Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

Comparision of how old age psychiatry and general adult psychiatry services meet the needs of elderly people with functional mental illness: cross-sectional survey.

BACKGROUND: There is little research evidence as to whether general adult psychiatry or old age psychiatry should look after old people with enduring mental illness. AIMS: To compare the extent to which general adult and old age psychiatric services meet the needs of older people with enduring mental illness. METHOD: A total of 74 elderly patients with functional psychiatric disorders were identified by reviewing the notes of patients over the age of 60 living in a defined inner urban catchment area. Data were collected on the morbidity and needs of the sample. Needs were assessed using the Elderly Psychiatric Needs Schedule (EPNS). RESULTS: The participants in contact with old age psychiatry had significantly fewer unmet needs compared with those in contact with general adult psychiatry (2.8 v. 5.6, t = 2.2, P<0.03). Total needs were not significantly different between those managed by old age and general adult services (8.0 v. 6.5 respectively, t = 1.2, P = 0.2). CONCLUSIONS: This study found that old age psychiatry services were better placed to meet the needs of elderly people with mental illness. This finding supports the need for a separate old age psychiatry service.

Lubiprostone plus PEG electrolytes versus placebo plus PEG electrolytes for outpatient colonoscopy preparation: a randomized, double-blind placebo-controlled trial.

Bowel preparation using large volume of polyethylene glycol (PEG) solutions is often poorly tolerated. Therefore, there are ongoing efforts to develop an alternative bowel cleansing regimen that should be equally effective and better tolerated. The aim of this study was to assess the efficacy of lubiprostone (versus placebo) plus PEG as a bowel cleansing preparation for colonoscopy. Our study was a randomized, double-blind placebo-controlled design. Patients scheduled for screening colonoscopy were randomized 1:1 to lubiprostone (group 1) or placebo (group 2) plus 1 gallon of PEG. The primary endpoints were patient's tolerability and endoscopist's evaluation of the preparation quality. The secondary endpoint was to determine any reduction in the amount of PEG consumed in the lubiprostone group compared with the placebo group. One hundred twenty-three patients completed the study and were included in the analysis. There was no difference in overall cleanliness. The volume of PEG was similar in both the groups. The volume of PEG approached significance as a predictor of improved score for both the groups (P = 0.054). Lubiprostone plus PEG was similar to placebo plus PEG in colon cleansing and volume of PEG consumed. The volume of PEG consumed showed a trend toward improving the quality of the colon cleansing.

Golimumab may induce exacerbation of inflammatory bowel disease when it is used for the treatment of ankylosing spondylitis: a case report with a review of literature.

Golimumab is a human IgG monoclonal antibody specific for human tumor necrosis factor alpha. Golimumab has been approved for use in rheumatological conditions; however, its use in inflammatory bowel disease is still being evaluated in clinical trials. We report a case of an exacerbation of ulcerative proctitis after starting on golimumab for ankylosing spondylitis.

Relationship of symptom duration and fecal bacteriotherapy in Clostridium difficile infection-pooled data analysis and a systematic review.

OBJECTIVE: Clostridium difficle-associated infection (CDI) is usually treated with antibiotics; nevertheless, the infection has a high relapse rate. Case series and case reports using fecal microbiota transplant (FMT) for CDI show promising results. However, there are no large studies to provide evidence for the efficacy of this therapy. The aim of this pooled patient data meta-analysis was to determine the efficacy of FMT in CDI. METHODS: We performed a literature search for FMT for CDI or pseudomembranous colitis. Individual patient data were obtained from each study. The primary endpoint was to assess the rate of diarrhea resolution. Secondary endpoints were to identify variables associated with treatment failure and side effects of therapy. RESULTS: A total of 289 patients from 25 published articles who received FMT for CDI were included in the pooled data analysis. FMT had an overall success rate of 91.2%. On univariate analysis, shorter duration of symptoms before FMT (< 60 days) and gastroduodenal route of fecal instillation were associated with treatment failure. On multivariate regression analysis, shorter duration of symptoms (< 60 days) before the FMT (OR= 11.08; p = 0.0009) was associated with treatment failure. Reported adverse events following FMT were irritable bowel syndrome (n = 1), symptoms of mild enteritis (n = 3), and suspected peritonitis following the procedure (n = 1). CONCLUSION: FMT is a safe and effective treatment option for CDI. Shorter duration of symptoms (< 60 days) before administering FMT is associated with treatment failure.

