NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Genetic variation in the beta-2 adrenergic receptor is associated with chronic musculoskeletal complaints in adolescents.

BACKGROUND: There is significant evidence to suggest that psychological and stress-related factors are important predictors of the onset of chronic widespread pain (CWP) and fibromyalgia (FM). The hypothalamic-pituitary-adrenal axis, together with the efferent sympathetic/adrenomedullary system, influence all body organs (including muscles) during short- and long-term threatening stimuli. The aim of this study was to investigate the relationship between genetic variants in adrenergic candidate genes and chronic musculoskeletal complaints (MSCs) in adolescents. METHODS: Adolescents from the Western Australian Pregnancy (Raine) Cohort attending the 17-year cohort review completed a questionnaire containing a broad range of psychosocial factors and pain assessment (n = 1004). Blood samples were collected for DNA extraction and genotyping. Genotype data was obtained for 14 single nucleotide polymorphisms (SNPs) in two candidate genes - beta-2 adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT). Haplotypes were reconstructed for all individuals with genotype data. RESULTS AND CONCLUSION: Both female gender and poor mental health were associated with (1) an increased risk for chronic, disabling comorbid neck and low back pain (CDCP); and (2) an increase in the number of areas of pain. Of the 14 SNPs evaluated, only SNP rs2053044 (ADRB2, recessive model) displayed an association with CDCP [odds ratio (OR) = 2.49; 95% confidence interval (CI) = 1.25, 4.98; p = 0.01] and pain in three to four pain areas in the last month (OR = 1.86; 95% CI = 1.13, 3.06; p = 0.02). These data suggest that genetic variants in ADRB2 may be involved in chronic MSCs.

'I am absolutely shattered': the impact of chronic low back pain on Australian Aboriginal people.

BACKGROUND: Aboriginal people in Australia have been uniquely identified as less susceptible to chronic low back pain (CLBP) disability when compared to non-Aboriginal populations, reportedly due to cultural beliefs about pain. A qualitative, culturally secure research approach was used to explore this assumption. METHODS: In-depth interviews were undertaken with 32 Aboriginal men and women with CLBP in regional and remote areas of Western Australia. Interviews were conducted collaboratively with male and female Aboriginal co-investigators, and with the support of local Aboriginal community organizations. A primary focus was to investigate the impact of CLBP from the perspective of Aboriginal people living with the condition. RESULTS: The experience of CLBP was found to be multidimensional, impacting on activities of daily life, employment, sport and family participation, emotional and cultural well-being. CONCLUSIONS: Contrary to previous assumptions, CLBP is profoundly disabling for some Aboriginal people and a priority health concern. Issues of gender, cultural obligations and the emotional consequences of CLBP are important consideration for health care. These findings, and the contextual approach used to gain an in-depth understanding of CLBP, may be relevant to populations elsewhere.

Effectiveness of using a behavioural intervention to improve dietary fibre intakes in children with constipation.

BACKGROUND: Functional constipation is common in childhood; diets in affluent industrialised countries may be a significant contributory factor as a result of inadequate fibre content. Only a few intervention studies have been reported where childhood constipation has been treated by increasing dietary fibre. The present study aimed to demonstrate that dietary fibre intakes of children with constipation can be increased using a specifically-designed behaviour modification technique with a self-monitoring and reward system. METHODS: Forty-three children, aged 2-14years, with functional constipation (defined as less than three bowel movements per week with hard stools and difficulty or delay in defecation) were randomised to one of two treatment groups: Control (n=20), receiving general advice on increasing dietary fibre intake, or Intervention (n=23), using the intervention tool. Fibre intake, laxative use and stool frequency were assessed at baseline, and at 3, 6 and 12months, using parent-filled diaries. RESULTS: A behavioural intervention method significantly increases the fibre intakes of children with constipation at 3 months compared to standard dietary treatment (P=0.005), remaining so after adjusting for baseline fibre intake (P=0.007). Follow-up at 6 and 12months showed no further increase. No significant benefit in terms of a reduction in laxative use or increased stool frequency associated with additional fibre intake was demonstrated. CONCLUSIONS: The findings confirm the difficulties encountered in beginning and maintaining high-fibre diets in children.

