Preferential depletion of gut CD4-expressing iNKT cells contributes to systemic immune activation in HIV-1 infection.

Chronic inappropriate immune activation is the central defect-driving loss of CD4(+) T helper cells and progression to AIDS in persons with HIV-1 infection, but the mechanisms remain controversial. We examined key regulatory invariant receptor natural killer T (iNKT) cells in the gut, the largest reservoir of lymphocytes and a key arena of HIV-1 pathogenesis. In healthy control persons, the anti-inflammatory CD4(+) iNKT-cell subset predominated over the pro-inflammatory CD4(-) iNKT-cell subset in the gut, but not in the blood, compartment. HIV-1 infection resulted in a preferential loss of this anti-inflammatory CD4(+) iNKT-cell subset within the gut. The degree of loss of the CD4(+) iNKT-cell subset in the gut, but not in the blood, correlated to the systemic immune activation and exhaustion that have been linked to disease progression. These results suggest a potentially important contribution of gut iNKT-cell imbalance in determining the systemic immune activation that is the hallmark of HIV-1 pathogenesis.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.

Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.

A preponderance of CCR5(+) CXCR4(+) mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection.

The gastrointestinal mucosa harbors the majority of the body's CD4(+) cells and appears to be uniquely susceptible to human immunodeficiency virus type 1 (HIV-1) infection. We undertook this study to examine the role of differences in chemokine receptor expression on infection of mucosal mononuclear cells (MMCs) and peripheral blood mononuclear cells (PBMCs) by R5- and X4-tropic HIV-1. We performed in vitro infections of MMCs and PBMCs with R5- and X4-tropic HIV-1, engineered to express murine CD24 on the infected cell's surface, allowing for quantification of HIV-infected cells and their phenotypic characterization. A greater percentage of MMCs than PBMCs are infected by both R5- and X4-tropic HIV-1. Significant differences exist in terms of chemokine receptor expression in the blood and gastrointestinal mucosa; mucosal cells are predominantly CCR5(+) CXCR4(+), while these cells make up less than 20% of the peripheral blood cells. It is this cell population that is most susceptible to infection with both R5- and X4-tropic HIV-1 in both compartments. Regardless of whether viral isolates were derived from the blood or mucosa of HIV-1-infected patients, HIV-1 p24 production was greater in MMCs than in PBMCs. Further, the chemokine receptor tropism of these patient-derived viral isolates did not differ between compartments. We conclude that, based on these findings, the gastrointestinal mucosa represents a favored target for HIV-1, in part due to its large population of CXCR4(+) CCR5(+) target cells and not to differences in the virus that it contains.

HIV-related diarrhea is multifactorial and fat malabsorption is commonly present, independent of HAART.

OBJECTIVE: Highly active antiretroviral therapy (HAART) has significantly decreased the incidence of infectious diarrhea affecting HIV-infected patients. Still, diarrhea remains a common symptom in HIV. We sought to determine the incidence of fat malabsorption as a cause of diarrhea in HIV patients receiving non-HAART (nucleoside analog only) and HAART (protease inhibitor-containing) antiretroviral regimens. METHODS: From June, 1995, to April, 1999, 88 HlV-infected patients underwent evaluation for diarrhea, which included endoscopy. We examined the incidence of fat malabsorption with a 24-h stool collection for fecal fat in a cohort of these patients (N = 33). Patients were divided into two groups, those receiving protease inhibitor-containing HAART and those receiving less intensive, nucleoside analog-only, non-HAART regimens. RESULTS: Thirty of 33 patients (90.9%) had fat malabsorption. Twenty of 21 patients not receiving HAART (95.2%) had fat malabsorption with a mean of 34 +/- 38 g of stool fat and a mean stool weight of 797 +/- 454 g. Ten of 12 patients receiving HAART (83.3%) had fat malabsorption with a mean of 46 +/- 86 g of stool fat and a mean stool weight of 800 +/- 647 g. Stool weight correlated with the degree of fat malabsorption (R = 0.77). CONCLUSION: Fat malabsorption represents a commonly undiagnosed entity in HIV-infected patients with diarrhea, whether or not they are receiving HAART therapy. Fecal fat determination should be considered a routine part of the diagnostic workup of HIV-infected patients experiencing diarrhea.

Sensitive and reproducible quantitation of mucosal HIV-1 RNA and DNA viral burden in patients with detectable and undetectable plasma viral HIV-1 RNA using endoscopic biopsies.

