Analysis of Gut Microbiome and Diet Modification in Patients with Crohn's Disease.

OBJECTIVE: The human intestine harbors trillions of commensal microbes that live in homeostasis with the host immune system. Changes in the composition and complexity of gut microbial communities are seen in inflammatory bowel disease (IBD), indicating disruption in host-microbe interactions. Multiple factors including diet and inflammatory conditions alter the microbial complexity. The goal of this study was to develop an optimized methodology for fecal sample processing and to detect changes in the gut microbiota of patients with Crohn's disease receiving specialized diets. DESIGN: Fecal samples were obtained from patients with Crohn's disease in a pilot diet crossover trial comparing the effects of a specific carbohydrate diet (SCD) versus a low residue diet (LRD) on the composition and complexity of the gut microbiota and resolution of IBD symptoms. The gut microbiota composition was assessed using a high-density DNA microarray PhyloChip. RESULTS: DNA extraction from fecal samples using a column based method provided consistent results. The complexity of the gut microbiome was lower in IBD patients compared to healthy controls. An increased abundance of Bacteroides fragilis (B. fragilis) was observed in fecal samples from IBD positive patients. The temporal response of gut microbiome to the SCD resulted in an increased microbial diversity while the LRD diet was associated with reduced diversity of the microbial communities. CONCLUSION: Changes in the composition and complexity of the gut microbiome were identified in response to specialized carbohydrate diet. The SCD was associated with restructuring of the gut microbial communities.

Dysregulation of anti-inflammatory annexin A1 expression in progressive Crohns Disease.

BACKGROUND: Development of inflammatory bowel disease (IBD) involves the interplay of environmental and genetic factors with the host immune system. Mechanisms contributing to immune dysregulation in IBD are not fully defined. Development of novel therapeutic strategies is focused on controlling aberrant immune response in IBD. Current IBD therapy utilizes a combination of immunomodulators and biologics to suppress pro-inflammatory effectors of IBD. However, the role of immunomodulatory factors such as annexin A1 (ANXA1) is not well understood. The goal of this study was to examine the association between ANXA1 and IBD, and the effects of anti-TNF-α, Infliximab (IFX), therapy on ANXA1 expression. METHODS: ANXA1 and TNF-α transcript levels in PBMC were measured by RT PCR. Clinical follow up included the administration of serial ibdQs. ANXA1 expression in the gut mucosa was measured by IHC. Plasma ANXA1 levels were measured by ELISA. RESULTS: We found that the reduction in ANXA1 protein levels in plasma coincided with a decrease in the ANXA1 mRNA expression in peripheral blood of IBD patients. ANXA1 expression is upregulated during IFX therapy in patients with a successful intervention but not in clinical non-responders. The IFX therapy also modified the cellular immune activation in the peripheral blood of IBD patients. Decreased expression of ANXA1 was detected in the colonic mucosa of IBD patients with incomplete resolution of inflammation during continuous therapy, which correlated with increased levels of TNF-α transcripts. Gut mucosal epithelial barrier disruption was evident by increased plasma bacterial 16S levels. CONCLUSION: Loss of ANXA1 expression may support inflammation during IBD and can serve as a biomarker of disease progression. Changes in ANXA1 levels may be predictive of therapeutic efficacy.

Sex differences matter in the gut: effect on mucosal immune activation and inflammation.

BACKGROUND: Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn's disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. METHODS: Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. RESULTS: Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1ß as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. CONCLUSION: In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites.

The gut mucosal viral reservoir in HIV-infected patients is not the major source of rebound plasma viremia following interruption of highly active antiretroviral therapy.

Interruption of suppressive highly active antiretroviral therapy (HAART) in HIV-infected patients leads to increased HIV replication and viral rebound in peripheral blood. Effects of therapy interruption on gut-associated lymphoid tissue (GALT) have not been well investigated. We evaluated longitudinal changes in viral replication and emergence of viral variants in the context of T cell homeostasis and gene expression in GALT of three HIV-positive patients who initiated HAART during primary HIV infection but opted to interrupt therapy thereafter. Longitudinal viral sequence analysis revealed that a stable proviral reservoir was established in GALT during primary HIV infection that persisted through early HAART and post-therapy interruption. Proviral variants in GALT and peripheral blood mononuclear cells (PBMCs) displayed low levels of genomic diversity at all times. A rapid increase in viral loads with a modest decline of CD4(+) T cells in peripheral blood was observed, while gut mucosal CD4(+) T cell loss was severe following HAART interruption. This was accompanied by increased mucosal gene expression regulating interferon (IFN)-mediated antiviral responses and immune activation, a profile similar to those found in HAART-naive HIV-infected patients. Sequence analysis of rebound virus suggested that GALT was not the major contributor to the postinterruption plasma viremia nor were GALT HIV reservoirs rapidly replaced by HIV rebound variants. Our data suggest an early establishment and persistence of viral reservoirs in GALT with minimal diversity. Early detection of and therapy for HIV infection may be beneficial in controlling viral evolution and limiting establishment of diverse viral reservoirs in the mucosal compartment.