Chylopericardium in a child with impaired venous access following small bowel transplantation.

A 10-yr-old child with impaired venous access (bilateral occlusion of internal jugular veins, subclavian veins, and inominate veins) underwent an isolated small bowel transplant. He presented with lethargy, shortness of breath 13 months into his follow-up and was diagnosed to have chylopericardium. MR venography and lymphangiography could not demonstrate the site of lymphatic leak. His chyloperciardium was treated with pericardiocentesis and MCT diet. The most likely cause for the chylopericardium was venous occlusion of the subclavian veins with backpressure resulting in a lymphatic leak. A brief review of literature along with treatment options is discussed.

Neck/shoulder pain is more strongly related to depressed mood in adolescent girls than in boys.

A cross-sectional study of 1258, 14 year old girls and boys used self-report and physical examination measures to assess neck/shoulder pain in the last month, depressed mood, physical fitness, body composition, self-efficacy, global self-worth, family functioning and social advantage. The data was used to compare the relationship between depressed mood and neck/shoulder pain (NSP) in adolescent girls and boys. The prevalence of NSP in girls (34%, 211/621) was significantly greater than in boys (21%, 134/637; p < .001). After controlling for covariates, girls with medium (OR = 4.28; CI = 2.31-7.92; p < .001) and high depressed mood (OR = 8.63; CI = 4.39-16.98; p < .001) were significantly more likely to report NSP than girls with low depressed mood. Depressed mood was also a significant correlate of NSP in boys after controlling for covariates, although the association was substantially weaker (OR = 2.44; CI = 1.29-4.61; p < .001). After controlling for relevant biological, psychological and social covariates, depressed mood was a significant correlate of NSP in both sexes; but the association between depressed mood and NSP was significantly stronger for girls than for boys.

Integration of subclassification strategies in randomised controlled clinical trials evaluating manual therapy treatment and exercise therapy for non-specific chronic low back pain: a systematic review.

BACKGROUND: There is lack of evidence for specific treatment interventions for patients with non-specific chronic low back pain (NSCLBP) despite the substantial amount of randomised controlled clinical trials evaluating treatment outcome for this disorder. HYPOTHESIS: It has been hypothesised that this vacuum of evidence is caused by the lack of subclassification of the heterogeneous population of patients with chronic low back pain for outcome research. STUDY DESIGN: A systematic review. METHODS: A systematic review with a meta-analysis was undertaken to determine the integration of subclassification strategies with matched interventions in randomised controlled clinical trials evaluating manual therapy treatment and exercise therapy for NSCLBP. A structured search for relevant studies in Embase, Cinahl, Medline, PEDro and the Cochrane Trials Register database, followed by hand searching all relevant studies in English up to December 2008. RESULTS: Only 5 of 68 studies (7.4%) subclassified patients beyond applying general inclusion and exclusion criteria. In the few studies where classification and matched interventions have been used, our meta-analysis showed a statistical difference in favour of the classification-based intervention for reductions in pain (p=0.004) and disability (p=0.0005), both for short-term and long-term reduction in pain (p=0.001). Effect sizes ranged from moderate (0.43) for short term to minimal (0.14) for long term. CONCLUSION: A better integration of subclassification strategies in NSCLBP outcome research is needed. We propose the development of explicit recommendations for the use of subclassification strategies and evaluation of targeted interventions in future research evaluating NSCLBP.

Inter-examiner reliability of a classification system for patients with non-specific low back pain.

There is a lack of studies examining whether mechanism-based classification systems (CS) acknowledging biological, psychological and social dimensions of long-lasting low back pain (LBP) disorders can be performed in a reliable manner. The purpose of this paper was to examine the inter-tester reliability of clinicians' ability to independently classify patients with non-specific LBP (NSLBP), utilising a mechanism-based classification method. Twenty-six patients with NSLBP underwent an interview and full physical examination by four different physiotherapists. Percentage agreement and Kappa coefficients were calculated for six different levels of decision making. For levels 1-4, percentage agreement had a mean of 96% (range 75-100%). For the primary direction of provocation Kappa and percentage agreement had a mean between the four testers of 0.82 (range 0.66-0.90) and 86% (range 73-92%) respectively. At the final decision making level, the scores for detecting psychosocial influence gave a mean Kappa coefficient of 0.65 (range 0.57-0.74) and 87% (range 85-92%). The findings suggest that the inter-tester reliability of the system is moderate to substantial for a range of patients within the NSLBP population in line with previous research.

