defined by the RADAR project. We compare four architectural options to access ambulatory health data through different components of healthcare and health research data infrastructures along the technical, organizational and regulatory conditions, the timetable of dissemination and the researcher's perspective. A high-level comparison showed a high degree of semantic overlap in the information models used. Electronic patient records and practice information systems are alternative data sources for ambulatory health data - but differ strongly in data richness and accessibility. Considering the compared dimensions of architectural routes to access health data for secondary research use we conclude that data extraction from practice information systems is currently the most promising way due to data availability on a mid-term perspective. Integration of routine data into the national research data infrastructures might be enforced by convergence of to date different information models.


The "parallel-cohort RCT": Novel design aspects and application in the Kids-DOTT trial of pediatric venous thromboembolism.
In traditional randomized controlled trial (RCT) designs, patients who are ineligible for randomization are excluded from study participation. However, these patients often constitute an important subgroup of the disease population. By extending existing RCT infrastructure, efforts to evaluate such patients in parallel cohort arms would provide an efficient means of generating multi-center prospective data on natural history, which would facilitate the development of future RCTs involving these subgroups of interest. This brief report discusses principles of the parallel-cohort RCT design, describes the few published trials in which it has been employed, and highlights novel aspects of its use in the Kids-DOTT trial-an ongoing multi-center randomized trial of the duration of anticoagulant therapy for venous thrombosis in children.


The effects of methylphenidate on cognitive performance of healthy male rats.
WE AIMED TO INVESTIGATE THE EFFECTS OF METHYLPHENIDATE (MPH) IN HEALTHY RATS ON TWO DISTINCT RADIAL MAZE TASKS WHICH RELY ON BRAIN STRUCTURES AND NEUROTRANSMITTERS KNOWN TO BE AFFECTED BY MPH: the Random Foraging Non-Delay Task (RFNDT) and the Delayed Spatial Win Shift Task (DSWT). Hooded Lister rats were trained to complete either the RFNDT or the DSWT having received oral treatment of either a vehicle or MPH (3.0 mg/kg and 5.0 mg/kg for RFNDT, 3.0 mg/kg for DSWT). We found no effect of MPH on the RFNDT relative to the control group. However, those treated with 5.0 mg/kg MPH did take significantly longer to reach criterion performance than those treated with the 3.0 mg/kg MPH, suggesting some doses of MPH can have detrimental effects. For the DSWT, if MPH was present in both phases, performance did not differ from when it was absent in both phases. However, when present in only one phase there was an increase in errors made, although this only reached significance for when MPH was present only in the test-phase. These data suggest that MPH may have detrimental effects on task performance and can result in state-dependent effects in healthy individuals.


Mechanoelectrical feedback: independent role of preload and contractility in modulation of canine ventricular excitability.
Mechanoelectrical feedback, defined as changes in mechanical state that precede and alter transmembrane potential, may have potential importance in understanding the role of altered load and contractility in the initiation and modulation of ventricular arrhythmias. To assess the independent effects of preload and contractility on myocardial excitability and action potential duration, we determined the stimulus strength-interval relationship and recorded monophasic action potentials in isolated canine left ventricles contracting isovolumically. The strength-interval relationship was characterized by three parameters: threshold excitability, relative refractory period, and absolute refractory period. The effects of a threefold increase in left ventricular volume or twofold increase in contractility on these parameters were independently assessed. An increase in preload did not change threshold excitability in 11 ventricles but significantly shortened the absolute refractory period from 205 +/- 15 to 191 +/- 14 ms (P less than 0.001) (mean +/- SD). Similarly, the relative refractory period decreased from 220 +/- 18 to 208 +/- 19 ms (P less than 0.002). Comparable results were observed when contractility was increased as a result of dobutamine infusion in 10 ventricles. That is, threshold excitability was unchanged but the absolute refractory period decreased from 206 +/- 14 to 181 +/- 9 ms (P less than 0.003), and the relative refractory period decreased from 225 +/- 17 to 205 +/- 18 ms (P less than 0.003). Similar results were obtained when contractility was increased with CaCl2, indicating that contractility associated changes were independent of beta-adrenergic receptor stimulation. An increase in preload or contractility was associated with shortening of the action potential. A threefold increase in preload and twofold increase in contractility were associated with a decrease in action potential duration of 22 and 24 ms, respectively. There was a significant linear correlation between action potential duration and excitability (absolute refractory period). The similar effects of increased preload and contractility on threshold excitability and refractoriness can be explained by the action these perturbations have on the time course of repolarization. Therefore, excitability of the ventricle is sensitive to and is modulated by alteration of load or inotropic state. The similar effects of either increased preload or contractility on excitability may be mediated by a common cellular mechanism which results in a rise in intracellular free Ca2+ and secondary abbreviation of the action potential.


