Megalencephaly secondary to a novel germline missense variant p.Asp322Tyr in AKT3 associated with growth hormone deficiency and central hypothyroidism: A case report.

Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a child with megalencephaly, who is a carrier of a novel heterozygous missense variant in the AKT3 gene NM_005465.7:c.964G>T,p.Asp322Tyr. The phenotype of this patient is associated with pituitary deficiencies diagnosed at 2 years of age: growth hormone (GH) deficiency responsible for growth delay and central hypothyroidism. After 6 months of GH treatment, intracranial hypertension was noted, confirmed by the observation of papilledema and increased intracranial pressure, requiring the initiation of acetazolamide treatment and the discontinuation of GH treatment. This is the second reported patient described with megalencephaly and AKT3 gene variant associated with GH deficiency . Other endocrine disorders have also been reported in few cases with hypothyroidism and hypoglycemia. Pituitary deficiency may be a part of the of megalencephaly phenotype secondary to germline variant in the AKT3 gene. Special attention should be paid to growth in these patients and search for endocrine deficiency is necessary in case of growth retardation or hypoglycemia.

Open-source deep learning-based air-void detection algorithm for concrete microscopic images.

Analysing concrete microscopic images is difficult because of its highly heterogeneous composition and the different scales involved. This article presents an open-source deep learning-based algorithm dedicated to air-void detection in concrete microscopic images. The model, whose strategy is presented alongside concrete compositions information, is built using the Mask R-CNN model. Model performances are then discussed and compared to the manual air-void enhancement technique. Finally, the selected open-source strategy is exposed. Overall, the model shows a good precision (mAP = 0.6452), and the predicted air void percentage agrees with experimental measurements highlighting the model's potential to assess concrete durability in the future.

Analyzing concrete microscopic images is difficult because of its highly heterogeneous composition and the different scales involved, e.g. cement paste, sand, and aggregates are the major phases at a microscopic scale. However, characterizing concrete microstructure is of paramount importance to assess its mechanical properties and durability. For example, air voids decrease the mechanical properties but can increase the resistance to freeze-thaw if correctly distributed and of small size. This article presents an open-source deep learning-based algorithm dedicated to air-void detection in concrete microscopic images. The model, whose strategy is presented alongside concrete compositions information, is built using the Mask R-CNN model. Model performances are then discussed and compared to the manual air-void enhancement technique, which involves coloring concrete surfaces and filling air voids with fine powder before taking images. Finally, the selected open-source strategy is exposed. Overall, the model shows a good precision (mAP = 0.6452), and the predicted air void percentage agrees with experimental measurements highlighting the model's potential to assess concrete durability in the future.

[Early intervention in bipolar affective disorders: Why, when and how]. / Intervenir précocement dans les stades débutants du trouble bipolaire : pourquoi, quand et comment.