Epstein-Barr virus replication linked to B cell proliferation in inflamed areas of colonic mucosa of patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Epstein-Barr virus (EBV) infection is associated with increased disease severity in therapeutically immunosuppressed IBD patients. The role of EBV infection in patients with IBD who are unresponsive to medical therapy is unclear. Anti-viral strategies may be a viable treatment option if severity of EBV infection, reflected in peripheral blood, contributes to IBD progression. OBJECTIVES: We investigated the role of EBV in IBD patients unresponsive to medical therapy by examining EBV reactivation and B-cell proliferation in colonic mucosa. STUDY DESIGN: EBV DNA copy numbers were measured by real-time PCR in peripheral blood mononuclear cells (PBMC) of 84 patients with IBD and 115 non-IBD controls in a retrospective cross-sectional study. EBV-infected cells in colonic mucosa were identified by immunohistochemistry. RESULTS: EBV load in PBMC was higher in patients with IBD than in non-IBD controls, especially in patients not responding to medication. Inflamed colonic mucosa of these patients had high levels of expression of lytic and latent EBV genes that localized to proliferating B-lymphocytes, which was not seen in patients responding to therapy. CONCLUSIONS: EBV replication was associated with severe IBD and mucosal inflammation. Increased proliferation and EBV infection of B-lymphocytes in inflamed colonic mucosa highlight the potential role of EBV in mucosal inflammation. The immunomodulatory effects of EBV could delay the resolution of the IBD associated inflammation, thus contributing to disease progression. These results indicate that anti-viral therapeutic strategies for the resolution of IBD may be useful.

Hepatosplenic T-cell lymphoma and inflammatory bowel disease.

OBJECTIVE: This article reviews the current literature and knowledge about hepatosplenic T-cell lymphoma (HSTCL), providing an overview of the clinical features, a description of its pathology and immunophenotypic traits in relation to other lymphomas. In addition, we explore the history of reported cases of hepatosplenic T-cell lymphoma in relation to the possible existence of a causal relationship between infliximab use and HSTCL. The treatments for HSTCL will be briefly addressed. METHODS: A comprehensive literature search using multiple databases was performed. Keyword search phrases including "lymphoma," "hepatosplenic T-cell lymphoma," "Inflammatory bowel disease," "6-mercaptopurine," and "infliximab" were used in various combinations. In addition references from published papers were reviewed as well. RESULTS: There are over 200 reported cases of HSTCL. Only 22 cases of hepatosplenic T-cell lymphoma are associated with IBD treatment. Clinicians usually reserve immunomodulators and biologics for moderate to severe IBD cases. The ultimate goal of therapy is to control inflammation and therefore allow mucosal healing. IBD patients demonstrating mucosal healing are less likely to undergo surgery and experience complications related to their disease. We manipulate the immune system with corticosteroids, immunomodulators, and biologics, therefore causing bone marrow suppression. With bone marrow suppression, malignant degeneration may begin through selective uncontrolled cell proliferation, initiating HSTCL development in the genetically susceptible. CONCLUSION: Hepatosplenic T-cell lymphoma is a rare disease, often with a poor outcome. With the increasing number of reported cases of HSTCL linked to the use of infliximab, adalimumab, and AZA/6-MP, there appears to be an undeniable association of HSTCL development with the use of these agents. This risk is unquantifiable. When considering the rarity of cases and the multiple complications with uncontrolled disease, however, the benefit of treatment far outweighs the risk.

A prospective evaluation of the impact of allopurinol in pediatric and adult IBD patients with preferential metabolism of 6-mercaptopurine to 6-methylmercaptopurine.