Antithrombotic management of stroke patients before colonoscopy.

BACKGROUND: Uncertainty exists regarding the management of antithrombotic medications in ischemic stroke and transient ischemic attack (TIA) patients around the time of colonoscopy. We sought to evaluate whether there was a difference in adverse events among patients who continued medications and those who had temporary discontinuation. METHODS: Using a hospital administrative database, electronic charts of patients with a diagnostic code for stroke or TIA and a procedural code for colonoscopy were reviewed. Information collected included baseline demographics, medical history, and antithrombotic medications. Outcome measures were stroke (ischemic and hemorrhagic), myocardial infarction, venous thromboembolism, and major systemic bleeding (i.e., requiring transfusion) up to 4 weeks after the procedure among patients who had medications continued versus temporarily discontinued. RESULTS: One hundred seventy-seven patients met inclusion criteria. Antithrombotic medication was temporarily discontinued in 42 patients and continued in 135 patients. Comparing patients who had medications held to those who had medications continued, stroke occurred in 1 (2.4%) versus 0 (0%; P = .237) patients; myocardial infarction in no patients in either group; venous thromboembolism in 0 (0%) versus 1 (0.7%; P > .99) patients; and major system bleeding in 2 (4.8%) versus 4 (3.0%; P = .628) patients. CONCLUSIONS: In this retrospective analysis, there was no significant difference in the occurrence of stroke, myocardial infarction, venous thromboembolism, and major bleeding between patients who had medications continued around the time of colonoscopy versus those who had temporary discontinuation. A prospective, randomized controlled study is warranted to further elucidate this issue.

Pregabalin for the treatment of abdominal adhesion pain: a randomized, double-blind, placebo-controlled trial.

Chronic pain related to postoperative abdominal adhesions is a common problem with no standard analgesic regimen currently established. In a double-blind, placebo-controlled trial, we examined the effects of pregabalin on pain modulation in patients with prior abdominal surgery and documented adhesion. The primary outcome measure was pain relief documented by a 2-point change on the Likert pain scale with a secondary pain measure of sleep interruption. A total of 18 women were randomized to receive either the drug (n = 11) or placebo (n = 7). Thirteen patients (eight pregabalin, five placebo) completed the blinded phase and 10 patients (seven pregabalin, three placebo) completed the open-label phase. Statistical analysis was performed in two settings: 1) Week 0 (as the baseline) through the end of Week 7 of the blinded fixed-dose phase; and 2) Week 7 (as the baseline) along With weeks 8 through 11 of the open-label phase. The pain score result from the blinded phase setting indicated that the amount of decrease was significantly greater in the drug group (P = 0.024), whereas the pain score result from the open-label setting indicated that the amount of decrease was significantly greater in the placebo group (P = 0.043). Only the sleep score result in the open-label setting was significantly greater in the placebo group (P = 0.024). We conclude that pregabalin significantly reduced patient-documented pain scores compared with placebo in our small cohort of patients with abdominal adhesion pain.

Mesalamine protects against colorectal cancer in inflammatory bowel disease.

BACKGROUND: Individuals with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC) compared with the general population. Previous studies show this risk is strongly associated with dysplasia, extent of disease, duration of disease, and degree of inflammation, while chemoprevention of CRC has less support. AIM: Evaluate factors influencing risk of colorectal cancer development in inflammatory bowel disease patients. METHODS: IBD patients with CRC were matched to controls by IBD type, age at diagnosis, sex, race, extent of disease, and disease duration. We compared body mass index, family history of IBD, family history of CRC, tobacco use, and cumulative and daily use of aminosalicylates, immunomodulators, folic acid, steroids, and nonsteroidal anti-inflammatory drugs. Statistical analysis was performed with logistic regression and receiver operating characteristic (ROC) curves. RESULTS: Of 1,594 IBD patients, 30 CRC patients were identified. Of these, 18 CRC patients were matched to 30 controls. More control patients used a cumulative aminosalicylate dose of >or=4,500 g (46.6% versus 5.6%; P = 0.047), folic acid (40.0% versus 16.7%; P = 0.002), cumulative folic acid dose of >or=1,400 mg (30.0% versus 11.1%; P = 0.014), and average daily folic acid dose of >or=1 mg (30.0% versus 16.7%; P = 0.002) compared with CRC patients. Multivariate analysis showed that a cumulative aminosalicylate dose of >or=4,500 g reduced the risk of CRC by 97.6% (P = 0.047). Folic acid reduced CRC risk by 89% (P = 0.002). CONCLUSIONS: Aminosalicylate and folic acid use may decrease the risk of CRC among IBD patients.

