Search

ImportanceDevelopment of noninvasive methodology to reproducibly measure tissue cystine crystal load to assess disease status and guide clinical care in cystinosis, an inherited lysosomal storage disorder characterized by widespread cystine crystal accumulation.ObjectiveTo develop an unbiased and semi-automated imaging methodology to quantify dermal cystine crystal accumulation in patients to correlate with disease status.Design, setting and participants101 participants, 70 patients and 31 healthy controls, were enrolled at the University of California, San Diego, Cystinosis Clinics, Rady Children's Hospital, San Diego and at the annual Cystinosis Research Foundation family conference for an ongoing prospective longitudinal cohort study of cystinosis patients with potential yearly follow-up.ExposuresIntradermal reflectance confocal microscopy (RCM) imaging, blood collection via standard venipuncture, medical record collection, and occasional skin punch biopsies.Main outcomes and measuresThe primary outcome was to establish an automated measure of normalized confocal crystal volume (nCCV) for each subject. Secondary analysis examined the association of nCCV with various clinical indicators to assess nCCV's possible predictive potential.ResultsOver 2 years, 57 patients diagnosed with cystinosis (median [range] age: 15.1 yrs [0.8, 54]; 41.4% female) were intradermally assessed by RCM to produce 84 image stacks. 27 healthy individuals (38.7 yrs [10, 85]; 53.1% female) were also imaged providing 37 control image stacks. Automated 2D crystal area quantification revealed that patients had significantly elevated crystal accumulation within the superficial dermis. 3D volumetric analysis of this region was significantly higher in patients compared to healthy controls (mean [SD]: 1934.0 μm3 [1169.1] for patients vs. 363.1 μm3 [194.3] for controls, P

Canine distemper virus remains an important source of morbidity and mortality in animal shelters. RT-PCR is commonly used to aid diagnosis and has been used to monitor dogs testing positive over time to gauge the end of infectious potential. Many dogs excrete viral RNA for prolonged periods which has complicated disease management. The goal of this retrospective study was to describe the duration and characteristics of viral RNA excretion in shelter dogs with naturally occurring CDV and investigate the relationship between that viral RNA excretion and infectious potential using virus isolation data. Records from 98 different humane organizations with suspect CDV were reviewed. A total of 5,920 dogs were tested with 1,393; 4,452; and 75 found to be positive, negative, or suspect on RT-PCR respectively. The median duration of a positive test was 34 days (n = 325), and 25% (82/325) of the dogs still excreting viral RNA after 62 days of monitoring. Virus isolation was performed in six dogs who were RT-PCR positive for > 60 days. Infectious virus was isolated only within the first two weeks of monitoring at or around the peak viral RNA excretion (as detected by the lowest cycle threshold) reported for each dog. Our findings suggest that peak viral RNA excretion and the days surrounding it might be used as a functional marker to gauge the end of infectious risk. Clarifying the earliest point in time when dogs testing positive for canine distemper by RT-PCR can be considered non-contagious will improve welfare and lifesaving potential of shelters by enabling recovered dogs to be cleared more quickly for live release outcomes.

Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.

Strict lockdown measures were introduced in response to the COVID-19 pandemic, which caused mass disruption to adolescent swimmers' daily routines. To measure how lockdown impacted nutritional practices in this cohort, three-day photograph food diaries were analysed at three time points: before (January), during (April), and after (September) the first UK lockdown. Thirteen swimmers (aged 15 ± 1 years) from a high-performance swimming club submitted satisfactory food diaries at all time points. During lockdown, lower amounts of energy (45.3 ± 9.8 vs. 31.1 ± 7.7 kcal∙kg BM∙day-1, p0.05), despite fewer training hours being completed (15.0 ± 1.4 vs. 19.1 ± 2.2 h∙week-1, p

BackgroundEosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGFβ1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGFβ1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE.MethodsGenotype at TGFβ1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype.ResultsThe TGFβ1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGFβ1 (CC subjects = 1300 per mm2; TT = 2250 per mm2) (p

High-risk neuroblastoma is associated with an overall survival rate of 30-50%. Neuroblastoma-expressed cell adhesion receptors of the integrin family impact cell adhesion, migration, proliferation and survival. Integrin α4 is essential for neural crest cell motility during development, is highly expressed on leukocytes, and is critical for transendothelial migration. Thus, cancer cells that express this receptor may exhibit increased metastatic potential. We show that α4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with the alternatively spliced connecting segment 1 of fibronectin, as well as vascular cell adhesion molecule-1 and increases migration. Integrin α4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin α4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin α4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin α4 is more frequently expressed in non-MYNC amplified tumors, and is selectively associated with poor prognosis in this subset of disease. These results reveal an unexpected role for integrin α4 in neuroblastoma dissemination and identify α4 as a potential prognostic indicator and therapeutic target.