Signal enhancement of glucuronide conjugates in LC-MS/MS by derivatization with the phosphonium propylamine cation tris(trimethoxyphenyl) phosphonium propylamine, for forensic purposes.
Although chemical derivatization for signal enhancement in drug testing is most often associated with gas chromatography, it also has the potential to improve the detection of analytes poorly ionized by atmospheric pressure ionization techniques, such as electrospray ionization used in liquid chromatography-mass spectrometry. A number of acidic compounds, namely drug glucuronides (e.g. conjugates of temazepam, oxazepam, lorazepam, morphine, testosterone, epitestosterone, 5-α-dihydrotestosterone, androsterone, p-nitrophenol, and paracetamol) were successfully derivatized with tris(trimethoxyphenyl) phosphoniumpropylamine to introduce a quaternary cation functionality to the analytes. Benzodiazepine glucuronides were more specifically investigated, and following positive mode electrospray ionization mass spectrometry, average improvements to peak areas as a result of derivatization were 67-, 6-, and 7- fold for temazepam, oxazepam, and lorazepam glucuronides. Average improvements to the signal-to-noise ratios for temazepam, oxazepam, and lorazepam glucuronides were 1336-, 371- and 217-fold, respectively. The values obtained for the derivatized conjugate were also typically higher than those for the underivatized parent drug. Urine containing benzodiazepine glucuronides was also successfully derivatized. The data indicates potential for the use of charge derivatization to improve the detection of molecules with acidic functionalities by liquid chromatography-mass spectrometry (LC-MS) techniques in certain scenarios.


Bortezomib Alone and in Combination With Salinosporamid A Induces Apoptosis and Promotes Pheochromocytoma Cell Death In Vitro and in Female Nude Mice.
Proteasome inhibitors have been frequently used in treating hematologic and solid tumors. They are administered individually or in combination with other regimens, to prevent severe side effects and resistance development. Because they have been shown to be efficient and are pharmaceutically available, we tested the first Food and Drug Administration-approved proteasome inhibitor bortezomib alone and in combination with another proteasome inhibitor, salinosporamid A, in pheochromocytoma cells. Pheochromocytomas/Paragangliomas (PHEOs/PGLs) are neuroendocrine tumors for which no definite cure is yet available. Therefore, drugs with a wide spectrum of mechanisms of action are being tested to identify suitable candidates for PHEO/PGL treatment. In the current study, we show that bortezomib induces PHEO cell death via the apoptotic pathway in vitro and in vivo. The combination of bortezomib with salinosporamid A exhibits additive effect on these cells and inhibits proliferation, cell migration and invasion, and angiogenesis more potently than bortezomib alone. Altogether, we suggest these proteasome inhibitors, especially bortezomib, could be potentially tested in PHEO/PGL patients who might benefit from treatment with either the inhibitors alone or in combination with other treatment options.


Neuroimaging of reading intervention: a systematic review and activation likelihood estimate meta-analysis.
A growing number of studies examine instructional training and brain activity. The purpose of this paper is to review the literature regarding neuroimaging of reading intervention, with a particular focus on reading difficulties (RD). To locate relevant studies, searches of peer-reviewed literature were conducted using electronic databases to search for studies from the imaging modalities of fMRI and MEG (including MSI) that explored reading intervention. Of the 96 identified studies, 22 met the inclusion criteria for descriptive analysis. A subset of these (8 fMRI experiments with post-intervention data) was subjected to activation likelihood estimate (ALE) meta-analysis to investigate differences in functional activation following reading intervention. Findings from the literature review suggest differences in functional activation of numerous brain regions associated with reading intervention, including bilateral inferior frontal, superior temporal, middle temporal, middle frontal, superior frontal, and postcentral gyri, as well as bilateral occipital cortex, inferior parietal lobules, thalami, and insulae. Findings from the meta-analysis indicate change in functional activation following reading intervention in the left thalamus, right insula/inferior frontal, left inferior frontal, right posterior cingulate, and left middle occipital gyri. Though these findings should be interpreted with caution due to the small number of studies and the disparate methodologies used, this paper is an effort to synthesize across studies and to guide future exploration of neuroimaging and reading intervention.


Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.
The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte-neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte-neuron metabolic cooperation.