OBJECTIVES: Bipolar disorder (BD) is a chronic and severe psychiatric disease. There are often significant delays prior to diagnosis, and only 30 to 40 % of patients will experience complete remission. Since BD occurs most often at a young age, the disorder can seriously obstruct future socio-professional development and integration. Vulnerability-stress model of BD is considered to be the result of an interaction between vulnerability genes and environmental risk factors, which leads to the onset of the disorder most often in late adolescence or early adulthood. The clinical "staging" model of BD situates the subject in a clinical continuum of varying degrees of severity (at-risk status, first episode, full-blown BD). Given the demonstrated effectiveness of early intervention in the early stages of psychotic disorder, we posit that early intervention for early stages of BD (i.e. at-risk status and first episode mania or hypomania) would reduce the duration of untreated illness and optimize the chances of therapeutic response and recovery. METHODS: We conducted a narrative review of the literature to gather updated data on: (1) features of early stages: risk factors, at-risk symptoms, clinical specificities of the first manic episode; (2) early screening: targeted populations and psychometric tools; (3) early treatment: settings and therapeutic approaches for the early stages of BD. RESULTS: (1) Features of early stages: among genetic risk factors, we highlighted the diagnosis of BD in relatives and affective temperament including as cyclothymic, depressive, anxious and dysphoric. Regarding prenatal environmental risk, we identified peripartum factors such as maternal stress, smoking and viral infections, prematurity and cesarean delivery. Later in the neurodevelopmental course, stressful events and child psychiatric disorders are recognized as increasing the risk of developing BD in adolescence. At-risk symptoms could be classified as "distal" with early but aspecific expressions including anxiety, depression, sleep disturbance, decreased cognitive performance, and more specific "proximal" symptoms which correspond to subsyndromic hypomanic symptoms that increase in intensity as the first episode of BD approaches. Specific clinical expressions have been described to assess the risk of BD in individuals with depression. Irritability, mixed and psychotic features are often observed in the first manic episode. (2) Early screening: some individuals with higher risk need special attention for screening, such as children of people with BD. Indeed, it is shown that children with at least one parent with BD have around 50 % risk of developing BD during adolescence or early adulthood. Groups of individuals presenting other risk factors, experiencing an early stage of psychosis or depressive disorders should also be considered as targeted populations for BD screening. Three questionnaires have been validated to screen for the presence of at-risk symptoms of BD: the Hypomanic Personality Scale, the Child Behavior Checklist-Paediatric Bipolar Disorder, and the General Behavior Inventory. In parallel, ultra-high risk criteria for bipolar affective disorder ("bipolar at-risk") distinguishing three categories of at-risk states for BD have been developed. (3) Early treatment: clinical overlap between first psychotic and manic episode and the various trajectories of the at-risk status have led early intervention services (EIS) for psychosis to reach out for people with an early stage of BD. EIS offers complete biopsychosocial evaluations involving a psychiatric examination, semi-structured interviews, neuropsychological assessments and complementary biological and neuroimaging investigations. Key components of EIS are a youth-friendly approach, specialized and intensive care and client-centered case management model. Pharmaceutical treatments for at-risk individuals are essentially symptomatic, while guidelines recommend the use of a non-antipsychotic mood stabilizer as first-line monotherapy for the first manic or hypomanic episode. Non-pharmacological approaches including psychoeducation, psychotherapy and rehabilitation have proven efficacy and should be considered for both at-risk and first episode of BD. CONCLUSIONS: EIS for psychosis might consider developing and implementing screening and treatment approaches for individuals experiencing an early stage of BD. Several opportunities for progress on early intervention in the early stages of BD can be drawn. Training first-line practitioners to identify at-risk subjects would be relevant to optimize screening of this population. Biomarkers including functional and structural imaging measures of specific cortical regions and inflammation proteins including IL-6 rates constitute promising leads for predicting the risk of transition to full-blown BD. From a therapeutic perspective, the use of neuroprotective agents such as folic acid has shown particularly encouraging results in delaying the emergence of BD. Large-scale studies and long-term follow-up are still needed to achieve consensus in the use of screening and treatment tools. The development of specific recommendations for the early stages of BD is warranted.

Parkinsonian gait in elderly people: Significance of the threshold value of two and more falls per year.

OBJECTIVES: Parkinsonism in the elderly presents a major risk factor for recurrent falls (2 and more falls per year), which is associated with increased morbidity. The main objective was to investigate explanatory variables relating to the risk of being recurrent fallers (RF) in persons with parkinsonian gait. METHODS: Seventy-nine among 172 eligible persons were enrolled in this prospective study, the findings of which were analyzed at 12 months. Motor and non-motor features, as well as follow-up interviews to identify falls, loss of ability to walk, fluctuating cognition, traumatic falls, all-cause hospitalizations and deaths were collated and results compared between non RF (zero and one fall per year) and RF. Bayesian model averaging was used to predict the probability of patients being RF from their medical history as well as from cognitive assessment, gait velocity, vision and posture. RESULTS: N=79, 0.58 men, 50% had Parkinson's disease, 14% other neurodegenerative parkinsonian syndrome, 23% vascular parkinsonism and 13% Lewy body disease, 58% were RF. Median age 81.2 years and median MMSE 25/30. A history of falls and of hallucinations, median odds ratio respectively 9.06 (CI 2.34-38.22), 4.21 (CI 1.04-18.67) were associated with the highest odds ratios along with fluctuating cognition and abnormal posture. Two or more falls a year was a relevant threshold to distinguish a population with a high risk of comorbidity. CONCLUSION: The whole history of falls, hallucinations and fluctuating cognition can be considered predictive of recurrent falls in elderly people with parkinsonian gait and provide a tracking tool for patient management.

Vitamin D supplementation improves the metabolic syndrome risk profile in postmenopausal women.