High-risk neuroblastoma is associated with an overall survival rate of 30-50%. Neuroblastoma-expressed cell adhesion receptors of the integrin family impact cell adhesion, migration, proliferation and survival. Integrin α4 is essential for neural crest cell motility during development, is highly expressed on leukocytes, and is critical for transendothelial migration. Thus, cancer cells that express this receptor may exhibit increased metastatic potential. We show that α4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with the alternatively spliced connecting segment 1 of fibronectin, as well as vascular cell adhesion molecule-1 and increases migration. Integrin α4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin α4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin α4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin α4 is more frequently expressed in non-MYNC amplified tumors, and is selectively associated with poor prognosis in this subset of disease. These results reveal an unexpected role for integrin α4 in neuroblastoma dissemination and identify α4 as a potential prognostic indicator and therapeutic target.

For animals in confinement housing the housing structure has tremendous potential to impact well being. Dogs in animal shelters are often housed in one of two types of confinement housing - single kennels and rooms or double compartment kennels and rooms most often separated by a guillotine door. This study examines the effect of housing on the location of elimination behavior in dogs housed in double compartment kennels were the majority of the dogs were walked daily. One side of the kennel contained the food, water and bed and the other side was empty and available except during cleaning time. Location of urination and defecation was observed daily for 579 dogs housed in indoor double compartment kennels for a total of 4440 days of observation. There were 1856 days (41.9%) when no elimination was noted in the kennel. Feces, urine or both were observed in the kennel on 2584 days (58.1%). When elimination occurred in the kennel the probability of fecal elimination on the opposite side of the bed/food/water was 72.5% (95% CI 69.05% to 75.69%). The probability of urination on the opposite side of the bed/food/water was 77.4% (95% CI 74.33% to 80.07%). This study demonstrates the strong preference of dogs to eliminate away from the area where they eat, drink and sleep. Double compartment housing not only allows this - it allows staff the ability to provide safe, efficient, humane daily care and confers the added benefits of reducing risks for disease transmission for the individual dog as well as the population.

ImportanceDevelopment of noninvasive methodology to reproducibly measure tissue cystine crystal load to assess disease status and guide clinical care in cystinosis, an inherited lysosomal storage disorder characterized by widespread cystine crystal accumulation.ObjectiveTo develop an unbiased and semi-automated imaging methodology to quantify dermal cystine crystal accumulation in patients to correlate with disease status.Design, setting and participants101 participants, 70 patients and 31 healthy controls, were enrolled at the University of California, San Diego, Cystinosis Clinics, Rady Children's Hospital, San Diego and at the annual Cystinosis Research Foundation family conference for an ongoing prospective longitudinal cohort study of cystinosis patients with potential yearly follow-up.ExposuresIntradermal reflectance confocal microscopy (RCM) imaging, blood collection via standard venipuncture, medical record collection, and occasional skin punch biopsies.Main outcomes and measuresThe primary outcome was to establish an automated measure of normalized confocal crystal volume (nCCV) for each subject. Secondary analysis examined the association of nCCV with various clinical indicators to assess nCCV's possible predictive potential.ResultsOver 2 years, 57 patients diagnosed with cystinosis (median [range] age: 15.1 yrs [0.8, 54]; 41.4% female) were intradermally assessed by RCM to produce 84 image stacks. 27 healthy individuals (38.7 yrs [10, 85]; 53.1% female) were also imaged providing 37 control image stacks. Automated 2D crystal area quantification revealed that patients had significantly elevated crystal accumulation within the superficial dermis. 3D volumetric analysis of this region was significantly higher in patients compared to healthy controls (mean [SD]: 1934.0 μm3 [1169.1] for patients vs. 363.1 μm3 [194.3] for controls, PConclusions and relevanceThis study used non-invasive RCM imaging to develop an intradermal cystine crystal quantification method. Results showed that cystinosis patients had increased nCCV compared to healthy controls. Level of patient nCCV correlated with several clinical outcomes suggesting nCCV may be used as a potential new biomarker for cystinosis to monitor long-term disease control and medication compliance.