Mucosal tissue is the main portal of entry for HIV-1 infection and, in macaques, has been demonstrated to be a significant compartment for viral replication and CD4+ T lymphocyte depletion. Quantitating tissue viral burden in addition to plasma viral load provides insights into HIV-1 pathogenesis and an additional means to gauge antiretroviral response. The aim of this study was to develop reliable, reproducible, and sensitive assays to quantitate tissue viral burden of HIV-1 RNA and DNA using 1-3 endoscopically acquired, rectosigmoid biopsies. Total DNA and RNA were simultaneously extracted following homogenization from the same tissue samples. Quantitative polymerase chain reaction (PCR) assay in the HIV-1 LTR region was used to detect viral DNA and RT-PCR for viral RNA. It was determined that HIV-1 RNA and DNA can be reproducibly quantified from a single rectosigmoid biopsy with minimal intra-assay or intra-patient variability. These results reflect high recovery of extracted nucleic acids with calculated results accurately reflecting in vivo levels. The techniques outlined differ from currently available approaches by incorporating control standards to identify loss or degradation of RNA and DNA from acquisition through the in vitro assay and permit extraction with high yields of RNA and DNA from the same tissue sample.

Despite high concordance, distinct mutational and phenotypic drug resistance profiles in human immunodeficiency virus type 1 RNA are observed in gastrointestinal mucosal biopsy specimens and peripheral blood mononuclear cells compared with plasma.

The gastrointestinal mucosa is a major lymphoid tissue reservoir for human immunodeficiency virus (HIV) replication. Genotypic and phenotypic resistance patterns of HIV type 1 (HIV-1) RNA isolated from colonic mucosa were compared with those from the plasma and peripheral blood mononuclear cells (PBMC) of 7 patients. Genotyping was performed using full-sequence analysis, and phenotyping was performed using a recombinant virus assay. Mutations in the reverse-transcriptase (kappa=.84) and protease (kappa=.73) genes were highly concordant among compartments. Similarly, phenotypic resistance patterns were highly concordant among compartments (intraclass correlation coefficient,.91). In 5 instances among 3 patients, a different genotypic result was observed between plasma and the other tissue compartments. Mixtures of wild-type and mutated HIV-1 RNA were present in the mucosa and PBMC but not in the plasma. Despite significant concordance among compartments, mucosal- and PBMC-derived viral RNA showed instances of discordance with plasma-derived virus that may suggest compartmentalization of virus.

Gastrointestinal mucosal biopsy in HIV disease and AIDS.

The role of the gastroenterologist as consultant for patients with HIV infection is reviewed, with a particular focus on when endoscopy with biopsy may be helpful in the diagnostic evaluation. Suggestions on where to biopsy, how to collect samples, and what pathologies might be anticipated are included. In the clinical setting of new antiviral therapies, there has been a dramatic change in the etiologic factors for common presentations such as diarrhea. A review of suspect infections and malignancies is included.

Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue.

OBJECTIVE: To examine compartmental differences in co-receptor expression on CD4 lymphocytes between blood and gut using endoscopic biopsies. DESIGN: Mucosal and peripheral CD4 T cells from healthy controls were compared for co-receptor expression and vulnerability to infection by HIV-1. METHODS: Expression of CCR5 and CXCR4 was quantified by flow cytometry on isolated mucosal CD4 lymphocytes obtained from endoscopic biopsies and blood from healthy controls. Vulnerability to in vitro infection by both R5 and X4 strains was assessed by measuring p24. RESULTS: Biopsies yielded sufficient lymphocytes for flow cytometric characterization and infectivity studies. The percentage of mucosal CD4 T lymphocytes that expressed CCR5 and the per cell expression of CCR5 were both significantly increased compared with that in peripheral blood CD4 T lymphocytes. CXCR4 was expressed on the majority of CD4 lymphocytes in both compartments. In vitro infection of mucosal mononuclear cells supported greater viral replication of both R5 and X4 strains than peripheral blood mononuclear cells. CONCLUSIONS: Enhanced expression of CXCR4 and CCR5 on CD4 lymphocytes in normal intestinal mucosa predicts increased vulnerability to infection by both R5 and X4 HIV-1. Endoscopic biopsies provide a useful mucosal tissue sampling technique to identify compartmental immunologic differences that may be exploited by HIV-1 in establishing initial mucosal infection.

Perceptual responses in patients with inflammatory and functional bowel disease.

