MDT practice determines treatment pathway for patients with advanced ovarian cancer: A multi-centre observational study.

OBJECTIVE: To investigate decision making for patients with advanced ovarian cancer as a possible explanation of geographical variation in treatment patterns. METHODS: We carried out a multi-centre observational study in multidisciplinary teams meetings for five major UK cancer centres. All patients presenting to five cancer centres with advanced ovarian cancer over a six-week period. The GO-MDT-MODe tool was used to provide a measure of participation and quality of case discussion for all cases of advanced ovarian cancer. MDT scores were correlated with surgical data extracted from national audit data. Data were recorded for overall MDT performance. RESULTS: A total of 870 case discussions, including 145 cases of advanced ovarian cancer, were observed. MDTs varied in structure, format and time allocation between centres. Cluster analysis showed significant variation in quality and participation of discussion between centres (p < 0.0025) and this correlated with the proportion of patients in the wider cancer alliance undergoing surgery. CONCLUSIONS: We have shown that at least part of the variation in practice seen in the UK correlates with different behaviours within MDTs. Increasing time for discussion and encouraging participation from all staff groups may increase proportions of patients undergoing optimal treatment regimens.

Synthesis of a Vocal Sound from the 3,000 year old Mummy, Nesyamun 'True of Voice'.

The sound of a 3,000 year old mummified individual has been accurately reproduced as a vowel-like sound based on measurements of the precise dimensions of his extant vocal tract following Computed Tomography (CT) scanning, enabling the creation of a 3-D printed vocal tract. By using the Vocal Tract Organ, which provides a user-controllable artificial larynx sound source, a vowel sound is synthesised which compares favourably with vowels of modern individuals.

The effect of non-steroidal anti-inflammatory drugs on severity of acute pancreatitis and pancreatic necrosis.

Introduction Acute pancreatitis (AP) is a common emergency presentation and can be disabling. There is significant morbidity and mortality associated with AP, and it places a considerable burden on the healthcare system. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to have a protective effect in some elective contexts. This retrospective study aimed to evaluate the effect of NSAIDs on the course of AP and the severity of the disease. Methods A retrospective analysis was carried out of 324 patients admitted as an emergency with a diagnosis of AP to two UK hospitals. Patients were divided into two groups: those already taking NSAIDs for other co-morbidities and those not taking NSAIDs. Variables compared included: admission to a high dependency or intensive care unit; pancreatic necrosis; pseudocyst development; need for surgery; serum inflammatory markers; modified early warning scores on days 1, 3 and 5; length of stay; and mortality. Results Patients not taking NSAIDs were more likely to have a C-reactive protein level of ≥150mg/l (p=0.007). Patients in the NSAID group experienced less pancreatic necrosis (p=0.019) and lower rates of pseudocyst formation (p=0.010). Other variables showed no difference between the two groups, specifically length of stay and mortality. Conclusions Routine NSAID use may exert a protective effect on the development of AP, its severity, and complications. Therapeutic use of NSAIDs in acute presentations with pancreatitis should be further evaluated.

Fasting gut hormone levels change with modest weight loss in obese adolescents.

BACKGROUND: Gut hormones change with weight loss in adults but are not well studied in obese youth. OBJECTIVE: The primary aim was to evaluate how gut hormones and subjective appetite measure change with dietary weight loss in obese adolescents. METHODS: Participants were a subset of those taking part in the 'Eat Smart Study'. They were aged 10-17 years with body mass index (BMI) > 90th centile and were randomized to one of three groups: wait-listed control, structured reduced carbohydrate or structured low-fat dietary intervention for 12 weeks. Outcomes were fasting glucose, insulin, leptin, adiponectin, total amylin, acylated ghrelin, active glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP) and total peptide tyrosine-tyrosine. Pre- and postprandial subjective sensations of appetite were assessed using visual analogue scales. RESULTS: Of 87 'Eat Smart' participants, 74 participated in this sub-study. The mean (standard deviation) BMI z-score was 2.1 (0.4) in the intervention groups at week 12 compared with 2.2 (0.4) in the control group. Fasting insulin (P = 0.05) and leptin (P = 0.03) levels decreased, while adiponectin levels increased (P = 0.05) in the intervention groups compared with control. The intervention groups were not significantly different from each other. A decrease in BMI z-score at week 12 was associated with decreased fasting insulin (P < 0.001), homeostatic model of assessment-insulin resistance (P < 0.001), leptin (P < 0.001), total amylin (P = 0.03), GIP (P = 0.01), PP (P = 0.02) and increased adiponectin (P < 0.001). There was no significant difference in appetite sensations. CONCLUSIONS: Modest weight loss in obese adolescents leads to changes in some adipokines and gut hormones that may favour weight regain.