The timing of sodium bicarbonate (NaHCO3) supplementation has been suggested to be most optimal when coincided with a personal time that bicarbonate (HCO3-) or pH peaks in the blood following ingestion. However, the ergogenic mechanisms supporting this ingestion strategy are strongly contested. It is therefore plausible that NaHCO3 may be ergogenic by causing beneficial shifts in the strong ion difference (SID), though the time course of this blood acid base balance variable is yet to be investigated. Twelve highly trained, adolescent swimmers (age: 15.9 ± 1.0 years, body mass: 65.3 ± 9.6 kg) consumed their typical pre-competition nutrition 1-3 hours before ingesting 0.3 g∙kg BM-1 NaHCO3 in gelatine capsules. Capillary blood samples were then taken during seated rest on nine occasions (0, 60, 75, 90, 105, 120, 135, 150, 165 min post-ingestion) to identify the time course changes in HCO3-, pH, and the SID. No significant differences were found in the time to peak of each blood measure (HCO3-: 130 ± 35 min, pH: 120 ± 38 min, SID: 98 ± 37 min; p = 0.08); however, a large effect size was calculated between time to peak HCO3- and the SID (g = 0.88). Considering that a difference between time to peak blood HCO3- and the SID was identified in adolescents, future research should compare the ergogenic effects of these two individualized NaHCO3 ingestion strategies compared to a traditional, standardized approach.

Exposure to stressful and potentially traumatic experiences is a risk for military personnel and for some this may increase susceptibility to reduced well-being. The aim of this systematic review was to examine the effectiveness of interventions to promote the well-being of military personnel adjusting to civilian life. Electronic databases were searched including MEDLINE, Embase, HMIC, PsycINFO, Pilots and CINAHL. Twelve articles, all conducted in the USA, were included in the review. Articles were synthesised narratively and assessed for bias against established criteria. The studies evaluated the effectiveness of interventions for current and former military personnel. The interventions included expressive writing, anger management, cognitive training, psycho-education, and techniques to promote relaxation, connection in relationships and resilience. Interventions had some significant positive effects mostly for veterans adjusting to civilian life and other family members. There was much heterogeneity in the design and the outcome measures used in the studies reviewed. The review highlights the need for future robust trials examining the effectiveness of well-being interventions in military groups with diverse characteristics; in addition qualitative research to explore a conceptualisation of well-being for this group and the acceptability of interventions which may be perceived as treatment. The results of the review will be of interest to a number of stakeholders in military, public health and mental health settings. PROSPERO Registration number: CRD42015026341.

We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3' (telomeric) to PAX6 and one within a gene desert 5' (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p.Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.

Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.

BackgroundMost hazardous and harmful drinkers are of working age and do not seek help with their drinking. Occupational health services are uniquely placed to universally screen employees across the range of socioeconomic and ethnic groups. The aim was to explore the feasibility and acceptability of offering electronic screening and brief intervention for alcohol misuse in the context of a health check in six different workplace settings.Methods and findingsEmployees were recruited from six workplaces across England, including three local authorities, one university, one hospital and one petro-chemical company. A total of 1,254 (8%) employees completed the health check and received personalised feedback on their alcohol intake, alongside feedback on smoking, fruit and vegetable consumption and physical activity. Most participants were female (65%) and of 'White British' ethnicity (94%), with a mean age of 43 years (SD 11). Participants were mostly in Intermediate occupations (58%), followed by Higher managerial / professional (39%) and Routine and manual occupations (2%). A quarter of participants (25%) were drinking at hazardous levels (33% male, 21% female), which decreased with age. Sixty-four percent (n=797) of participants completed online follow-up at three months. Most participants were supportive of workplaces offering employees an online health check (95%), their preferred format was online (91%) and many were confident of the confidentiality of their responses (60%). Whilst the feedback reminded most participants of things they already knew (75%), some were reportedly motivated to change their behaviour (13%).ConclusionsOnline health screening and personalised feedback appears feasible and acceptable, but challenges include low participation rates, potentially attracting 'worried well' employees rather than those at greatest health risk, and less acceptance of the approach among older employees and those from ethnic minority backgrounds and routine or manual occupations.