Client and family engagement in rehabilitation research: a framework for health care organizations.
To describe the development and implementation of an organizational framework for client and family-centered research. Case report. While patient-centered care is now well established, patient-centered research remains underdeveloped. This is particularly true at the organizational level (e.g., hospital based research institutes). In this paper we describe the development of an organizational framework for client and family centered research at Holland Bloorview Kids Rehabilitation Hospital in Toronto, Canada. It is our hope that, by sharing our framework other research institutions can learn from our experience and develop their own research patient/client/family engagement programs. Implications for rehabilitation Family engagement in rehabilitation research •Rehabilitation research is crucial to the development and improvement of rehabilitative care. •The relevance, appropriateness, and accountability of research to patients, clients and families could be improved. •Engaging clients and families as partners in all aspects of the research process is one way to address this problem. •In this paper, we describe a framework for engaging clients and families in research at the organizational level.


WINCS Harmoni: Closed-loop dynamic neurochemical control of therapeutic interventions.
There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.


Simultaneous ultra-high frequency photoacoustic microscopy and photoacoustic radiometry of zebrafish larvae in vivo.
With their optically transparent appearance, zebrafish larvae are readily imaged with optical-resolution photoacoustic (PA) microscopy (OR-PAM). Previous OR-PAM studies have mapped endogenous chromophores (e.g. melanin and hemoglobin) within larvae; however, anatomical features cannot be imaged with OR-PAM alone due to insufficient optical absorption. We have previously reported on the photoacoustic radiometry (PAR) technique, which can be used simultaneously with OR-PAM to generate images dependent upon the optical attenuation properties of a sample. Here we demonstrate application of the duplex PAR/PA technique for label-free imaging of the anatomy and vasculature of zebrafish larvae in vivo at 200 and 400 MHz ultrasound detection frequencies. We then use the technique to assess the effects of anti-angiogenic drugs on the development of the larval vasculature. Our results demonstrate the effectiveness of simultaneous PAR/PA for acquiring anatomical images of optically transparent samples in vivo, and its potential applications in assessing drug efficacy and embryonic development.


Emerging uses of glucagon-like peptide 1 (GLP-1) receptor agonists following ileal resection: literature review and case examples.
Following ileal resection, the combination of severe bile acid (BA) malabsorption, rapid small bowel transit and unrestricted upper gastrointestinal (GI) secretion results in severe diarrhoea that can prove refractory to pharmacological therapies. While established therapies, including BA sequestrants and antidiarrhoeal drugs seek to ameliorate symptoms, they do not target the underlying pathophysiological mechanisms in this patient group. Their use can also be limited by both intolerance and adverse effects. The novel use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) in these patients may allow restoration of the physiological negative feedback mechanisms lost in ileal resection and reduce diarrhoea by prolonging small bowel transit time, limiting upper GI secretions and perhaps by inhibiting hepatic BA synthesis. While recent evidence supports the use of GLP-1 RAs as a safe and effective therapy for bile acid diarrhoea (BAD), it remains uncertain whether those with severe BAD and subsequent short bowel syndrome secondary to extensive ileal resection will benefit. Here, we present three cases of severe diarrhoea secondary to extensive ileal resection in which the use of the GLP-1 RA, liraglutide, was well tolerated and resulted in an objective improvement in diarrhoeal symptoms. We further provide a narrative review of the emerging evidence base supporting the use of GLP therapies in this challenging condition.


Histone acetyltransferase activity is conserved between yeast and human GCN5 and is required for complementation of growth and transcriptional activation.
Yeast and human ADA2 and GCN5 (y- and hADA2 and y- and hGCN5, respectively) have been shown to potentiate transcription in vivo and may function as adaptors to bridge physical interactions between DNA-bound activators and the basal transcriptional machinery. Recently it was shown that yGCN5 is a histone acetyltransferase (HAT), suggesting a link between enzymatic modification of nucleosomes and transcriptional activation. In this report, we demonstrate that hGCN5 is also an HAT and has the same substrate specificity as yGCN5. Since hGCN5 does not complement functional defects caused by deletion of yGCN5, we constructed a series of hGCN5-yGCN5 chimeras to identify human regions capable of activity in yeast. Interestingly, only the putative HAT domain of hGCN5, when fused to the remainder of yGCN5, complemented gcn5- cells for growth and transcriptional activation. Moreover, an amino acid substitution mutation within the HAT domain reduced both HAT activity in vitro and transcription in vivo. These findings directly link enzymatic histone acetylation and transcriptional activation and show evolutionary conservation of this potentially crucial pathway in gene regulation.