Objective: This study aimed to evaluate the effect of isolated vitamin D (VD) supplementation on the metabolic syndrome (MetS) risk profile in postmenopausal women.Methods: In this double-blind, placebo-controlled trial, 160 postmenopausal women aged 50-65 years were randomized into two groups: VD group, supplementation with 1000 IU vitamin D3/day (n = 80); or placebo group (n = 80). The intervention time was 9 months, and the women were assessed at baseline and endpoint. Clinical and anthropometric data were collected. Biochemical parameters, including total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, and insulin, were measured. The plasma concentration of 25-hydroxyvitamin D (25(OH)D) was measured by high-performance liquid chromatography.Results: After 9 months, there was a significant increase in the 25(OH)D levels for VD group (+45.4%, p < 0.001), and a decrease (-18.5%, p = 0.049) in the placebo group. In the VD group, a significant reduction was observed in triglycerides (-12.2%, p = 0.001), insulin (-13.7%, p = 0.008), and the homeostasis model assessment of insulin resistance (-17.9%, p = 0.007). In the placebo group, there was an increase in glucose (+6.2%, p = 0.009). Analysis of the risk adjusted for age, time since menopause, and body mass index showed that women supplemented with VD had a lower risk of MetS (odds ratio [OR] 0.42; 95% confidence interval [CI] 0.21-0.83), hypertriglyceridemia (OR 0.43; 95% CI 0.22-0.85), and hyperglycemia (OR 0.23; 95% CI 0.10-0.52) compared to the placebo group (p < 0.05).Conclusions: In postmenopausal women with VD deficiency, isolated supplementation with 1000 IU vitamin D3 for 9 months was associated with a reduction in the MetS risk profile. Women undergoing VD supplementation had a lower risk of MetS, hypertriglyceridemia, and hyperglycemia.

Altered rumen fermentation patterns in lactating dairy cows supplemented with phytochemicals improve milk production and efficiency.

Tannins and other phytochemicals are known to improve RUP in the diet by binding protein and then limiting ruminal degradation, which may improve milk yield and milk protein synthesis. The objective of this study was to evaluate the effects of dietary phytochemicals (tannins and Capsicum species) as rumen modifiers on production parameters and milk efficiency in dairy cows. Twenty-four multiparous Holstein cows (96 ± 16 d in milk; mean ± standard deviation) were used in a replicated 3 × 3 Latin square design balanced to measure carryover effects. Cows were blocked according to days in milk, milk production, and body weight and randomly assigned to 1 of 3 groups (n = 8/group). Each group was assigned to a unique treatment sequence across the 3 periods in the Latin square. The experiment consisted of a 14-d covariate period and three 30-d treatment periods. Cows received a basal diet supplemented with soybean meal pellets (SB) as the control diet, phytochemicals (RUM; Rumiviv, CCPA, Janzé, France) pelleted with soybean meal, or expeller soybean meal (ESBM; SoyPlus, West Central Soy, Ralston, IA). Milk production and dry matter intake during the last 4 d of each period were used for statistical analysis. Blood and rumen fluid samples were collected on d 27 of each period. Rumen fluid was analyzed for ammonia N and volatile fatty acids as well as ruminal bacteria via quantitative PCR amplification of 16S ribosomal DNA genes. Greater milk yield (37.9 vs. 36 kg/d), energy-corrected milk (39.7 vs 37.1 kg/d), and protein yield (1.15 vs. 1.08 kg/d) were observed in RUM compared with SB, but these parameters were similar between RUM and ESBM. Concentrations of total volatile fatty acids (118.1 vs. 101.5 mM) were greater in RUM in comparison to SB and ESBM diets. Cows fed RUM had greater ß-hydroxybutyrate (0.49 vs. 0.42 mmol/L) than SB and ESBM. Selenomonas ruminantium, Succinimonas amylolytica, and Streptococcus bovis in rumen fluid were lower in RUM fed cows in comparison to SB and ESBM. Increased total volatile fatty acids and lower ruminal abundance of bacteria associated with low feed efficiency in RUM cows can partially explain the improvements observed in milk yield and milk efficiency. Overall, these data suggest that feeding a combination of tannin mixture and Capsicum can significantly affect rumen fermentation characteristics via partial manipulation of rumen microbiota, and these effects were reflected in improved milk production and efficiency.

Effects of timing of artificial insemination and treatment of semen with a Slo3 potassium channel blocker on fertility of dairy heifers subjected to the 5-day CIDR-Synch protocol.