Impact of an integrated model of care on potentially preventable hospitalizations for people with Type 2 diabetes mellitus.

AIMS: To evaluate the impact of an integrated model of care for patients with complex Type 2 diabetes mellitus on potentially preventable hospitalizations. METHODS: A prospective controlled trial was conducted comparing a multidisciplinary, community-based, integrated primary-secondary care diabetes service with usual care at a hospital diabetes outpatient clinic. Study and hospital admissions data were linked for the period from 12 months before to 24 months after commencement of the trial. The primary outcome was the number of potentially preventable hospitalizations with diabetes-related principal diagnoses. Length of stay once hospitalized was also reported. RESULTS: Of 327 adult participants, 206 were hospitalized and accounted for 667 admissions during the study period. Compared with the usual care group, patients in the integrated model of care group were nearly half as likely to be hospitalized for a potentially preventable diabetes-related principal diagnosis in the 24 months after study commencement (incidence rate ratio 0.53, 95% CI 0.29, 0.96; P = 0.04). The magnitude of the result remained similar after adjusting for age, sex, education and baseline HbA1c concentration (incidence rate ratio 0.54, 95% CI 0.29, 1.01; P = 0.05).When hospitalized, patients in the integrated care group had a similar length of stay compared with those in the usual care group (median difference -2 days, 95% CI -6.5, 2.3; P = 0.33). CONCLUSIONS: Patients receiving the integrated model of care had a reduction in the number of hospitalizations when the principal diagnosis for admission was a diabetes-related complication. Integrated models of care for people with complex diabetes can reduce hospitalizations and help attempts to curtail increasing demand on finite health services.

Targeted case finding for hepatitis B using dry blood spot testing in the British-Chinese and South Asian populations of the North-East of England.

Chronic infection with the hepatitis B virus (HBV) is a frequent cause of cirrhosis and liver cancer. Targeted HBV screening is recommended by the Centre for Disease Control (CDC) and Prevention for subjects born in countries with >2% HBV prevalence. However, there are no UK guidelines. Here, we applied the (CDC) recommendations to the British-Chinese and British-South Asian community of North-East (NE) England. British-Chinese and South Asian subjects were invited to attend for HBV education and screening sessions held in community centres. Hepatitis B surface antigen (HBsAg) and hepatitis B core total antibody (HBcAb) were tested with dry blood spot tests. South Asians were also tested for hepatitis C antibody (HCVAb). A total of 1126 subjects (606 Chinese and 520 South Asian) were screened. Sixty-two (5.5%) were HBsAg positive. Ten of these reported a previous diagnosis of HBV. The prevalence of HBsAg positivity was 4.6% when previously diagnosed individuals were excluded. The HBsAg prevalence was significantly higher in the Chinese subjects compared with South Asians (8.7% VS. 1.7% P < 0.001). In Chinese subjects, HBsAg positivity was highest in subjects born in Vietnam (17.4%), followed by China (11%), Hong Kong (7.8%) and the UK (6.7%). Subjects from Pakistan had the highest HBsAg and HCV Ab prevalence in the South Asians (3.1% and 1.8%, respectively). Ten percentage of HBsAg positive patients who had follow-up assessment had active disease requiring antiviral treatment. Undiagnosed HBV infection was above the 2% threshold for screening suggested by the CDC in the British-Chinese and Pakistani community of NE England, which provides evidence for a UK HBV-targeted screening programme.

Model of care for the management of complex Type 2 diabetes managed in the community by primary care physicians with specialist support: an open controlled trial.