BACKGROUND: 6-mercaptopurine (6-MP) is used for the induction and maintenance of remission of inflammatory bowel disease (IBD). 6-MP is converted into 6-methylmercaptopurine (6-MMP) or 6-thioguanine nucleotides (6-TGN) intracellularly. Treatment response in IBD patients correlates with 6-TGN levels. This study prospectively evaluated the effect of allopurinol on 6-MP metabolites in adult and pediatric IBD patients. Additionally, we quantified the prevalence of preferential metabolism towards 6-MMP through a retrospective analysis of IBD patients. METHODS: Twenty patients (10 adult; 10 pediatric) with evidence of preferential metabolism towards 6-MMP, (6-TGN<250 pmol/8×108 RBCs and 6-MMP>5000 pmol/8×108 RBCs) were prospectively treated with allopurinol 100 mg daily and up to 100 mg of 6-MP. 6-MP dose was adjusted after a 3-week metabolite measurement. RESULTS: The median dose of 6-MP for adults decreased from 100mg daily (range: 37.5-150 mg) to 25mg daily (range: 12.5-50 mg). The median dose of 6-MP for pediatric patients decreased from 50 mg (range: 25-50 mg) to 10.7 mg (range: 10.7 to 21.4 mg). Mean 6-TGN levels in all subjects increased from 197.4 (± 59) to 284.8 (± 107) pmol/8×108 RBCs (p=0.0005). Mean 6-MMP levels in all subjects decreased from a mean of 7719.8 (± 4716) to 404.8 (± 332) pmol/8×108 RBCs (p=0.0004). There were no complications associated with allopurinol therapy. Eighty-eight (30.9%) of 285 IBD patients had evidence of preferential metabolism towards 6-MMP. The proportion of preferential metabolism was equal in adults and pediatric patients. CONCLUSION: Our results indicate that the addition of allopurinol safely shifts metabolite production in both adult and pediatric IBD patients and that there is a high prevalence of preferential metabolism towards 6-MMP among IBD patients.

Unusual presentations of eosinophilic gastroenteritis: case series and review of literature.

Eosinophilic gastroenteritis (EG) is an uncommon disease characterized by focal or diffuse eosinophilic infiltration of the gastrointestinal tract, and is usually associated with dyspepsia, diarrhea and peripheral eosinophilia. Diffuse gastrointestinal tract and colonic involvement are uncommon. The endoscopic appearance may vary from normal to mucosal nodularity and ulceration. Gastrointestinal obstruction is unusual and is associated with predominantly muscular disease. We present five unusual cases of EG associated with gastric outlet and duodenal obstruction. Two cases presented with acute pancreatitis and one had a history of pancreatitis. Four cases responded well to medical therapy and one had recurrent gastric outlet obstruction that required surgery. Four out of the five cases had endoscopic and histological evidence of esophagitis and two had colitis. Two patients had ascites. These cases reaffirm that EG is a disorder with protean manifestations and may involve the entire gastrointestinal tract. Gastric outlet and/or small bowel obstruction is an important though uncommon presentation of EG. It may also present as esophagitis, gastritis with polypoid lesions, ulcers or erosions, colitis and pancreatitis and may mimic malignancy.

Capsule endoscopy's impact on clinical management and outcomes: a single-center experience with 145 patients.

BACKGROUND: Capsule endoscopy (CE) is a new technology that has been shown to have superior diagnostic yield compared with other methods of evaluating the small bowel. However, there have not been many studies supporting capsule endoscopy's impact on clinical outcomes. This study is a chart review evaluating the diagnostic yield and the impact of CE on management and clinical outcomes. METHODS: Retrospective chart review was performed on 145 patients who had undergone capsule endoscopy. Demographic characteristics, indication, prior diagnostic tests, capsule findings, interventions, and clinical outcomes up to 8 months following CE were evaluated. Indications included five main categories that were overt gastrointestinal (GI) bleed, occult GI bleed, abdominal pain, Crohn's disease, and iron deficiency anemia. Findings on capsule endoscopy were classified into angiodysplasias, ulcers, gastritis and/or duodenitis, ulcers suggestive of Crohn's and normal findings. Interventions performed based on capsule findings were recorded, which included the discontinuation of nonsteroidal anti-inflammatory drugs (NSAIDS), further diagnostic or therapeutic studies, increase in medications, and surgery. Positive outcomes including stabilization or improvement of hemoglobin, decreased need for transfusions, improved symptoms of pain, and a decrease in medications based on interventions were assessed. RESULTS: There were 145 patients who underwent CE. The indications for CE were overt GI bleed (38%), occult GI bleed (22%), abdominal pain (20%), Crohn's (12%), iron deficiency anemia (2.7%), and miscellaneous (4%). Eighty percent achieved completion and 6 patients had complications of capsule retention with 4 requiring surgery. The overall diagnostic yield was 69% and included findings of angiodysplasias (24%), intestinal ulcers (13%) gastritis or duodenitis (13.8%), ulcers suggestive of Crohn's disease (8.9%), and mass or polyp (3.4%). Based on capsule findings, 35.8% of patients had an intervention. Of the patients who received intervention, 71.7% had a positive clinical outcome (P= 0.032). CONCLUSIONS: The high diagnostic yield of CE influences clinical management leading to improved outcomes. However, the utility of CE may be greater in patients who are referred for certain indications or have specific findings. Additional studies are needed to clarify the role of capsule endoscopy in the evaluation of various indications as well as identify factors associated with positive outcomes.