Two experiments were conducted to evaluate the effects of the timing of artificial insemination (AI) and incorporation of the Slo3 K+ channel blocker 4-(4-chlorophenyl)butyl-diethyl-heptylammonium to semen extender (CSE) on pregnancy per AI (P/AI) and pregnancy loss in dairy heifers. In experiment 1, Holstein heifers were subjected to the 5-d CIDR-Synch protocol: d -8 GnRH and controlled internal drug-release device (CIDR); d -3 PGF2α and CIDR removal; d -2 PGF2α; d 0 GnRH) and assigned randomly to receive timed AI with control semen on d 0 (72-CON; n = 104), control semen on d -1 (48-CON; n = 100), or CSE-treated semen on d -1 (48-CSE; n = 98). Heifers were fitted with collar-mounted automated estrus detection devices to monitor physical activity and rumination. In experiment 2, Holstein heifers were subjected to the 5-d CIDR-Synch protocol and received a mount detection patch at the first PGF2α injection. Heifers detected in estrus before d 0 were inseminated on the same day, whereas those not detected in estrus received the second GnRH injection and timed AI on d 0. Heifers were assigned randomly to receive AI with control (AI-CON; n = 148) or CSE-treated semen (AI-CSE; n = 110). Four bulls with proven fertility were used in both experiments, and ejaculates from each sire were divided and processed as CON or CSE. Pregnancy was diagnosed by transrectal ultrasonography at 29 and 54 d after AI. Data were analyzed by logistic regression, and statistical models included the fixed effects of treatment and enrollment week. In experiment 1, orthogonal contrasts were built to assess the effects of day of AI (72-CON vs. 48-CON + 48-CSE) and treatment of semen with CSE (48-CON vs. 48-CSE). Pregnancy per AI on d 29 (72-CON = 60.8, 48-CON = 35.2, 48-CSE = 39.8%) and d 54 (72-CON = 58.2, 48-CON = 31.6, 48-CSE = 36.2%) was greater for heifers inseminated on d 0 compared with d -1. However, no effect of semen extender on P/AI was observed in heifers inseminated on d -1. In experiment 2, P/AI tended to be greater for AI-CSE than for AI-CON on d 29 (58.6 vs. 47.3%) and d 54 after AI (55.6 vs. 43.7%). Advancing AI by 24 h decreased the likelihood of pregnancy, and use of CSE was unable to overcome the expected asynchrony between insemination and ovulation. Nevertheless, incorporation of CSE in semen processing tended to improve P/AI when heifers received AI upon detected estrus or timed AI concurrently with the final GnRH of the 5-d CIDR-Synch protocol.

Hematological and biochemical parameters of dairy calves submitted to pegbovigrastim administration.

This study was designed to evaluate the response of hematological and biochemical parameters submitted to pegbovigrastim administration and postchallenge with lipopolysaccharide (LPS). In experiment 1, 20 newborn Holstein calves were divided into 2 groups: the Imrestor (Elanco Saúde Animal, São Paulo, Brazil) group (IMR, n = 10), which received a 25 µg/kg of body weight (BW) subcutaneous administration of pegbovigrastim, and the control group (CTR, n = 10), which received a subcutaneous administration of 0.9% saline solution. Blood samples were collected on d 0, 10, 12, and 14 relative to birth to analyze the biochemical and hematological parameters. Moreover, growth measurements were taken on d 0, 7, 14, 21, and 60 relative to birth. The number of total leukocytes in the IMR group increased on d 12 and 14 in comparison to the CTR group, as well as the counts of segmented neutrophils, band cells, and monocytes. No differences were observed in the other hematological, biochemical, and growth parameters. In experiment 2, 20 Holstein calves from 30 to 60 d old were divided into 4 groups: group 1 (LPS, n = 5) received a 0.25 µg/kg of BW single intravenous dose of Escherichia coli LPS at d 0; group 2 (IMR, n = 5) received a 25 µg/kg of BW subcutaneous dose of pegbovigrastim at d 1; group 3 (IMR + LPS, n = 5) received a 0.25 µg/kg of BW intravenous LPS dose at d 0 and a 25 µg/kg of BW subcutaneous dose of pegbovigrastim at d 1; and group 4 (CTR, n = 5) received an intravenous dose of 0.9% sodium chloride at d 0 and a subcutaneous dose of 0.9% sodium chloride at d 1. For the analysis of biochemical and hematological parameters, blood samples were collected on d -1, 0, 1, 2, 3, 4, 8, 14, and 21 relative to LPS administration. An increase in the number of total leukocytes was observed in the IMR, IMR + LPS, and LPS groups, and the IMR group remained as the highest from d 2 to 21. The levels of paraoxonase 1 were higher in the IMR group compared with all the others. The administration of pegbovigrastim in the dairy calves increased the number of circulating leukocytes, especially neutrophils, with an increase in paraoxonase 1, without altering the metabolites for the hepatic function.