BACKGROUND AND AIMS: Enhanced visceral sensitivity following a transient inflammatory process in the gut has been postulated as an aetiological mechanism of irritable bowel syndrome (IBS). In this study we compared perceptual responses to rectosigmoid distension in patients with mild chronic inflammation of the rectum (ulcerative colitis (UC)) and patients without mucosal inflammation (IBS) to determine if chronic low grade mucosal inflammation may be a plausible explanation for rectosigmoid hypersensitivity reported in both IBS and UC patients. METHODS: UC disease activity was quantified using activity index scores. Perception thresholds for discomfort during rectosigmoid distension were compared between 11 UC patients with quiescent or mild disease activity, 18 IBS patients, and 13 healthy controls. RESULTS: Although UC activity index scores negatively correlated with perceptual thresholds for discomfort (r=-0.76, p=0.016), UC patients had higher discomfort thresholds compared with IBS patients and controls before (p=0.02) and after (p<0.001) a noxious sigmoid conditioning stimulus. CONCLUSIONS: Rectal perception was attenuated in UC but enhanced in IBS. In chronic mild inflammation, activation of antinociceptive mechanisms may prevent the development of visceral hyperalgesia. Low grade mucosal inflammation alone is unlikely to be responsible for symptoms in functional gastrointestinal disorders.

Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects.

We have genetically engineered CD4(+) and CD8(+) T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4zeta, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (zeta) chain of the T-cell receptor (which mediates T-cell activation). Twenty-four HIV-positive subjects received a single infusion of 2 to 3 x 10(10) autologous CD4zeta-modified CD4(+) and CD8(+) T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/microL and viral loads of at least 1000 copies/mL at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks. CD4zeta was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue-associated HIV RNA was observed for at least 14 days, suggesting compartmental antiviral activity of CD4zeta T cells. CD4(+) counts increased by 73/microL at 8 weeks in the group receiving IL-2. There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function.

Socially inhibited individuals show heightened DTH response during intense social engagement.

To determine whether altered cellular immune response might mediate the increased health risks associated with social inhibition, we examined delayed type hypersensitivity (DTH) responses in 36 adults under conditions of low and high intensity social engagement. Participants come from a study of psychological factors in functional bowel disease and fibromyalgia. Under high engagement conditions, socially inhibited individuals showed significantly increased induration in response to intradermal tetanus toxoid. Under low engagement conditions, these individuals showed less pronounced DTH responses that did not differ in magnitude from those of uninhibited individuals. This pattern of results was found using two different measures of social inhibition and was independent of social inhibition's definition as a continuously distributed trait vs a discrete category. These data are consistent with the general hypothesis that social inhibition represents a predisposition to physiologic hyperresponsiveness that requires an exogenous social trigger for expression.

An international survey of the use and attitudes regarding alternative medicine by patients with inflammatory bowel disease.

OBJECTIVE: There is a perception of increasing and widespread use of alternative medicine for inflammatory bowel disease (IBD). We assessed the usage of alternative therapies among patients with IBD, whether there were similar or contrasting variables that were predictive of such use, and contrasted the use in four different centers in North America and Europe. METHODS: Patients in four IBD centers completed a self-administered questionnaire regarding alternative medicine. The centers were in Cork, Los Angeles, Stockholm, and Winnipeg. Patient demographics, the use of 18 types of alternative medicine, and attitudes towards alternative and conventional medicine were compared. A multiple logistic regression analysis was used. RESULTS: Fifty-one percent of 289 patients used some form of alternative medicine. The percentages of use by site were Cork = 31%, Los Angeles = 68%, Stockholm = 32%, and Winnipeg = 57%. The six most commonly used therapies in descending order were: exercise (28%), prayer (18%), counseling (13%), massage (11%), chiropractic (11%), and relaxation (10%). Only 7% used acupuncture or homeopathy and 5% used herbal medicine. The highest odds ratios (confidence intervals [CIs]) for using any form of alternative medicine were associated with: being single 3.1 (1.7-5.7), Los Angeles patient 4.4 (2.3-8.3), Winnipeg patient 2.7 (1.3-5.9), and an increase of alternative medicine use of 2.7% for every M.D. visit (CI, 2-11%/visit). The patient age, gender, disease diagnosis, or duration of disease were not predictive of any type of alternative medicine use. Regarding attitudes, respondents from Cork were most favorable toward alternative medicine use and least favorable toward conventional medicine. Based on attitudes, subjects were more likely to use alternative medicine if they were not satisfied with conventional therapy, viewed hospitals as dangerous places, thought that alternative medicine practitioners should have a role in hospitals, and felt their medical situation was hopeless. CONCLUSIONS: Fifty-one percent of respondents used some form of alternative medicine. The use was greater among the North American patients than the European ones. Respondents were more likely to use alternative medicine if they were single, in a higher income bracket, and an urban dweller.

Stress and mind-body impact on the course of inflammatory bowel diseases.