AIMS: To evaluate patient outcomes for a novel integrated primary/specialist model of community care for complex Type 2 diabetes mellitus management compared with outcomes for usual care at a tertiary hospital for diabetes outpatients. METHODS: This was a prospective open controlled trial performed in a primary and tertiary care setting in Australia. A total of 330 patients with Type 2 diabetes aged >18 years were allocated to an intervention (n=185) or usual care group (n=145). The intervention arm was a community-based model of care led by a general practitioner with advanced skills and an endocrinologist partnership. Usual care was provided via the hospital diabetes outpatient department. The primary end point was HbA(1c) concentration at 12 months. Secondary end points included serum lipids and blood pressure. RESULTS: The mean change in HbA1c concentration in the intervention group was -9 mmol/mol (-0.8%) at 12 months and in the usual care group it was -2 mmol/mol (-0.2%) (95% CI -5,1). The percentage of patients in the intervention group achieving the HbA(1c) target of ≤53 mmol/mol (7%) increased from 21 to 42% (P<0.001); for the usual care group there was a 1% increase to 39% of patients attaining this target (P=0.99). Patients in the intervention group experienced significant improvements in blood pressure and total cholesterol compared with those in the usual care group. The percentage of patients achieving clinical targets was greater in the intervention group for the combined target of HbA(1c) concentration, blood pressure and LDL cholesterol. CONCLUSIONS: A community-based, integrated model of complex diabetes care, delivered by general practitioners with advanced skills, produced clinical and process benefits compared with a tertiary diabetes outpatient clinic.

Treadmill interventions with partial body weight support in children under six years of age at risk of neuromotor delay: a report of a Cochrane systematic review and meta-analysis.

UNLABELLED: Delayed motor development may occur in children with Down syndrome, cerebral palsy or children born preterm, which in turn may limit the child's opportunities to explore the environment. Neurophysiologic and early intervention literature suggests that task-specific training facilitates motor development. Treadmill intervention is a good example of locomotor task-specific training. AIM: The aim of this paper was to assess the effectiveness of treadmill intervention on locomotor motor development in pre-ambulatory infants and children under six years of age who are at risk for neuromotor delay. DESIGN: A Cochrane systematic review with meta-analysis. METHODS: We employed a comprehensive search strategy. We included randomised, quasi-randomised and controlled clinical trials that evaluated the effect of treadmill intervention in children up to six years of age with delays in gait development or the attainment of independent walking or who were at risk of neuromotor delay. We searched CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, Science Citation Index, PEDro, CPCI-S and LILACS; and also ICTRP, ClinicalTrials.gov, mRCT and CenterWatch. Four authors independently extracted the data using standardized forms. RESULTS: We included five studies, which reported on treadmill intervention in 139 children. Of the 139 children, 73 were allocated to treadmill intervention groups. The studies varied in the type of population studied, the type of comparison, the time of evaluation and the parameters assessed. Due to the diversity of the studies, we were only able to use data from three studies in meta-analyses and these were limited to two outcomes: age of onset of independent walking and gross motor function. Evidence suggested that treadmill intervention could lead to earlier onset of independent walking when compared to no treadmill intervention (effect estimate -1.47; 95% CI: -2.97, 0.03), though these trials studied two different populations: Down syndrome and children at risk of neuromotor disabilities. Children with Down syndrome seemed to benefit while it was not clear if this was the case for children at high risk of neuromotor disabilities. Two other studies, both in children with Down syndrome, compared different types of treadmill intervention (high versus low intensity training). Both were inconclusive regarding the impact of these different protocols on the age at which children started to walk. There is insufficient evidence to determine whether treadmill intervention improves gross motor function (effect estimate 0.88; 95% CI: -4.54, 6.30). CONCLUSION: The current review provided only limited evidence of the efficacy of treadmill intervention in children up to six years of age. Few studies have assessed treadmill interventions in young children using an appropriate control group. The available evidence indicates that treadmill intervention may accelerate the development of independent walking in children with Down syndrome. Further research is needed to confirm this and should also address whether intensive treadmill intervention can accelerate walking onset in young children with cerebral palsy and high risk infants, and whether treadmill intervention has a general effect on gross motor development in the various subgroups of young children at risk for developmental delay.

Renal disease in cats infected with feline immunodeficiency virus.