Effect of isolated vitamin D supplementation on bone turnover markers in younger postmenopausal women: a randomized, double-blind, placebo-controlled trial.

Vitamin D (VD) plays an important role in bone mineralization. The present study investigates the effect of VD supplementation alone on bone turnover markers in younger postmenopausal women. It has been shown that VD supplementation in postmenopausal women with hypovitaminosis D is associated with a reduction in bone turnover markers. PURPOSE: The purpose of this study is to evaluate the effect of VD supplementation alone on bone turnover markers in younger postmenopausal women. METHODS: In this double-blind, placebo-controlled trial, 160 women were randomized into the VD group (supplementation with 1000 IU of vitamin D3/day, orally; n = 80) or placebo group (n = 80). Women aged 50-65 years with amenorrhea ≥ 12 months and normal bone mineral density were included. The intervention lasted 9 months, and the participants were assessed at the beginning and end of treatment. Serum levels of total calcium, parathormone (PTH), alkaline phosphatase (AP), and 24-h urine calcium were determined. Serum C-terminal telopeptide of type I collagen (s-CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured by immunoassay as markers of bone resorption and formation, respectively. Plasma 25-hydroxyvitamin-D [25(OH)D] concentrations were measured by HPLC. Intention-to-treat analysis was performed using ANOVA, Student's t test, Tukey's test, and gamma distribution. RESULTS: Over the period of 9 months, 25(OH)D concentrations increased from 15.0 ± 7.5 to 27.5 ± 10.4 ng/mL (+ 45.4%) in the VD group and decreased from 16.9 ± 6.7 to 13.8 ± 6.0 ng/mL (- 18.5%) in the placebo group (p < 0.001). There was a decrease (- 21.3%) of PTH levels in the VD group with a significant difference between groups at the end of the study (p < 0.001). No significant differences were observed in the other laboratory parameters (total calcium, AP, and calciuria) in either group (p > 0.05). A comparison of bone turnover markers showed a significant reduction in of s-CTX (- 24.2%, p < .0001) and P1NP (- 13.4%, p = 0.003) levels in the VD group. No significant variations in bone turnover markers were observed in the placebo group (s-CTX, - 6.9%, p = 0.092 and P1NP, - 0.6%, p = 0.918). CONCLUSION: In younger postmenopausal women with VD deficiency, isolated supplementation with 1000 IU of vitamin D3 for 9 months is associated with a reduction in bone turnover markers. However, any between-group differences was not observed in bone turnover markers.

Health benefits of multicomponent training programmes in seniors: a systematic review.

BACKGROUND: The ageing process is intrinsically associated with decline in physical endurance, muscle strength and gait ability and balance, which all contribute to functional disability. Regular physical training, and more particularly multicomponent training (MCT), has demonstrated many health benefits. OBJECTIVE: To evaluate the evidence of the health benefits of MCT including endurance training, muscle strengthening, balance exercises, and/or stretching (i.e. flexibility training) and/or coordination training in adults aged 65 years or over. METHODS: A comprehensive, systematic database search for manuscripts was performed in CINAHL Plus, Embase, Medline, PubMed Central, ScienceDirect, Scopus, Sport Discus and Web of Science using key words. For potential inclusion, two reviewers independently assessed all intervention studies published in English language from 1 January 2000 to 30 April 2015. RESULTS: Of 2525 articles initially identified, 27 studies were finally included in this systematic review. They were all divided into five categories according to their main outcome measurements (cardio-respiratory fitness, metabolic outcomes, functional and cognitive functions and quality of life, QoL). These studies reported that MCT has a significant beneficial effect on cardio-respiratory fitness and on metabolic outcomes. Substantial improvement in functional and cognitive performance was also measured and a slighter but positive effect on QoL. CONCLUSION: Overall, this review demonstrates a positive effect of MCT with functional benefits and positive health outcomes for seniors. Based on this evidence, clinicians should encourage all adults aged 65 or over to engage in MCT programmes to favour healthy ageing and keeping older members of our society autonomous and independent.

French consensus procedure for assessing cognitive function in Parkinson's disease.