Mast cells are early responders after hypoxia-ischemia in immature rat brain.

BACKGROUND AND PURPOSE: Perinatal hypoxia-ischemia (HI) produces acute and prolonged inflammation of the brain. Mast cells (MCs), numerous in the pia and CNS of neonatal rats, can initiate inflammation attributable to preformed mediators. MCs contribute to HI brain damage in the neonatal rat; MC stabilization protects through 48 hours of reperfusion. Here we hypothesize that HI induces early MC migration, activation, and release of proinflammatory molecules. METHODS: HI was induced by right CCA ligation and 75 minutes 8% oxygen. Histochemistry and immunocytochemistry described the time course of early cellular changes in the CNS. For neuroprotection by MC stabilization, pups were treated with Cromolyn (CR) during the initial 24 hours post-HI; brains were examined through 4 weeks. RESULTS: Brain MC number and activation were elevated in ipsilateral hemisphere immediately after HI (P<0.05), before detection of cleaved caspase-3 in neurons (NeuN+; 2 hours post-HI), astroglial activation (GFAP+ with swollen cell body, 4 hours post-HI), or microglial activation (OX42+, 4 hours post-HI). TNF-alpha-positive MCs were present in a subpopulation of MCs in control animals and the percent of TNF-alpha MCs increased dramatically ipsilaterally immediately after HI (P<0.01). Microglial TNF-alpha was evident at 4 hours; endothelial cells had no detectable TNF-alpha until 48 hours post-HI. Cromolyn prevented MC migration, reduced brain damage/neuronal loss, glial activation, and brain atrophy through 4 weeks of recovery (P<0.05). CONCLUSIONS: MCs are early responders to HI in neonatal brain. MC stabilization provides lasting protection and suggests a new target for therapeutic interventions.

An extra pair of hands? A case study of the introduction of support workers in community mental health teams for older adults.

BACKGROUND: Despite the expanding deployment of support workers in mental health services, little evidence exists on what managers and professional practitioners should expect of such staff in community settings. AIMS: This case study evaluated the introduction of support workers in community mental health teams for older adults. METHOD: A multiple method design engaged support workers and professional colleagues in individual interviews, a focus group and a work satisfaction survey. RESULTS: While the new resource boosted service provision, disparity between the intended role and the assumptions of professional practitioners caused confusion and dissatisfaction. CONCLUSIONS: The study highlights the need for managers to ensure role clarity when non-professional workers are introduced into multidisciplinary community teams. IMPLICATIONS FOR NURSING MANAGEMENT: Promoting diversity of skills in the mental health workforce is a progressive move in tuning services to the heterogenous needs of clients in the community. However, introducing unqualified workers into multi-disciplinary teams necessitates clear guidance to prevent their activity being confined within existing professional models. Support workers offer much potential in innovative service delivery.

Mast cell stabilization limits hypoxic-ischemic brain damage in the immature rat.

