LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation.

The blood-brain barrier (BBB) is a term used to describe the unique properties of central nervous system (CNS) blood vessels. One important BBB property is the formation of a paracellular barrier made by tight junctions (TJs) between CNS endothelial cells (ECs). Here, we show that Lipolysis-stimulated lipoprotein receptor (LSR), a component of paracellular junctions at points in which three cell membranes meet, is greatly enriched in CNS ECs compared with ECs in other nonneural tissues. We demonstrate that LSR is specifically expressed at tricellular junctions and that its expression correlates with the onset of BBB formation during embryogenesis. We further demonstrate that the BBB does not seal during embryogenesis in Lsr knockout mice with a leakage to small molecules. Finally, in mouse models in which BBB was disrupted, including an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and a middle cerebral artery occlusion (MCAO) model of stroke, LSR was down-regulated, linking loss of LSR and pathological BBB leakage

Investigating Executive Working Memory and Phonological Short-Term Memory in Relation to Fluency and Self-Repair Behavior in L2 Speech

This paper reports the findings of a study investigating the relationship of executive working memory (WM) and phonological short-term memory (PSTM) to fluency and self-repair behavior during an unrehearsed oral task performed by second language (L2) speakers of English at two levels of proficiency, elementary and lower intermediate. Correlational analyses revealed a negative relationship between executive WM and number of pauses in the lower intermediate L2 speakers. However, no reliable association was found in our sample between executive WM or PSTM and self-repair behavior in terms of either frequency or type of self-repair. Taken together, our findings suggest that while executive WM may enhance performance at the conceptualization and formulation stages of the speech production process, self-repair behavior in L2 speakers may depend on factors other than working memory

Indications for Systemic Fluoroquinolone Therapy in Europe and Prevalence of Primary-Care Prescribing in France, Germany and the UK:Descriptive Population-Based Study

BACKGROUND AND OBJECTIVES: In the USA the benefit-risk profile of fluoroquinolones for treating patients with acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections (uUTIs) is considered unfavorable. However, the number of fluoroquinolone products in the EU indicated and prescribed for these infections is uncertain. The objective of this study was to provide data on indications for fluoroquinolones in Europe and examine the prevalence of prescribing in France, Germany and the UK.METHODS: Descriptive analysis of indications for systemic fluoroquinolone antibiotics across the European Economic Area (EEA) and descriptive analysis of systemic fluoroquinolone antibiotic prescribing in France, Germany and UK electronic health records (2000-2015).RESULTS: All EEA countries had fluoroquinolone products indicated for acute sinusitis, acute bronchitis, or uUTIs, with differences in the number of products between countries for: acute sinusitis (19.5-51.9%), acute bronchitis (22.2-73.4%), and uUTIs (52.0-89.1%). The prevalence of fluoroquinolone prescribing for the treatment of respiratory tract infections (RTIs) appeared to fall with time in all countries and for UTI in France and UK only. Changes were greatest in the UK. In France, Germany, and the UK, respectively: acute sinusitis accounted for 29.5, 20.6, and 40.7% of all oral fluoroquinolone prescriptions for upper RTIs; acute bronchitis accounted for 63.0, 83.0, and 89.9% of all fluoroquinolone prescriptions for lower RTIs; uUTIs accounted for 83.3, 89.9, and 32.2% of all fluoroquinolone prescriptions for UTIs.CONCLUSION: Large numbers of fluoroquinolone products in Europe are listed for the treatment of milder infections such as acute bronchitis, acute sinusitis and uUTIs. Among the countries assessed, fluoroquinolones were commonly prescribed for these conditions and potentially should lead to a review of therapeutic guidelines.</p

The Adolescent Cardio-Renal Intervention Trial (AdDIT): retinal vascular geometry and renal function in adolescents with type 1 diabetes

Aims/hypothesis We examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes. Methods A cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 ± 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log10 ACR into tertiles: upper tertile ACR was defined as ‘high-risk’ for future albuminuria and the lower two tertiles were deemed ‘low-risk’. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1–Q5) for associations with log10 ACR and ACR risk groups. Results Greater log10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2–Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1–Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control. Conclusions/interpretation Higher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications.This work was supported by the National Health and Medical Research Council of Australia (NHMRC 632521), JDRF (08-2007-902), Diabetes UK (DUK PO NO 2177 BDA:RD06/003341) and the British Heart Foundation

Reading during the composition of multi-sentence texts: an eye-movement study

Writers composing multi-sentence texts have immediate access to a visual representation of what they have written. Little is known about the detail of writers’ eye movements within this text during production. We describe two experiments in which competent adult writers’ eye-movements were tracked while performing short expository writing tasks. These are contrasted with conditions in which participants read and evaluated researcher-provided texts. Writers spent a mean of around 13% of their time looking back into their text. Initiation of these look-back sequences was strongly predicted by linguistically important boundaries in their ongoing production (e.g., writers were much more likely to look back immediately prior to starting a new sentence). 36% of look-back sequences were associated with sustained reading and the remainder with less patterned forward and backward saccades between words ("hopping"). Fixation and gaze durations and the presence of word-length effects suggested lexical processing of fixated words in both reading and hopping sequences. Word frequency effects were not present when writers read their own text. Findings demonstrate the technical possibility and potential value of examining writers’ fixations within their just-written text. We suggest that these fixations do not serve solely, or even primarily, in monitoring for error, but play an important role in planning ongoing production

Diabetes MILES – The Netherlands: rationale, design and sample characteristics of a national survey examining the psychosocial aspects of living with diabetes in Dutch adults