INTRODUCTION: One of the objectives of the French expert centers for Parkinson's disease (NS-Park) network was to determine a consensus procedure for assessing cognitive function in patients with Parkinson's. This article presents this procedure and briefly describes the selected tests. METHODS: A group of 13 experts used the Delphi method for consensus building to define the overall structure and components of the assessment procedure. For inclusion in the battery, tests had to be validated in the French language, require little motor participation, have normative data and be recognized by the international community. Experimental tasks and tests requiring specific devices were excluded. RESULTS: Two possibilities were identified, depending on whether an abbreviated or comprehensive assessment of cognitive function was necessary. For an abbreviated assessment, the experts recommended the Montreal Cognitive Assessment (MoCA) as a screening test for cognitive impairment or dementia. For a comprehensive neuropsychological assessment, the experts recommended assessing global efficiency plus the five main cognitive domains (attention and working memory, executive function, episodic memory, visuospatial function and language) that may be impaired in Parkinson's disease, using two tests for each domain. DISCUSSION AND CONCLUSION: A common procedure for assessing cognitive function is now available across the French network dedicated to Parkinson's disease, and is recommended for both research and clinical practice. It will also help to promote standardization of the neuropsychological assessment of Parkinson's disease.

Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutières and Singleton-Merten syndromes.

Cutaneous lesions described as chilblain lupus occur in the context of familial chilblain lupus or Aicardi-Goutières syndrome. To date, seven genes related to Aicardi-Goutières syndrome have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (also known as MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi-Goutières syndrome. It is of note that none of the patients with a neurological phenotype so far described with mutations in this gene was reported to demonstrate cutaneous involvement. We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon-stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be confined predominantly to the skin, while also highlighting phenotypic overlap with both Aicardi-Goutières syndrome and Singleton-Merten syndrome.

Tick saliva increases production of three chemokines including monocyte chemoattractant protein-1, a histamine-releasing cytokine.

The effect of Ixodes ricinus tick saliva on the production of various cytokines and chemokines by mouse splenocytes was tested by a cytokine array. We demonstrated a strong upregulation of three chemokines, monocyte chemoattractant protein-1 (MCP-1), thymus-derived chemotactic agent 3 (TCA-3) and macrophage inflammatory protein 2 (MIP-2). MCP-1 could be induced by tick saliva itself. While TCA-3 and MIP-2 are engaged in Th2 polarization of the host immune response associated with tick feeding, MCP-1 may act as a histamine release factor, increasing blood flow into the feeding lesion thus facilitating tick engorgement in the late, rapid feeding phase.

Enhanced immunogenicity of multivalent MUC1 glycopeptide antitumour vaccines based on hyperbranched polymers.

Enhancing the immunogenicity of an antitumour vaccine still poses a major challenge. It depends upon the selected antigen and the mode of its presentation. We here describe a fully synthetic antitumour vaccine, which addresses both aspects. For the antigen, a tumour-associated MUC1 glycopeptide as B-cell epitope was synthesised and linked to the immunostimulating T-cell epitope P2 derived from tetanus toxoid. The MUC1-P2 conjugate is presented multivalently on a hyperbranched polyglycerol to the immune system. In comparison to a related vaccine of lower multivalency, this vaccine exposing more antigen structures on the hyperbranched polymer induced significantly stronger immune responses in mice and elicited IgG antibodies of distinctly higher affinity to epithelial tumour cells.

Effects of omega-3 on metabolic markers in postmenopausal women with metabolic syndrome.

OBJECTIVE: The aim of this study was to evaluate the effect of diet alone or combined with omega-3 supplementation on metabolic and inflammatory markers in postmenopausal women with metabolic syndrome. METHODS: This randomized, controlled trial included 87 Brazilian women (age ≥ 45 years and with amenorrhea ≥ 12 months). Exclusion criteria were: cardiovascular disease, insulin-dependent diabetes, cancer, autoimmune diseases and use of either statins or hormone therapy. Participants were randomized to diet alone (n = 43, control) or diet plus omega-3 supplementation, 900 mg/day orally (n = 44). All women were provided with an individualized dietary prescription. Clinical, anthropometrical (body mass index and waist circumference) and biochemical variables were measured. The inflammatory profile included C-reactive protein, tumor necrosis factor α and interleukins (IL-1ß and IL-6). The intervention time was 6 months, with assessments at initiation and completion. Data were analyzed according to intention-to-treat, using the independent t-test and ANOVA. RESULTS: There were significant reductions in body mass index and waist circumference in both groups (p < 0.05) without significant changes in body fat or muscle mass. Intervention with diet plus omega-3 was associated with significant reduction in systolic (< 12.2%) and diastolic (< 8.2%) blood pressure, serum triglyceride concentration (< 21.4%), and insulin resistance (< 13.1%) (p < 0.05), as well as a reduction in serum IL-6 concentration (< 28.5%) (p = 0.034). CONCLUSION: In postmenopausal women with metabolic syndrome, dietary intervention plus supplementation of omega-3 resulted in a further decrease in triglycerides and blood pressure and also in an improvement in insulin resistance and inflammatory markers, important components of metabolic syndrome.