Fundoplication versus post-operative medication for gastro-oesophageal reflux in children with neurological impairment undergoing gastrostomy.

BACKGROUND: Children with neurological impairments (NI) frequently experience feeding difficulties which can lead to malnutrition and growth failure. Gastrostomy feeding is now the preferred method of providing nutritional support to children with NI who are unable to feed adequately by mouth. Complications may arise as a result of gastrostomy placement and the development or worsening of gastro-oesophageal reflux (GOR) has been widely reported. This has led to the frequent use of surgical anti-reflux treatment in the form of a fundoplication, or other Anti-Reflux Procedures. Fundoplication is associated with a high recurrence rate, surgical failure and significant morbidity and mortality. Since Proton Pump Inhibitors (PPIs) were introduced in the 1990s they have come to play a larger part in the medical management of GOR in children with NI. Uncontrolled studies suggest that PPIs may be a safe, appropriate treatment for GOR. Other agents currently used include milk thickeners, acid suppression drugs, acid buffering agents, gut motility stimulants and sodium alginate preparations. There are risks and benefits associated with both surgical and medical interventions and further comparison is necessary to determine the optimal treatment choice. OBJECTIVES: To compare the effectiveness of anti-reflux surgery and anti-reflux medications for children with NI and GOR who are undergoing placement of a gastrostomy feeding tube. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) up to Issue 2, 2006, MEDLINE (1966 to June 2006), EMBASE (1980 to week 33, 2006), CINAHL (1982 -to May, week 4, 2006), LILACS (1982 to June 2006), ISI Web of Science (1970 to June 2006) and the Child Health Library (searched June 2006). We also performed online searches of trial registries, medical journals, conference proceedings, dissertations and theses. Specialists in the medical and industry setting were contacted for knowledge of completed or ongoing trials. SELECTION CRITERIA: We sought to include only randomised controlled trials that recruited children up to the age of 18 years with NI and GOR who were undergoing gastrostomy tube insertion. DATA COLLECTION AND ANALYSIS: Two reviewers worked independently on selected trials and performed data extraction and assessment of trial quality. MAIN RESULTS: No trials were identified that satisfied the criteria for this review. AUTHORS' CONCLUSIONS: There remains considerable uncertainty regarding the optimal treatment when faced with the decision of fundoplication surgery versus anti-reflux medications for gastro-oesophageal-reflux in the child with neurological impairment who is undergoing gastrostomy insertion. There is a need for robust scientific evidence in order to provide data on the comparable risks or benefits of the two interventions.

Parent satisfaction in a nurse led clinic compared with a paediatric gastroenterology clinic for the management of intractable, functional constipation.

AIMS: To assess parent satisfaction with a nurse led clinic for children with intractable, functional constipation compared with a paediatric gastroenterology outpatient clinic. METHODS: A validated questionnaire covering six separate domains in 48 statements (provision of information, empathy with the patient, technical quality and competence, attitude towards the patient, access to and continuity with the caregiver, and overall satisfaction) was employed. For all outcomes, the data were analysed on an intention-to-treat basis. RESULTS: 90/107 (84%) questionnaires were returned: 40/51 (78%) from the paediatric gastroenterology clinic and 50/56 (89%) from the nurse led clinic. Results indicated a high "total" satisfaction with the clinical care, but these were statistically significantly higher in the nurse led clinic compared with the paediatric gastroenterology clinic (median score 8.7 and 7.3 respectively, out of a maximum score of 10). This difference was consistent across all domains when the scores from those attending the nurse led clinic were compared with those attending the paediatric gastroenterology clinic (information median score 8.7 v 7.5; empathy 9.0 v 7.3; competence 9.1 v 8.0; attitude 8.7 v 7.3; access 8.2 v 6.7). All comparisons were highly statistically significant. CONCLUSION: These results provide firm evidence that parents of children with intractable constipation are satisfied with the care they receive in both the paediatric and nursing clinic setting. Parent satisfaction, however, was significantly higher in those attending the nurse led clinic. This study adds further support to the development of a nurse led service to manage intractable, functional constipation in children.