At present, the medical management of inflammatory bowel diseases (IBD) including Crohn's disease and ulcerative colitis, are focused on topical, locally active antiinflammatories and systemic immunosuppressives, which are thought to exert their targeted effects in the gastrointestinal mucosa. There is a paucity of controlled trials assessing the impact of mind, central nervous system (CNS), and neuromodulation on the overly active immune response in the intestinal mucosa. Patients and their physicians have long been aware of a strong association between attitude, stress, and flares of their IBD. Although reports to date remain mostly anecdotal, the degree to which mind-body influences and stress impact levels of local inflammation deserves closer attention with the aim of identifying contributing mechanisms, which may highlight new therapeutic interventions, as well as assist in identifying particular subsets of patients that may respond to novel forms of adjunctive treatments for IBD, including hypnosis, meditation, neuropeptide receptor modulation, and cortisol-releasing factor (CRF) modulation.

Neuroimmunomodulation in inflammatory bowel disease. How far from "bench" to "bedside"?

The chronic inflammatory bowel diseases (BID), Crohn's disease and ulcerative colitis, are characterized by recurrent periods of inflammation and tissue destruction. The clinical course is influenced by genetics, environmental factors, and the immune system. Recent insights (bench trials) benefiting from advances in genetic engineering and molecular biology have contributed to clinical care (bedside) in terms of actual or potential therapies. Does the neuroendocrine system significantly modify disease activity? Although conceptually appealing, evidence remains circumstantial. Compelling anecdotal reports exist that "stress" affects disease activity in terms of the frequency and severity of IBD flares (bedside), but the mechanisms underlying these observations are unknown. Evidence that neuroendocrine factors play a significant role in immunomodulation is progressing (bench). (i) Trinitrobenzene sulfonic acid (TNB)-induced colitis, although similar in unstressed Fisher and Lewis rats, shows marked worsening in stressed Lewis rats. (ii) Early studies of rectal pain perception suggest there are specific differences in neuroimaging studies (PET scans) in IBD patients compared to controls. (iii) Levels of substance P (SP) and its receptor are altered. (iv) Preliminary clinical studies with SP receptor antagonists show a trend toward improvement. (v) Importantly, the placebo response in clinical trials is as high as 45%. Evidence that neuroendocrine systems significantly modulate local inflammation is rapidly accumulating (bench), which will facilitate enhanced coordination of clinically relevant therapies (bedside).

Localization of human intestinal defensin 5 in Paneth cell granules.

Antibiotic peptides of higher animals include the defensins, first discovered in phagocytic cells but recently also found to be produced by epithelial cells. We biosynthesized recombinant human intestinal defensin 5 (rHD-5) using the baculovirus-insect cell expression system. Since insect cells process defensin incompletely and secrete the precursor proHD-5, we substituted a methionine for an alanine at a likely processing site to allow selective chemical cleavage with cyanogen bromide, and rHD-5 was used to elicit polyclonal antibodies. By the immunoperoxidase-staining technique, the antibodies selectively stained Paneth cells of the normal adult small intestine. Immunogold electron microscopy further localized HD-5 to the Paneth cell secretory granules. Since some defensins exert activity cytotoxic to mammalian cells, we assayed the effect of rHD-5 on the human intestinal cell lines Caco2 and Int407. proHD-5 did not exert cytotoxic activity, and rHD-5 showed only minimal activity against Int407 and was inert against Caco2. Since Paneth cells release their granules adjacent to the mitotic cells of the intestinal crypts, HD could protect this cell population against invasion and parasitization by microbes.

Quantification of the placebo response in ulcerative colitis.

BACKGROUND & AIMS: There is consistently a measurable benefit noted among placebo users in treatment trials of ulcerative colitis (UC). The aim of this study was to define the placebo response in active UC and identify study features that influence the placebo response. METHODS: MEDLINE database was searched for placebo-controlled treatment studies of active UC. Data extraction was performed by two reviewers, and one separate investigator reviewed all trials and data extraction before data tabulation. Placebo remission and benefit rates were determined for clinical, endoscopic, and histological outcomes. Synthesis analysis on the weighted proportions from the different studies explored the placebo response as it related to eight study variables. RESULTS: Thirty-eight of 44 studies identified were included in the analysis. The clinical remission rate was 9.1% (confidence interval [CI], 6.6-11.6) and the benefit rate was 26.7% (CI, 24.1-29.2). Similar rates were observed endoscopically and histologically. The number of study visits (< or =3 vs. >3) modified placebo response as assessed by clinical benefit (P = 0.05), endoscopic remission (P = 0.02), and histological remission (P = 0.04). Other study variables were not significant placebo response modifiers. CONCLUSIONS: In trials of active UC, the placebo remission rate is approximately 10% and the placebo benefit rate is approximately 30%. These rates are consistent regardless of assessment end point. The placebo response is greater in trials with more frequent study visits (more than three).