Long-term follow-up of the endoscopic treatment of strictures in pediatric and adult patients with inflammatory bowel disease.

BACKGROUND: Strictures are a common complication of inflammatory bowel disease (IBD) and are usually treated by surgical resection or strictureplasty. As an alternative to surgery, endoscopic balloon dilation and steroid injection have been used to relieve symptoms. GOALS: To assess patient or stricture characteristics that may predict a better outcome and duration of response as endoscopic therapy is not without its risks. STUDY: A retrospective review of patients with IBD strictures who underwent dilations between 1996 and 2005 was performed. The patients were followed in the adult and pediatric IBD clinics at a single center. Information was collected from medical records. RESULTS: Strictures were identified in the small and large bowel of 24 patients (22 adult and 2 pediatric). The majority had Crohn's disease (22/24). In total, 71 dilations were performed on 29 strictures; 46 dilations for 17 strictures were augmented with triamcinolone. Mean duration of follow-up was 32 months. This study included 1 stomal, 12 anastomotic, and 16 de novo strictures. Of 12 anastomotic strictures, 6 were complex. Endoscopic dilation was uneventful in 22/24 patients. Bleeding and perforation occurred on separate occasions in 1/6 complex stricture patients and rupture of a paracolonic abscess in another patient with a de novo sigmoid stricture. Surgery was performed on 2 patients, 1 for refractory disease and 1 for noncompliance with therapy. CONCLUSIONS: Endoscopic dilation can provide long-term effective palliation of symptoms with minimal risk in patients with simple strictures. Complex anastomotic strictures are technically more challenging compared with de novo strictures.

Combined EUS with FNA and ERCP for the evaluation of patients with obstructive jaundice from presumed pancreatic malignancy.

BACKGROUND: An EUS-guided FNA (EUS-FNA) and a therapeutic ERCP are frequently required for the evaluation of patients who were seen for an obstructing periampullary lesion. OBJECTIVE: To determine the feasibility and outcomes of combining an EUS-FNA and a therapeutic ERCP into a single session. DESIGN: Retrospective single-center study. SETTING: Tertiary-referral cancer center. PATIENTS: A total of 114 patients with a suspected malignant obstructing lesion in the pancreatic head. INTERVENTIONS: An EUS with or without FNA plus an ERCP. MAIN OUTCOME MEASUREMENTS: Duration, diagnostic yield, and complication rate of the combined procedures. RESULTS: The mean (SD) total procedure time (EUS, with or without FNA plus ERCP) was 73.6 +/- 30 minutes, with a median of 66 minutes (range 25-148 minutes). In many cases, cytologic diagnosis from FNA became available during an ERCP, which obviated the need for further sampling. EUS-FNA had a sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of 84.6%, 100%, 100%, 62.9%, and 87.8%, respectively. During an ERCP, endoscopic sphincterotomies were performed in 51 patients, and biliary stents were placed in 96 patients. Twelve patients (10.5%) had a complication, with 6 having postprocedural pancreatitis. LIMITATIONS: Retrospective single-center experience. CONCLUSIONS: Combined EUS-FNA and therapeutic ERCP is technically feasible, with a complication rate no higher than the component procedures, while efficiently providing tissue diagnosis and biliary drainage.

Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration.