BACKGROUND: Feline immunodeficiency virus (FIV) and human immunodeficiency virus (HIV) infection cause similar clinical syndromes of immune dysregulation, opportunistic infections, inflammatory diseases, and neoplasia. Renal disease is the 4th most common cause of death associated with HIV infection. OBJECTIVE: To investigate the association between FIV infection and renal disease in cats. ANIMALS: Client-owned cats (153 FIV-infected, 306 FIV-noninfected) and specific-pathogen-free (SPF) research colony cats (95 FIV-infected, 98 FIV-noninfected). METHODS: A mixed retrospective/prospective cross-sectional study. Blood urea nitrogen (BUN), serum creatinine, urine specific gravity (USG), and urine protein:creatinine ratio (UPC) data were compared between FIV-infected and FIV-noninfected cats. In FIV-infected cats, total CD4+ and CD8+ T lymphocytes were measured using flow cytometry, and CD4+:CD8+ T lymphocyte ratio was calculated. Renal azotemia was defined as a serum creatinine ≥ 1.9 mg/dL with USG ≤ 1.035. Proteinuria was defined as a UPC > 0.4 with an inactive urine sediment. RESULTS: Among the client-owned cats, no association was detected between FIV infection and renal azotemia (P = .24); however, a greater proportion of FIV-infected cats were proteinuric (25.0%, 16 of 64 cats) compared to FIV-noninfected cats (10.3%, 20 of 195 cats) (P < .01). Neither neuter status nor health status were risk factors for proteinuria in FIV-infected cats, but UPC was positively correlated with the CD4+:CD8+ T lymphocyte ratio (Spearman's rho = 0.37, P = .01). Among the SPF research colony cats, no association was detected between FIV infection and renal azotemia (P = .21) or proteinuria (P = .25). CONCLUSIONS AND CLINICAL IMPORTANCE: Proteinuria but not azotemia was associated with natural FIV infection.

Germicidal activity of antimicrobials and VIOlight Personal Travel Toothbrush sanitizer: an in vitro study.

OBJECTIVES: The study evaluated the antibacterial effect of VIOlight (VL) Personal Travel Toothbrush Sanitizer on biofilms after toothbrush exposure to human saliva compared to Listerine Antiseptic (LA), 3% hydrogen peroxide (3%HP) and water. METHODS: Twenty toothbrush heads (n=5/Gp) were immersed in saliva and to allow for bacterial growth and biofilm formation for 24h. VL sanitizer and antiseptic(s) were used for 7 min; after treatment, brush heads were rinsed and placed into 10 mL of 2x AOAC Letheen Broth, sonicated and vortexed for 10s. Tenfold serial dilutions were prepared and plated and incubated aerobically and anaerobically. Log(10)CFU/mL data were compared utilizing ANOVA (p<0.05). RESULTS: Results showed 3%HP with significantly lower counts than LA, VL and control for aerobic and anaerobic bacteria. LA had significantly lower counts than VL and control for both types of bacteria and VIOlight had significantly lower counts than the control for aerobic bacteria. 3%HP and LA were most effective in rapidly killing bacteria when compared to VIOlight. CONCLUSIONS: Results showed that 3% hydrogen peroxide was most effective in reducing the numbers of both aerobic and anaerobic bacteria present on the toothbrush heads. Under the same test conditions, Listerine Antiseptic was shown to be secondarily effective for the same bacteria while the VIOlight unit was the least effective when compared to the other treatment groups.

Pharmacogenetics of low dose clonidine in irritable bowel syndrome.

Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (gastrointestinal, GI) sensorimotor functions. We aimed to determine whether candidate ADR-SER genes affect GI responses to low dose clonidine (CLO) in humans. Forty healthy and 120 irritable bowel syndrome (IBS) participants received CLO, 0.1 mg or 0.15 mg b.i.d., for 6 days. At baseline and post-CLO, we measured: gastric volume (GV); satiation volume; rectal compliance, sensation thresholds and ratings with distensions. Genetic variations tested were: alpha2A (C-1291G), alpha2C (Del 322-325), GNbeta3 (C825T) and solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4) (serotonin transporter linked polymorphic region). CLO reduced volume to satiation (P = 0.002), postprandial GV (P < 0.001), sensation threshold for pain (<0.001); CLO increased rectal compliance (P = 0.024). There were significant associations between post-CLO responses and gene variations for DeltaGV (alpha2A and SLC6A4), rectal sensation of gas (alpha2A, GNbeta3), urgency (alpha2A); and pain (GNbeta3 and SLC6A4); and rectal compliance (SLC6A4). alpha2A, GNbeta3 and SLC6A4 genotypes significantly modify responses to CLO on sensory and motor GI functions in health and IBS.

Abdominal wall dimensions and umbilical position vary widely with BMI and should be taken into account when choosing port locations.