Perinatal hypoxic-ischemic (HI) brain damage is a major cause of mortality and neurological morbidity in infants and children. Using an established model of unilateral hypoxia-ischemia in neonatal rats, the present study focused on mast cells (MCs), important regulators of inflammatory processes, as potential contributors to HI damage. MCs are present in the pia of the neonatal rat, entering the central nervous system (CNS) during cerebral development along penetrating blood vessels. Following hypoxia-ischemia, MC numbers increased dramatically in the ipsilateral (ischemic) hemisphere (p < 0.01). In animals exposed to hypoxia only, the numbers of MCs were elevated in both hemispheres to an extent equal to that observed in the contralateral hemisphere of HI animals (p < 0.05 vs. control). Within damaged areas (ipsilateral only), MCs were observed in regions of activated microglia and astroglia that characterize the ischemic hemisphere. Using a triple-label paradigm, MCs were observed along elongating blood vessels, some of which express the GLUT1 isoform of the glucose transporter protein, indicative of blood-brain barrier vessels. To determine whether MC activation has a role in HI brain damage, rat pups were treated with the MCs stabilizer, disodium cromoglycate (cromolyn), prior to and/or following hypoxia-ischemia. The cromolyn treatment inhibited MC migration into the CNS (p < 0.05) and limited brain damage more than 50% (p < 0.01) vs. saline controls. These data support the hypothesis that MCs are key contributors to the extent of brain damage due to hypoxia-ischemia in the immature animal.

Brain mast cell relationship to neurovasculature during development.

Mast cells, derived from the hematopoietic stem cell, are present in the brain from birth. During development, mast cells occur in two locations, namely the pia and the brain parenchyma. The current hypothesis regarding their origin states that brain mast cells (or their precursors) enter the pia and access the thalamus by traveling along the abluminal wall of penetrating blood vessels. The population in the pia reaches a maximum at postnatal (PN) day 11, and declines rapidly thereafter. Chromatin fragmentation suggests that this cell loss is due to apoptosis. In contrast, the thalamic population expands from PN8 to reach adult levels at PN30. Stereological analysis demonstrates that mast cells home to blood vessels. More than 96% of mast cells are inside the blood-brain barrier, with ~90% contacting the blood vessel wall or its extracellular matrix. Mast cells express alpha4 integrins -- a potential mechanism for adhesion to the vascular wall. Despite the steady increase in the volume of microvasculature, at all ages studied, mast cells are preferentially located on large diameter vessels (>16 microm; possibly arteries), and contact only those maturing blood vessels that are ensheathed by astroglial processes. Mast cells not only home to large vessels but also maintain a preferential position at branch points, sites of vessel growth. This observation presents the possibility that mast cells participate in and/or regulate vasculature growth or differentiation. The biochemical and molecular signals that induce mast cell homing in the CNS is an area of active investigation.

The role of serine proteases and serine protease inhibitors in the migration of gonadotropin-releasing hormone neurons.

BACKGROUND: Mechanisms regulating neuronal migration during development remain largely undefined. Extracellular matrix cues, target site released factors, and components of the migratory neurons themselves are likely all coordinated in time and space directing neurons to their appropriate locations. We have studied the effects of proteases and their inhibitors on the extracellular matrix and the consequences to the migration of gonadotropin releasing hormone (GnRH) neurons in the embryonic chick. Chick GnRH neurons differentiate in the olfactory epithelium, migrate along the olfactory nerve and enter the forebrain. The accessibility of this coherent cell group make it amenable for studying protease/inhibitor roles in migratory processes. RESULTS: Affigel blue beads were used to deliver a serine protease inhibitor, protease nexin-1 (PN-1), and a target protease, trypsin, to the olfactory epithelium coincident with initiation of GnRH neuronal migration. PN-1 inhibited neuronal migration while trypsin accelerated their transit into the CNS. Prior to initiation of migration, neither PN-1 nor trypsin altered the timing of neuronal exit. Trypsin did, however, accelerate the timing of neuronal crossing into the nerve-forebrain junction. CONCLUSIONS: These data support the hypothesis that protease activity modulates neuronal movements across barriers. Moreover, the data suggest, for the first time, that aspects of GnRH neuronal migration may be cell autonomous but modulated by ECM alterations.

Post-bloodmeal diuretic shedding of hepatitis B virus by mosquitoes (Diptera: Culicidae).

Persistence and diuretic shedding of hepatitis B virus (HBV) by mosquitoes (Diptera: Culicidae) was studied by using infectious blood feedings, intrathoracic inoculations, and detection of virus by polymerase chain reaction (PCR) and Southern hybridization. Results showed that both Anopheles stephensi Liston and Ochlerotatus triseriatus (Say) shed HBV during diuresis for up to 72 h after feeding on an HBV-positive serum drawn from a human donor. HBV did not persist in the bodies of either An. stephensi or Oc. triseriatus past 72 h by infectious feeding or intrathoracic inoculation of HBV suspension. Viral dissemination did not occur by infectious feeding in An. stephensi or Oc. triseriatus, or by intrathoracic inoculation in An. stephensi, Oc. triseriatus, or Culex quinquefasciatus Say. These results suggest that HBV could be transmitted to humans by a stercorarian route, especially if mosquitoes that fed on an HBV-positive human are interrupted during feeding and move to another person to resume feeding.