High-risk neuroblastoma is associated with an overall survival rate of 30-50%. Neuroblastoma-expressed cell adhesion receptors of the integrin family impact cell adhesion, migration, proliferation and survival. Integrin α4 is essential for neural crest cell motility during development, is highly expressed on leukocytes, and is critical for transendothelial migration. Thus, cancer cells that express this receptor may exhibit increased metastatic potential. We show that α4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with the alternatively spliced connecting segment 1 of fibronectin, as well as vascular cell adhesion molecule-1 and increases migration. Integrin α4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin α4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin α4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin α4 is more frequently expressed in non-MYNC amplified tumors, and is selectively associated with poor prognosis in this subset of disease. These results reveal an unexpected role for integrin α4 in neuroblastoma dissemination and identify α4 as a potential prognostic indicator and therapeutic target.

A significant proportion of children (up to 7% in the UK) present with pronounced language difficulties that cannot be explained by obvious causes like other neurological and medical conditions. A substantial genetic component is predicted to underlie such language problems. Copy number variants (CNVs) have been implicated in neurodevelopmental and psychiatric conditions, such as autism and schizophrenia, but it is not fully established to what extent they might contribute to language disorders. We conducted a CNV screen in a longitudinal cohort of young children with language-related difficulties (n = 85), focusing on single events at candidate loci. We detected a de novo deletion on chromosome 15q13.1-13.3. The adjacent 15q11-13.1 locus is disrupted in Prader-Willi and Angelman syndromes, while disruptions across the breakpoints (BP1-BP6) have previously been implicated in different neurodevelopmental phenotypes including autism, intellectual disability (ID), seizures and developmental delay (DD). This is the first report of a deletion at BP3-BP5 being linked to a deficit confined to language impairment, in the absence of ID, expanding the range of phenotypes that implicate the chromosome 15q13 locus.

Eosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGFβ1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGFβ1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE.Genotype at TGFβ1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype.The TGFβ1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGFβ1 (CC subjects = 1300 per mm2; TT = 2250 per mm2) (p

BackgroundAlcohol misuse is common in people attending emergency departments (EDs) and there is some evidence of efficacy of alcohol screening and brief interventions (SBI). This study investigated the effectiveness of SBI approaches of different intensities delivered by ED staff in nine typical EDs in England: the SIPS ED trial.Methods and findingsPragmatic multicentre cluster randomized controlled trial of SBI for hazardous and harmful drinkers presenting to ED. Nine EDs were randomized to three conditions: a patient information leaflet (PIL), 5 minutes of brief advice (BA), and referral to an alcohol health worker who provided 20 minutes of brief lifestyle counseling (BLC). The primary outcome measure was the Alcohol Use Disorders Identification Test (AUDIT) status at 6 months. Of 5899 patients aged 18 or more presenting to EDs, 3737 (63·3%) were eligible to participate and 1497 (40·1%) screened positive for hazardous or harmful drinking, of whom 1204 (80·4%) gave consent to participate in the trial. Follow up rates were 72% (n = 863) at six, and 67% (n = 810) at 12 months. There was no evidence of any differences between intervention conditions for AUDIT status or any other outcome measures at months 6 or 12 in an intention to treat analysis. At month 6, compared to the PIL group, the odds ratio of being AUDIT negative for brief advice was 1·103 (95% CI 0·328 to 3·715). The odds ratio comparing BLC to PIL was 1·247 (95% CI 0·315 to 4·939). A per protocol analysis confirmed these findings.ConclusionsSBI is difficult to implement in typical EDs. The results do not support widespread implementation of alcohol SBI in ED beyond screening followed by simple clinical feedback and alcohol information, which is likely to be easier and less expensive to implement than more complex interventions.Trial registrationCurrent Controlled Trials ISRCTN 93681536.