BACKGROUND: Many surgeons rely on the umbilicus when determining the location of ports for laparoscopic procedures and falsely assume that it is located in the vertical midline. The purpose of this study was to assess the degree of variation in umbilical position and abdominal dimensions in the general population. METHODS: Torso length, abdominal girth, weight, and height were recorded for 259 patients over a 9-month period. Body mass index (BMI) was calculated and used to classify patients into four groups: underweight, normal, overweight, and obese. RESULTS: Average umbilical position for all BMI groups was below the true vertical midpoint and dropped further caudally as BMI increased. In addition, average abdominal dimensions increased with increasing BMI. There was no statistical difference between males and females in each BMI group regarding umbilical position or abdominal dimensions. CONCLUSION: There is a clear relationship between increasing BMI and a drop in umbilical position as well as an increase in abdominal dimensions. We recommend determining umbilical position and abdominal dimensions prior to placing ports and shifting port positions toward target quadrants.

Relationship of cytochrome P450 pharmacogenetics to the effects of yohimbine on gastrointestinal transit and catecholamines in healthy subjects.

Alpha-2 adrenergic receptors tonically inhibit colonic motility and the alpha(2)-adrenergic antagonist yohimbine, given intravenously, increased colonic tone in humans. However, the effect of yohimbine on colonic transit in humans is unknown. In this study, 30 healthy volunteers were randomized to yohimbine 16.2 mg p.o. t.i.d. or identical placebo for 7 days. We evaluated gastric emptying, small intestinal, and colonic transit by scinitigraphy, bowel habits, haemodynamics and plasma catecholamines. As cytochrome P450 enzymes metabolize yohimbine, P450 genotypes (CYP2D6 and CYP3A4) were determined in 25 of 30 subjects who consented to genetic studies. The relationship between drug metabolizer status predicted by CYP2D6 and CYP3A4 and effects of yohmibine were assessed. Compared to placebo, yohimbine increased (P < or = 0.02) diastolic blood pressure, plasma noradrenaline concentrations and maximum tolerated volume during the satiation test [yohimbine (1241 +/- 88, mean +/- SEM) vs placebo (1015 +/- 87), P = 0.054]. However, yohimbine did not affect gastrointestinal transit. Based on CYP2D6 and CYP3A4 alleles, seven and 18 subjects were, respectively, extensive (EM) and poor (PM) metabolizers of yohimbine. Compared to EM, PM of yohimbine had a greater increase in plasma noradrenaline (P = 0.1 for PM vs EM), lower maximum tolerated volumes (1120 +/- 95 vs 1484 + 131 mL, P = 0.02), and faster colonic transit (i.e. GC(24) was 3.0 +/- 0.4 vs 2.1 +/- 0.5, P = 0.1). These data suggest that CYP2D6 and CYP3A4 genotypes which determine the metabolism of yohimbine may influence its sympathetic and gastrointestinal effects.

Partnership for rehabilitation: looking beyond impairments.

Rehabilitation of leprosy-affected persons extends beyond the physical domain of prevention and treatment of impairments. A holistic rehabilitative approach should include addressing those problems that people may have in activities and difficulties that may prevent people from fully participating in social functions, i.e. being fully accepted as integrated members of the societies and communities to which they belong. This article highlights the activities of the Partnership for the Rehabilitation Program (PFR) of the International Nepal Fellowship (INF), Pokhara, Nepal. These activities aim to prevent, reduce or alleviate problems and difficulties that leprosy-affected persons may face in being respected and being contributing members of the communities of which they are a part.

An exploratory study of the association of adrenergic and serotonergic genotype and gastrointestinal motor functions.

Adrenergic and serotonergic mechanisms alter human gut motor functions. Genotype variation influences phenotype. Our aim was to test the hypothesis that variation in genes that control these functions is associated with gastrointestinal (GI) motor functions in humans with functional GI disorders (FGID). A database of 251 people was assembled by combining genotype data with measurements of gut transit and gastric volumes. Genetic variations evaluated were: alpha(2A) adrenergic (C-1291G), alpha(2C) (Del 332-325), 5-HT transporter (SLC6A4) and GNbeta3 (C825T). We sought associations between motor function or disease groups and genotypes, adjusting for age, gender and body mass index. Among 251 participants, 82 were healthy, 20 with irritable bowel syndrome (IBS) with mixed bowel habit, 49 with constipation-predominant IBS, 67 with diarrhoea-predominant IBS and 33 with functional dyspepsia. For all candidate genes, there was no significant association between motor function and wildtype vs non-wildtype gene status. There were significant interactions between genotype and motility phenotype, specifically GNbeta3 and alpha(2A) and gastric emptying at 4 h. Borderline associations were noted for SCL6A4 and alpha(2A) and postprandial gastric volume, and for alpha(2C) and gastric emptying at 2 h. We conclude that genotype variation may affect gastric motor functions in different FGID phenotypes. However, these candidate genes account for only a limited amount of the variance in gastric function of patients with FGID.