Gut-associated lymphoid tissue (GALT) is an early target for human immunodeficiency virus type 1 (HIV-1) infection and is a site for severe CD4(+) T-cell depletion. HIV-associated enteropathy is well-documented in chronic HIV-1 infection. However, the initial host responses to HIV infection in GALT and the early molecular correlates of HIV enteropathogenesis have not been characterized during primary HIV infection. In this study, we provide evidence of viral replication in GALT resident CD4(+) T cells and macrophages in primary-stage patients and identify early patterns of host mucosal responses and changes in the molecular microenvironment through gene expression profiling. High levels of viral replication in GALT and marked CD4(+) T-cell depletion correlated with decreased expression levels of genes regulating epithelial barrier maintenance and digestive/metabolic functions. These changes coincided with a marked increase in the transcription of immune activation-, inflammation-, and apoptosis-associated genes. Our findings indicate that HIV-induced pathogenesis in GALT emerges at both the molecular and cellular levels prior to seroconversion in primary HIV infection, potentially setting the stage for disease progression by impairing the ability to control viral replication and repair and regenerate intestinal mucosal tissues.

Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection.

Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11 alpha, alpha(E)beta 7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.

Prevalence of enterotoxigenic Bacteroides fragilis in hospital-acquired diarrhea.

Stool specimens from 152 hospitalized patients with diarrhea were analyzed for the presence of enterotoxigenic Bacteroides fragilis (ETBF) by a nested polymerase chain reaction (PCR) assay. ETBF gene sequences were directly detected in 14/152 (9.21%) stools of patients. The prevalence of ETBF in hospital-acquired diarrhea was statistically significant when compared to a prevalence of 2.3% in control subjects (P = 0.04). B. fragilis was cultured from 19.7% (30/152) patients with diarrhea; 4 of these isolates were enterotoxigenic. To determine whether colonization with B. fragilis is heterogeneous in nature, multiple colonies from 17 individual patients were analyzed for enterotoxin gene sequences and genotyped by arbitrarily primed PCR. Of these 17 patients, 13 harbored multiple strain types suggesting heterogeneity of colonization with both enterotoxigenic and non-enterotoxigenic strains. Identification of ETBF in the stools of 10 patients in the absence of a positive culture is likely due to the noted heterogeneity and suggests that detection of enterotoxin by PCR should be performed directly in the stool. These preliminary data indicate that ETBF may play a role in hospital-acquired diarrhea of unknown origin and suggest the need for further studies.

Eosinophilic gastroenteritis and citrus-induced urticaria.

The immunological basis of eosinophilic gastroenteritis (EGE) is an interesting contrast between the enigma of urticaria and the increasing usage of molecular technology in clinical allergy. Little is known about the natural history of EGE. It has been known to spontaneously remit, but the typical course, especially in adults, is one of chronic and intermittent disease. Given the often chronic nature of this disease, it is important to use relatively benign treatments initially and limit the use of systemic corticosteroids. Also, given the fact that eosinophilic infiltration of the gastrointestinal tract may also be a manifestation of other potentially dangerous disease processes, such as malignancy or hypereosinophilic syndrome, which may be initially diagnosed as EGE, routine surveillance of the cardiopulmonary and gastrointestinal systems is important. We present a patient who demonstrates the variability of presentation and treatment response in this multifaceted disease. The fact that he has apparently entered remission also makes his an uncommon presentation of EGE.

Diphenhydramine as an adjunct to sedation for colonoscopy: a double-blind randomized, placebo-controlled study.

BACKGROUND: Intravenous benzodiazepines in combination with opiates are used to achieve moderate sedation for colonoscopy. Although effective, these agents have potential adverse effects, such as respiratory depression and hypotension. Diphenhydramine hydrochloride possesses central nervous system depressant effects that theoretically could provide a synergistic effect for sedating patients. OBJECTIVE: The objective was to assess the efficacy of adding diphenhydramine hydrochloride as an adjunct to improve sedation and to reduce the amount of standard sedatives used during colonoscopy. DESIGN: We conducted a prospective, randomized, double-blind, placebo-controlled study. SETTING: The study was conducted in a university hospital with an active GI fellowship training program. PATIENTS: The study group comprised 270 patients undergoing screening/diagnostic/therapeutic colonoscopy were enrolled. INTERVENTIONS: Patients were randomized to receive either 50 mg of diphenhydramine or placebo, given intravenously 3 minutes before starting conscious sedation with intravenous midazolam and meperidine. MAIN OUTCOME MEASUREMENTS: The main outcome measure was anesthetic effect as assessed by the endoscopy team and by the patient; quantity of adjunctive sedatives to achieve adequate sedation. RESULTS: Of 270 patients, data were analyzed for 258 patients, with 130 patients in the diphenhydramine group and 128 patients in the placebo group. There was a 10.1% reduction in meperidine usage and 13.7% reduction in midazolam usage in favor of the diphenhydramine group. The mean evaluation scores as judged by the faculty, the fellows, and the nurses were statistically significant in favor of the diphenhydramine group. In addition, patient scores for overall sedation and pain level favored the group that received diphenhydramine. CONCLUSIONS: Intravenous diphenhydramine given before initiation of standard sedation offers a significant benefit to conscious sedation for patients undergoing colonoscopy.