Fecal Bacteriotherapy: A Case Report in an Immunosuppressed Patient with Ulcerative Colitis and Recurrent Clostridium difficile Infection.

We report a case of ulcerative colitis (UC) and recurrent Clostridium difficile infection (CDI) where the patient was on immunomodulatory therapy and had successful CDI eradication after fecal transplantation. This is the first case report in the literature documenting successful C. difficile eradication in an immunosuppressed patient. We feel that fecal transplantation should be studied as a treatment option in these patients.

Mast cells are necessary for the hypothermic response to LPS-induced sepsis.

As central nervous system residents, mast cells contain many cytokines and are localized primarily near large blood vessels in the diencephalon and within the leptomeninges, making them candidates for immune to neural "cross talk." Using mast cell-deficient Kit(W-sh/W-sh) mice, we assessed the role of these cells in the thermoregulatory component of the immune response to lipopolysaccharide (LPS). Kit(W-sh/W-sh) and wild-type (WT) mice differed in several respects in response to injection of a high dose of LPS (1 mg/kg ip). Core temperature (T(c)) of WT mice decreased by approximately 3 degrees C, whereas Kit(W-sh/W-sh) mice did not become hypothermic but instead exhibited pronounced low-frequency T(c) oscillations around their baseline temperature. In addition, Kit(W-sh/W-sh) mice had lower levels of whole brain TNF-alpha but no differences in IL-1beta, IL-6, IFN-gamma, or histamine compared with WT mice following injection of the high dose of LPS, consistent with the role of TNF-alpha in sepsis. Kit(W-sh/W-sh) mice had increased resistance to LPS, and some survived a dose of LPS that was lethal in littermate controls. In contrast, Kit(W-sh/W-sh) and WT mice were similar in other aspects, namely, in the hyperthermia following injection of TNF-alpha (1.5 microg icv), reduced nighttime T(c) and locomotor activity (to 1 mg/kg LPS), response to a low dose of LPS (10 microg/kg ip), and response to subcutaneous turpentine injection. These results indicate that mast cells play a role in the regulation of thermoregulatory responses and survival following sepsis induction and suggest a brain site of action.

The burden of acute nonfulminant drug-induced hepatitis in a United States tertiary referral center [corrected].

BACKGROUND/GOALS: There are limited data regarding the frequency and proportionality of drug-induced hepatotoxicity in the United States. We sought to determine the scope of nonfulminant drug-induced hepatitis as seen in a community-based hepatology referral service. STUDY: From a population of 4,039 outpatients referred for evaluation of acute (n = 96) and chronic (n = 3,943) liver disease over a 10-year period, we reviewed the records of those patients diagnosed with acute bona fide drug-induced hepatitis. RESULTS: Thirty-two patients presented with self-limited acute drug-induced hepatitis, representing 0.8% of all hepatology patients and 33% of those patients presenting with acute liver injury. Antibiotics (amoxicillin/clavulanic acid, minocycline, nitrofurantoin, an investigational ketolide antibiotic, trimethoprim-sulfamethoxazole, and trovafloxacin) were the class of drugs most frequently implicated (14 of 32; 44%), while amiodarone was the single agent most commonly associated with liver injury (7 of 32; 22%). The mean age of affected patients was 52.2 years, and we found a male predominance (18 of 32; 56%). The mean time to biochemical resolution after discontinuation of the offending agent was 14.1 weeks. CONCLUSIONS: Drug-induced hepatitis is an uncommon entity in clinical hepatology but does represent a significant proportion of acute self-limited liver disease in the United States. Antibiotics and amiodarone were the most common drug culprits in our population. Time to resolution following the discontinuation of the offending agent may be protracted. Prospective studies are needed to further assess the burden of drug-induced liver injury.