Does gastrostomy tube feeding in children with cerebral palsy increase the risk of respiratory morbidity?

BACKGROUND: Children with severe neurological impairment may have significant oral motor dysfunction and are at increased risk of nutritional deficiencies, poor growth, and aspiration pneumonia. Gastrostomy tube feeding is increasingly being used for nutritional support in these children. AIM: To examine the occurrence of respiratory morbidity before and after gastrostomy feeding tube insertion in children with severe neurological disabilities. METHODS: This study was nested in a longitudinal, prospective, uncontrolled, multicentre cohort study designed to investigate the outcomes of gastrostomy tube feeding in 57 children with severe neurological disabilities. Parents completed a questionnaire prior to (visit 1) and 6 and 12 months (visits 2 and 3) following the gastrostomy, detailing number of chest infections requiring antibiotics and/or hospital admission. RESULTS: Mean number of chest infections requiring antibiotics was 1.8 on visit 1 and 0.9 on visit 3. Hospital admissions for chest infections fell significantly from 0.5 to 0.09. CONCLUSION: This study provides no evidence for an increase in respiratory morbidity following insertion of a feeding gastrostomy in children with cerebral palsy.

The inter-examiner reliability of a classification method for non-specific chronic low back pain patients with motor control impairment.

The importance of classifying chronic low back pain (LBP) patients into homogeneous sub-groups has recently been emphasized. This paper reports on two studies examining clinicians ability to agree independently on patients' chronic LBP classification, using a novel classification system (CS) proposed by O'Sullivan. In the first study, a sub-group of 35 patients with non-specific chronic LBP were independently classified by two 'expert' clinicians. Almost perfect agreement (kappa-coefficient 0.96; %-of-agreement 97%) was demonstrated. In the second study, 13 clinicians from Australia and Norway were given 25 cases (patients' subjective information and videotaped functional tests) to classify. Kappa-coefficients (mean 0.61, range 0.47-0.80) and %-of-agreement (mean 70%, range 60-84%) indicated substantial reliability. Increased familiarity with the CS improved reliability. These studies demonstrate the reliability of this multi-dimensional mechanism-based CS and provide essential evidence in a multi-step validation process. A fully validated CS will have significant research and clinical application.

Nurse management of intractable functional constipation: a randomised controlled trial.

AIMS: To evaluate the effectiveness of a nurse led clinic (NLC) compared with a consultant led paediatric gastroenterology clinic (PGC) in the management of chronic constipation. METHODS: Children (age 1-15 years) with functional constipation were randomised following a detailed medical assessment to follow up in either the NLC or PGC. An escalating algorithm of treatment was used as the basis of management in both the NLC and PGC. Main outcome measures were: time to cure at last visit or later confirmed by telephone; time to cure at last visit; and time to prematurely leaving the study. RESULTS: A total of 102 children were recruited, of whom 52 were randomly assigned to NLC and 50 to PGC. Outcome assessment showed that 34 children in the NLC and 25 children in the PGC were confirmed cured at their last visit or later confirmed by telephone. The median time to cure was 18.0 months in the NLC and 23.2 months in the PGC. The probability of being cured was estimated as 33% higher in the NLC compared to PGC (hazard ratio 1.33). Attending the NLC hastened time to cure by an estimated 18.4%. CONCLUSION: Children who attend an NLC are equally as, if not more likely to be cured of intractable constipation, than those attending a PGC and on average their cure will occur sooner. Results suggest that an NLC can significantly improve follow up for children with intractable constipation and highlight the important role for clinic nurse specialists in management of children with gastrointestinal disease.