Health benefits of endurance training alone or combined with diet for obese patients over 60: a review.

BACKGROUND: The prevalence of obesity is rapidly increasing in older patients and it is ubiquitous in many developed countries. Obesity is related to various negative health outcomes, making it a major public health target for intervention. PURPOSE: The aim of this study was to explore and summarise the literature that addresses endurance training alone or combined with nutrition interventions to combat obesity in obese patients over age 60. METHODS: We searched online electronic databases up to September 2014 for original observational and intervention studies published between 1995 and 2014 on the relationship between endurance training alone or combined with a diet in obese patients over 60 regarding health outcomes. RESULTS: Twenty-six studies examined interventions aimed specifically at promoting endurance training alone or combined with diet for older obese patients over 60. These studies demonstrated a positive effect of this intervention on the primary prevention of cardiovascular disease, and a significant beneficial effect on the lipid profile. Improvement of body composition and insulin sensitivity, and a reduction in blood pressure were also well established. CONCLUSIONS: Overall, this review demonstrates a positive effect of endurance training alone or combined with diet on health outcomes and metabolic benefits in older adults. Clinicians can now use this evidence to formulate actions to encourage the older obese to profit from the health benefits of endurance training and diet. This will not only help reduce the dramatic increase in the number of older obese but also help prevent sarcopenic obesity, which is a complex challenge for healthcare professionals.

A long-term study examining the antibacterial effectiveness of Agion silver zeolite technology on door handles within a college campus.

Laboratory studies have shown that small concentrations of silver are effective at inhibiting the growth micro-organisms through the disruption of important cell structures and processes. The additional ability to incorporate silver into surfaces has increased the usage of silver in the medical field and expanded its use into the consumer market. To understand the impact of increased silver-containing antimicrobial use, it is important to determine whether silver-based consumer goods are effective at reducing bacterial populations. Our study examined the antibacterial effectiveness of Agion silver zeolite technology applied to 25 silver- and control-coated door handles across a college campus. Door handles were sampled for 6 week periods in both the fall and spring semester, and bacteria were cultured and enumerated on tryptic soy agar (TSA), MacConkey agar (MAC) and mannitol salt agar (MSA). A significant difference was observed between the bacterial populations isolated from silver- and control-coated door handles after 3 years. However, bacteria were consistently isolated from silver-coated door handles suggesting that the silver zeolite was only effective against a portion of the bacterial populations, and further studies are necessary to determine the identities of the isolated bacteria and the prevalence of silver resistance.

The role of regulatory T cell (Treg) subsets in gestational diabetes mellitus.

Physiological changes during normal pregnancy are characterized by an inflammatory immune response and insulin resistance. Therefore, we hypothesize that gestational diabetes mellitus (GDM) may be caused by an inappropriate adaption of the maternal immune system to pregnancy. In this study we examined the role of regulatory T cell (Treg) differentiation for the development of GDM during pregnancy. We used six-colour flow cytometric analysis to demonstrate that the total CD4(+) CD127(low+/-) CD25(+) forkhead box protein 3 (FoxP3(+)) T(reg) pool consists of four different T(reg) subsets: naive CD45RA(+) T(regs), HLA-DR(-) CD45RA(-) memory T(regs) (DR(-) T(regs)) and the highly differentiated and activated HLA-DR(low+) CD45RA(-) and HLA-DR(high+) CD45RA(-) memory T(regs) (DR(low+) and DR(high+) T(regs)). Compared to healthy pregnancies, the percentage of CD4(+) CD127(low+/-) CD25(+) FoxP3(+) T(regs) within the total CD4(+) T helper cell pool was not different in patients affected by GDM. However, the suppressive activity of the total CD4(+) CD127(low+/-) CD25(+) T(reg) pool was significantly reduced in GDM patients. The composition of the total T(reg) pool changed in the way that its percentage of naive CD45RA(+) T(regs) was decreased significantly in both patients with dietary-adjusted GDM and patients with insulin-dependent GDM. In contrast, the percentage of DR(-) -memory T(regs) was increased significantly in patients with dietary-adjusted GDM, while the percentage of DR(low+) and DR(high+) memory T(regs) was increased significantly in patients with insulin-dependent GDM. Hence, our findings propose that alterations in homeostatic parameters related to the development and function of naive and memory T(regs) may cause the reduction of the suppressive capacity of the total T(reg) pool in GDM patients. However, as this is an exploratory analysis, the results are only suggestive and require further validation.