Crohn's disease associated with Sweet's syndrome and Sjögren's syndrome treated with infliximab.

The association of Crohn's disease (CD) and Sweet's syndrome is rare and the presence of Sjögren's syndrome in Crohn's disease is even rarer, with only three reports found in the literature. We describe two cases of Crohn's disease associated with Sweet's syndrome, one of which is the first case of CD and Sweet's concomitantly associated with Sjogren's syndrome. Both cases responded rapidly to Infliximab therapy with complete resolution of the skin lesions.

Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1-infected nonprogressors.

Limited information is available on the molecular mechanisms by which long-term HIV-1-infected nonprogressors suppress HIV-1 infection and maintain immune functions. The intestinal mucosal immune system is an early target for HIV-1 infection and severe CD4+ T cell depletion. We evaluated mucosal T lymphocyte subsets, virus-specific cellular responses, gene expression profiles, and viral loads in intestinal mucosal biopsies of long-term nonprogressor (LTNP) patients as compared to chronically HIV-1-infected patients with high viral loads (HVLs) and CD4+ T cell loss, as well as HIV-seronegative healthy individuals. This study aims to identify the mucosal correlates of HIV disease progression and to determine the molecular changes associated with immune and intestinal dysfunction. LTNP patients had undetectable viral loads, normal CD4+ T cell levels, and virus-specific cellular responses in peripheral blood and mucosal compartments. Microarray analysis revealed a significant increase in gene expression regulating immune activation, cell trafficking, and inflammatory response in intestinal mucosa of HVL patients as compared to LTNP patients. Genes associated with cell cycle regulation, lipid metabolism, and epithelial cell barrier and digestive functions were down-regulated in both HVL and LTNP patients. This may adversely influence nutrient adsorption and digestive functions, with the potential to impact the efficacy of antiretroviral therapy. We demonstrate that the maintenance of mucosal T cells, virus-specific responses, and distinct gene expression profiles correlate with clinical outcome in LTNP patients. However, the intestinal mucosal immune system remains an important target of HIV-1 infection in LTNP, and these effects may ultimately contribute toward disease progression.

Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy.

Gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes in the body and is an important target for human immunodeficiency virus type 1 (HIV-1). We analyzed longitudinal jejunal biopsy samples from HIV-1-infected patients, during both primary and chronic stages of HIV-1 infection, prior to and following the initiation of highly active antiretroviral therapy (HAART) to determine the onset of CD4(+) T-cell depletion and the effect of HAART on the restoration of CD4(+) T cells in GALT. Severe depletion of intestinal CD4(+) T cells occurred during primary HIV-1 infection. Our results showed that the restoration of intestinal CD4(+) T cells following HAART in chronically HIV-1-infected patients was substantially delayed and incomplete. In contrast, initiation of HAART during early stages of infection resulted in near-complete restoration of intestinal CD4(+) T cells, despite the delay in comparison to peripheral blood CD4(+) T-cell recovery. DNA microarray analysis of gene expression profiles and flow-cytometric analysis of lymphocyte homing and cell proliferation markers demonstrated that cell trafficking to GALT and not local proliferation contributed to CD4(+) T-cell restoration. Evaluation of jejunal biopsy samples from long-term HIV-1-infected nonprogressors showed maintenance of normal CD4(+) T-cell levels in both GALT and peripheral blood. Our results demonstrate that near-complete restoration of mucosal immune system can be achieved by initiating HAART early in HIV-1 infection. Monitoring of the restoration and/or maintenance of CD4(+) T cells in GALT provides a more accurate assessment of the efficacy of antiviral host immune responses as well as HAART.