Background : As the number of people with diabetes is increasing rapidly worldwide, a more thorough understanding of the psychosocial aspects of living with this condition has become an important health care priority. While our knowledge has grown substantially over the past two decades with respect to the physical, emotional and social difficulties that people with diabetes may encounter, many important issues remain to be elucidated. Under the umbrella of the Diabetes MILES (Management and Impact for Long-term Empowerment and Success) Study International Collaborative, Diabetes MILES &ndash; The Netherlands aims to examine how Dutch adults with diabetes manage their condition and how it affects their lives. Topics of special interest in Diabetes MILES - The Netherlands include subtypes of depression, Type D personality, mindfulness, sleep and sexual functioning. Methods/design : Diabetes MILES &ndash; The Netherlands was designed as a national online observational study among adults with diabetes. In addition to a main set of self-report measures, the survey consisted of five complementary modules to which participants were allocated randomly. From September to October 2011, a total of 3,960 individuals with diabetes (40% type 1, 53% type 2) completed the battery of questionnaires covering a broad range of topics, including general health, self-management, emotional well-being and contact with health care providers. People with self-reported type 1 diabetes (specifically those on insulin pump therapy) were over-represented, as were those using insulin among respondents with self-reported type 2 diabetes. People from ethnic minorities were under-represented. The sex distribution was fairly equal in the total sample, participants spanned a broad age range (19&ndash;90 years), and diabetes duration ranged from recent diagnosis to living with the condition for over fifty years. Discussion : The Diabetes MILES Study enables detailed investigation of the psychosocial aspects of living with diabetes and an opportunity to put these findings in an international context. With several papers planned resulting from a pooled Australian-Dutch dataset and data collections planned in other countries, the Diabetes MILES Study International Collaborative will contribute substantially to identifying potentially unmet needs of those living with diabetes and to inform clinical research and care across the globe. <br /

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps.

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.Pediatric Research advance online publication, 11 April 2018; doi:10.1038/pr.2018.38

Social Determinants of Health Are Associated with Markers of Renal Injury in Adolescents with Type 1 Diabetes.

OBJECTIVE: To examine the relationship between the social determinants of health and markers of early renal injury in adolescent patients with type 1 diabetes (T1D). STUDY DESIGN: Renal outcomes included estimated glomerular filtration rate (eGFR) and albumin-creatinine excretion ratio (ACR). Differences in urinary and serum inflammatory markers also were assessed in relation to social determinants of health. Regression analysis was used to evaluate the association between the Ontario Marginalization Index (ON-Marg) as a measure of the social determinants of health, patient characteristics, ACR, eGFR, and renal filtration status (hyperfiltration vs normofiltration). RESULTS: Participants with T1D (n = 199) with a mean age of 14.4 ± 1.7 years and diabetes duration of 7.2 ± 3.1 years were studied. Mean eGFR was 122.0 ± 19.4 mL/min/1.73 m2. Increasing marginalization was positively associated with eGFR (P < .0001) but not with ACR (P = .605). Greater marginalization was associated with greater median levels of urinary interleukin (IL)-2, IL-12 (p40), macrophage-derived chemokine, monocyte chemoattractant protein-3, and tumor necrosis factor-β and serum IL-2. ON-Marg was significantly associated with eGFR after we controlled for age, sex, body mass index z score, ethnicity, serum glucose, and hemoglobin A1c in linear regression. A similar association between hyperfiltration and ON-Marg score was observed in multivariable logistic regression. CONCLUSION: Increasing marginalization is significantly associated with both eGFR and hyperfiltration in adolescents with T1D and is associated with significant changes in urinary inflammatory biomarkers. These findings highlight a potentially important interaction between social and biological determinants of health in adolescents with T1D

Abdominal pain with a twist

Malrotation in children is due to either an incomplete or non-rotation of the foetal mid-gut during perinatal development. Presentation is usually in the first few weeks of life, often with life-threatening volvulus and ischaemia. However, it can be a rare cause of abdominal pain in older children and young adults. We present such a case, as a reminder to emergency physicians that malrotation should be considered in the differential diagnosis of recurrent or chronic abdominal pain not only in children but also in adolescents

Medication adherence during adjunct therapy with statins and ACE inhibitors in adolescents with type 1 diabetes

OBJECTIVE: Suboptimal adherence to insulin treatment is a main issue in adolescents with type 1 diabetes. However, to date, there are no available data on adherence to adjunct noninsulin medications in this population. Our aim was to assess adherence to ACE inhibitors and statins and explore potential determinants in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS:There were 443 adolescents with type 1 diabetes recruited into the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and exposed to treatment with two oral drugs—an ACE inhibitor and a statin—as well as combinations of both or placebo for 2–4 years. Adherence was assessed every 3 months with the Medication Event Monitoring System (MEMS) and pill count. RESULTS: Median adherence during the trial was 80.2% (interquartile range 63.6–91.8) based on MEMS and 85.7% (72.4–92.9) for pill count. Adherence based on MEMS and pill count dropped from 92.9% and 96.3%, respectively, at the first visit to 76.3% and 79.0% at the end of the trial. The percentage of study participants with adherence ≥75% declined from 84% to 53%. A good correlation was found between adherence based on MEMS and pill count (r = 0.82, P < 0.001). Factors associated with adherence were age, glycemic control, and country. CONCLUSIONS: We report an overall good adherence to ACE inhibitors and statins during a clinical trial, although there was a clear decline in adherence over time. Older age and suboptimal glycemic control at baseline predicted lower adherence during the trial, and, predictably, reduced adherence was more prevalent in subjects who subsequently dropped out