Mucosal substance P receptor expression in HIV infection and inflammatory bowel disease.

Gastrointestinal (GI) disease is a common manifestation of HIV infection. Symptoms may result from the acquisition of intestinal infection, but in certain cases functional and mucosal abnormality may result from mucosal HIV infection. The pathogenesis of HIV enteropathy is poorly understood, but a range of neuroenteric disturbances has been described including a reduction in mucosal substance P (SP). Inflammatory bowel disease (IBD) is a generic term used to describe two major clinical entities; Crohn's disease (CD) and ulcerative colitis (UC). Dysregulation of mucosal neuropeptide expression has been implicated in the pathogenesis of CD and UC. Mucosal SP expression has been variously described as increased, normal or reduced in intestinal tissue from patients with IBD. In contrast, uniform increases in mucosal SP receptor (SPR) have been described in patients with IBD using quantitative autoradiography. The purpose of this study was to characterize intestinal mucosal SPR mRNA expression in control, HIV and IBD patients using semiquantitative reverse transcription PCR. Intestinal tissue was obtained during diagnostic colonoscopy from 7 control, 9 HIV-infected and 28 (12 CD and 16 UC) IBD patients. RNA was isolated from the tissue biopsies, reverse transcribed and amplified with primers specific for SPR. SPR mRNA expression was detected in 7/7 (100%) of control, 2/9 (22%) of HIV-infected, 12/12 (100%) of CD and 11/16 (69%) of UC intestinal biopsies. These data demonstrate that SPR mRNA expression is significantly reduced in patients with HIV infection. Reduced mucosal SPR expression may contribute to the mucosal abnormality, altered intestinal motility and GI symptoms associated with HIV infection.

A randomized, placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory bowel disease: a pilot study.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have a high prevalence of osteoporosis. A number of studies have found that corticosteroid use is associated with the development of osteoporosis in these patients. Calcium supplementation may be of benefit in corticosteroid-induced osteoporosis and calcium may be a nutrient that patients with IBD lack. AIM: To test the benefit of calcium supplementation on bone density in a pilot study over a 1-year period, in a group of corticosteroid-using patients with IBD, in a randomized, double-blind, placebo-controlled treatment study. METHODS: Corticosteroid-using patients with IBD including males over the age of 18 years and premenopausal females, were randomized to receive either calcium carbonate 1000 mg plus vitamin D 250 IU (Oscal) or an identically matched placebo. Dual energy X-ray absorptiometry measurements of bone density were obtained at entry and at 1 year. At entry, and every 3 months thereafter, serum was collected for the measurement of haemoglobin, biochemistry and bone hormones. Simultaneously a 24-h urine collection was analysed for calcium excretion and creatinine clearance, and a 4-day food record was collected to document dietary calcium and vitamin D ingestion. RESULTS: We found a high prevalence of moderately severe decreased bone density in corticosteroid-using patients with IBD. The dose of prednisone in the year prior to study entry was inversely correlated with bone density at the hip (R = -0.67, P = 0.004). At study entry serum osteocalcin was inversely correlated with corticosteroid dose in the year prior to the study (R = -0.64, P = 0.02) and at study end, directly correlated with the percentage change in spine bone density (R = 0.59, P = 0.01). The dietary calcium intake of these patients was close to the current RDA (recommended daily intake) for premenopausal, post-adolescent adults. Calcium supplementation with small extra doses of vitamin D conferred no obvious benefit to bone density at the end of 1 year. There was no correlation between oral calcium ingestion and bone mass measurements. Both the treatment and placebo groups' bone density remained relatively stable at 1 year, suggesting that bone loss in corticosteroid-using patients may peak early into the use of the corticosteroids. CONCLUSIONS: Calcium supplementation (1000 mg/day) conferred no significant benefit to bone density at 1 year in patients with corticosteroid-using IBD patients with osteoporosis. Future investigations should explore other therapeutic avenues that may have greater effects on increasing bone density in patients who already have considerable osteoporosis.

Chylothorax due to Mycobacterium tuberculosis.

Chylothorax in an adult is a rare cause of pleural effusion. Mycobacterium tuberculosis may cause chylous effusion, but usually in association with extensive intrapulmonary involvement. A case of chylothorax is presented in which M tuberculosis was isolated from the pleural fluid and was the only intrathoracic manifestation of tuberculosis.