For animals in confinement housing the housing structure has tremendous potential to impact well being. Dogs in animal shelters are often housed in one of two types of confinement housing - single kennels and rooms or double compartment kennels and rooms most often separated by a guillotine door. This study examines the effect of housing on the location of elimination behavior in dogs housed in double compartment kennels were the majority of the dogs were walked daily. One side of the kennel contained the food, water and bed and the other side was empty and available except during cleaning time. Location of urination and defecation was observed daily for 579 dogs housed in indoor double compartment kennels for a total of 4440 days of observation. There were 1856 days (41.9%) when no elimination was noted in the kennel. Feces, urine or both were observed in the kennel on 2584 days (58.1%). When elimination occurred in the kennel the probability of fecal elimination on the opposite side of the bed/food/water was 72.5% (95% CI 69.05% to 75.69%). The probability of urination on the opposite side of the bed/food/water was 77.4% (95% CI 74.33% to 80.07%). This study demonstrates the strong preference of dogs to eliminate away from the area where they eat, drink and sleep. Double compartment housing not only allows this - it allows staff the ability to provide safe, efficient, humane daily care and confers the added benefits of reducing risks for disease transmission for the individual dog as well as the population.

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.

Pediatric Crohn's disease is a chronic auto inflammatory bowel disorder affecting children under the age of 17 years. A putative etiopathogenesis of Crohn's disease (CD) is associated with disregulation of immune response to antigens commonly present in the gut microenvironment. Heat shock proteins (HSP) have been identified as ubiquitous antigens with the ability to modulate inflammatory responses associated with several autoimmune diseases. The present study tested the contribution of immune responses to HSP in the amplification of autoimmune inflammation in chronically inflamed mucosa of pediatric CD patients. Colonic biopsies obtained from normal and CD mucosa were stimulated with pairs of Pan HLA-DR binder HSP60-derived peptides (human/bacterial homologues). The modulation of RNA and protein levels of induced proinflammatory cytokines were measured. We identified two epitopes capable of sustaining proinflammatory responses, specifically TNF< and IFN induction, in the inflamed intestinal mucosa in CD patients. The responses correlated positively with clinical and histological measurements of disease activity, thus suggesting a contribution of immune responses to HSP in pediatric CD site-specific mucosal inflammation.

The timing of sodium bicarbonate (NaHCO3) supplementation has been suggested to be most optimal when coincided with a personal time that bicarbonate (HCO3–) or pH peaks in the blood following ingestion. However, the ergogenic mechanisms supporting this ingestion strategy are strongly contested. It is therefore plausible that NaHCO3 may be ergogenic by causing beneficial shifts in the strong ion difference (SID), though the time course of this blood acid base balance variable is yet to be investigated. Twelve highly trained, adolescent swimmers (age: 15.9 ± 1.0 years, body mass: 65.3 ± 9.6 kg) consumed their typical pre-competition nutrition 1–3 hours before ingesting 0.3 g∙kg BM-1 NaHCO3 in gelatine capsules. Capillary blood samples were then taken during seated rest on nine occasions (0, 60, 75, 90, 105, 120, 135, 150, 165 min post-ingestion) to identify the time course changes in HCO3–, pH, and the SID. No significant differences were found in the time to peak of each blood measure (HCO3–: 130 ± 35 min, pH: 120 ± 38 min, SID: 98 ± 37 min; p = 0.08); however, a large effect size was calculated between time to peak HCO3– and the SID (g = 0.88). Considering that a difference between time to peak blood HCO3– and the SID was identified in adolescents, future research should compare the ergogenic effects of these two individualized NaHCO3 ingestion strategies compared to a traditional, standardized approach. [ABSTRACT FROM AUTHOR]

High-risk neuroblastoma is associated with an overall survival rate of 30–50%. Neuroblastoma-expressed cell adhesion receptors of the integrin family impact cell adhesion, migration, proliferation and survival. Integrin α4 is essential for neural crest cell motility during development, is highly expressed on leukocytes, and is critical for transendothelial migration. Thus, cancer cells that express this receptor may exhibit increased metastatic potential. We show that α4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with the alternatively spliced connecting segment 1 of fibronectin, as well as vascular cell adhesion molecule-1 and increases migration. Integrin α4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin α4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin α4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin α4 is more frequently expressed in non-MYNC amplified tumors, and is selectively associated with poor prognosis in this subset of disease. These results reveal an unexpected role for integrin α4 in neuroblastoma dissemination and identify α4 as a potential prognostic indicator and therapeutic target. [ABSTRACT FROM AUTHOR]