Hepatic purinergic signaling gene network expression and its relationship with inflammation and oxidative stress biomarkers in blood from peripartal dairy cattle.

The liver plays a central role in allowing dairy cattle to make a successful transition into lactation. In liver, as in other tissues, extracellular nucleotides and nucleosides trigger cellular responses through adenosine and ATP receptors. Adenosine triphosphate and certain nucleotides serve as signals that can heighten purinergic receptor activation in several pathologic processes. We evaluated the mRNA expression of genes associated with the purinergic signaling network in liver tissue during the peripartal period. Seven multiparous Holstein cows were dried off at d -50 relative to expected parturition and fed a controlled-energy diet (net energy for lactation=1.24 Mcal/kg of DM) for ad libitum intake during the entire dry period. After calving, all cows were fed a common lactation diet (net energy for lactation=1.65 Mcal/kg of DM) until 30 DIM. Biopsies of liver were harvested at d -10, 7, and 21 for mRNA expression of 9 purinergic receptors, 7 ATP and adenosine transport channels, and 10 enzymes associated with ATP hydrolysis. Blood collected at d -21, -10, 7, 14, and 21 was used to measure concentrations of inflammation and oxidative stress biomarkers. The expression of type 1 purinergic receptors (ADORA2A and ADORA3), several nucleoside hydrolases [ectonucleoside triphosphate diphosphohydrolase 7 (ENTPD7), ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), ENPP3, and adenosine deaminase (ADA)], and a type 2 purinergic receptor (P2RX7) was downregulated after calving. In contrast, the expression of type 2 purinergic receptors (P2RX4 and PR2Y11), an ATP release channel (gap junction hemichannel GJB1), and an adenosine uptake protein (SLC29A1) followed the opposite response, increasing after calving and remaining elevated through 21 d. Haptoglobin, ceruloplasmin, and reactive oxygen metabolite concentrations increased gradually from d -21 d through at least d 7. The opposite response was observed for albumin, paraoxonase, α-tocopherol, and nitric oxide, which decreased gradually to a nadir at 7 and 14 d. Our results suggest that alterations after calving of the expression of hepatic purinergic signaling genes could be functionally important because in nonruminants, they play roles in bile formation, glucose metabolism, cholesterol uptake, inflammation, and steatosis. The correlation analysis provided evidence of a link between purinergic signaling genes and biomarkers of inflammation and oxidative stress.

CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs.

CD4(+) helper T cells orchestrate protective immunity against pathogens, yet can also induce undesired pathologies including allergies, transplant rejection and autoimmunity. Non-depleting CD4-specific antibodies such as clone YTS177.9 were found to promote long-lasting T cell tolerance in animal models. Thus, CD4 blockade could represent a promising therapeutic approach for human autoimmune diseases. However, the mechanisms underlying anti-CD4-induced tolerance are incompletely resolved. Particularly, multiple immune cells express CD4 including Foxp3(+) regulatory T cells (Tregs) and dendritic cells (DCs), both controlling the activation of CD4(+)Foxp3(-) helper T cells. Utilizing mixed leukocyte reactions (MLRs) reflecting physiological interactions between T cells and DCs, we report that anti-CD4 treatment inhibits CD4(+)Foxp3(-) T cell proliferation in an IL-2-independent fashion. Notably, YTS177.9 binding induces a rapid internalization of CD4 on both CD4(+)Foxp3(-) T cells and Foxp3(+) Tregs. However, no expansion or activation of immunosuppressive CD4(+)Foxp3(+) Tregs was observed following anti-CD4 treatment. Additionally, cytokine production, maturation and T cell priming capacity of DCs are not affected by anti-CD4 exposure. In line with these data, the selective ablation of Foxp3(+) Tregs from MLRs by the use of diphtheria toxin (DT)-treated bacterial artificial chromosome (BAC)-transgenic DEREG mice completely fails to abrogate the suppressive activity of multiple anti-CD4 antibodies. Instead, tolerization is associated with the defective expression of various co-stimulatory receptors including OX40 and CD30, suggesting altered signaling through the TCR complex. Consistent with our findings in mice, anti-CD4 treatment renders human CD4(+) T cells tolerant in the absence of Tregs. Thus, our results establish that anti-CD4 antibodies can directly tolerize pathogenic CD4(+)Foxp3(-) helper T cells. This has important implications for the treatment of human inflammatory diseases.