Effects of glucagon-like peptide-1 and sympathetic stimulation on gastric accommodation in humans.

In humans, glucagon-like peptide-1 (GLP-1) delays gastric emptying by inhibiting vagal activity and also increases gastric volumes, by unclear mechanisms. Because GLP-1 inhibits intestinal motility by stimulating the sympathetic nervous system in rats, we assessed the effects of a GLP-1 agonist and yohimbine, an alpha(2)-adrenergic antagonist, on gastric volumes in humans. In this double-blind study, 32 healthy volunteers were randomized to placebo, a GLP-1 agonist, yohimbine or GLP-1 and yohimbine. Gastric volumes (fasting predrug and postdrug, and postprandial postdrug) were measured by (99m)Tc single photon emission computed tomography imaging. Plasma catecholamines and haemodynamic parameters were assessed. Compared with placebo, GLP-1 increased (P = 0.03) but yohimbine did not affect fasting gastric volume. However, GLP-1 plus yohimbine increased (P < 0.001) postprandial gastric accommodation vs placebo and vs GLP-1 alone [postprandial volume change = 542 +/- 29 mL (mean +/- SEM, placebo), 605 +/- 31 mL (GLP-1), 652 +/- 54 mL (yohimbine) and 810 +/- 37 mL (GLP-1 and yohimbine)]. Plasma noradrenaline and dihydroxyphenylglycol concentrations were higher for yohimbine vs placebo and for GLP-1 and yohimbine vs GLP-1. Yohimbine stimulates central sympathetic activity and in combination with GLP-1, augments postprandial accommodation in humans.

Does co-administration of a non-selective opiate antagonist enhance acceleration of transit by a 5-HT4 agonist in constipation-predominant irritable bowel syndrome? A randomized controlled trial.

Opioid neurons exhibit tonic restraint on intestinal motility; opioid antagonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) agonists combined with selective opioid antagonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.

Is minocycline therapy in acne associated with antineutrophil cytoplasmic antibody positivity? A cross-sectional study.

BACKGROUND: Minocycline (MN), one of the commonly prescribed therapies for acne, is known to be associated with autoimmune disorders including drug-induced lupus. However, data are sparse regarding the prevalence of autoimmune disease in acne or in patients with acne treated with MN. OBJECTIVES: To establish the prevalence of antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA) and new autoimmune syndromes in an MN-exposed and unexposed population with acne. METHODS: In a cross-sectional study, 252 patients with acne vulgaris were assessed. Sixty-nine per cent had been exposed to MN at some point or were taking the drug at the time of the interview. Data recorded included duration of disease (acne) and drug history as well as possible side-effects of drugs, in particular joint symptoms (pain and swelling). In addition, blood was taken for ANA, ANCA, liver function tests and HLA analysis. RESULTS: There was no statistical difference in the prevalence of ANA positivity between patients exposed (13%) or not exposed (11%) to MN. However, higher titres of ANA (1/160 or higher) were found in the MN-exposed group (45% compared with 12% in the unexposed group). ANCA positivity was found in 7% of the MN-exposed group but no positivity was found in the unexposed cohort (P = 0.022). In 58% of cases, the ANCA detected were of the perinuclear pattern (p-ANCA) with myeloperoxidase specificity, and this finding was associated with clinical symptoms in the majority of cases. Two p-ANCA-positive patients were thought in retrospect to have developed a drug-induced lupus syndrome. CONCLUSIONS: ANA positivity is seen in patients with acne irrespective of exposure to MN; however, p-ANCA appear to be a serological marker for developing autoimmune disease in patients receiving MN.

TLX1/HOX11-induced hematopoietic differentiation blockade.

Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.

Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women.

Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty-nine postmenopausal females were randomized to receive for 7 days 400 mg day(-1) micronized progesterone, 0.2 mg day(-1) oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m-labeled technetium-egg meal and 111-labeled indium-charcoal via a delayed-release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half-life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.