Search

Medicaid is an important source of supplemental health care coverage for low-income seniors, yet little is known about the effect of state policy on Medicaid enrollment by eligible elderly. Data from a nationally representative survey were used to examine Medicaid enrollment by elderly, low-income Medicare beneficiaries living in states that liberalize or restrict Medicaid eligibility criteria using the 1986 Omnibus Budget Reconciliation Act or provision 209(b) of the 1972 Social Security Act Amendment, respectively. Controlling for demographics and health status, residence in states applying these laws was significantly, though modestly, associated with Medicaid enrollment. Additionally, 73% of eligible elderly Medicare beneficiaries were not enrolled in Medicaid, and most have serious chronic health problems. These findings suggest that a significant number of eligible elderly are not enrolled in Medicaid and that liberalizing or tightening Medicaid eligibility criteria can have an impact on Medicaid enrollment by low-income elderly patients.

Dysregulated innate immune responses to commensal bacteria contribute to the development of inflammatory bowel disease (IBD). TLR4 is overexpressed in the intestinal mucosa of IBD patients and may contribute to uncontrolled inflammation. However, TLR4 is also an important mediator of intestinal repair. The aim of this study is to examine the effect of a TLR4 antagonist on inflammation and intestinal repair in two murine models of IBD. Colitis was induced in C57BL/6J mice with dextran sodium sulfate (DSS) or by transferring CD45RbhiT cells into RAG1−/− mice. An antibody (Ab) against the TLR4/MD-2 complex or isotype control Ab was administered intraperitoneally during DSS treatment, recovery from DSS colitis, or induction of colitis in RAG1−/− mice. Colitis severity was assessed by disease activity index (DAI) and histology. The effect of the Ab on the inflammatory infiltrate was determined by cell isolation and immunohistochemistry. Mucosal expression of inflammatory mediators was analyzed by real-time PCR and ELISA. Blocking TLR4 at the beginning of DSS administration delayed the development of colitis with significantly lower DAI scores. Anti-TLR4 Ab treatment decreased macrophage and dendritic cell infiltrate and reduced mucosal expression of CCL2, CCL20, TNF-α, and IL-6. Anti-TLR4 Ab treatment during recovery from DSS colitis resulted in defective mucosal healing with lower expression of COX-2, PGE2, and amphiregulin. In contrast, TLR4 blockade had minimal efficacy in ameliorating inflammation in the adoptive transfer model of chronic colitis. Our findings suggest that anti-TLR4 therapy may decrease inflammation in IBD but may also interfere with colonic mucosal healing.

Background Early readmissions are important indicators of quality of care. Limited data exist describing hospital readmissions in ulcerative colitis (UC). The aim of this study was to describe unplanned, 30-day readmissions among adult UC patients and to assess readmission predictors. Methods We analyzed the 2013 United States National Readmission Database and identified UC admissions using administrative codes in patients from 18 to 80 years of age. Our primary outcome was a 30-day, unplanned readmission rate. We used chi-square tests, t tests, and Wilcoxon rank-sum tests for descriptive analyses and survey logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations with readmissions adjusting for confounders. Results Among 26,094 hospitalizations with a primary UC diagnosis, there were 2757 (10.6%) 30-day, unplanned readmissions. The most common readmission diagnoses were reasons related to UC (58%), complications of surgical procedures/medical care (5.5%), Clostridium difficile (4.8%), and septicemia (4.3%). In multivariable analysis, length of stay ≥7 days (aOR 1.54, 95% CI, 1.24-1.90), not having an endoscopy (aOR 1.20, 95% CI, 1.04-1.38), and depression (aOR 1.40, 95% CI, 1.16-1.66) were significantly associated with readmission. 58.2% of readmissions had at least one of these factors. Patients were also less likely to be admitted if they were women or had self-pay payer status. Having a colectomy did not significantly increase readmissions (aOR 1.14, 95% CI, 0.86-1.52). Conclusions On a national level, 1 in 10 hospitalizations for UC was followed by an unplanned readmission within 30 days. Not having an endoscopy on the index hospitalization and depression were independently associated with readmissions. Further studies should examine if strategies that address these predictors can decrease readmissions.

The objective of this study was to perform a meta-analysis investigating antibiotic exposure as a risk factor for developing inflammatory bowel disease (IBD).A literature search using Medline, Embase, and Cochrane databases was performed to identify studies providing data on the association between antibiotic use and newly diagnosed IBD. Included studies reported Crohn's disease (CD), ulcerative colitis (UC), or a composite of both (IBD) as the primary outcome and evaluated antibiotic exposure before being diagnosed with IBD. A random-effects meta-analysis was conducted to determine overall pooled estimates and 95% confidence intervals (CIs).A total of 11 observational studies (8 case-control and 3 cohort) including 7,208 patients diagnosed with IBD were analyzed. The pooled odds ratio (OR) for IBD among patients exposed to any antibiotic was 1.57 (95% CI 1.27-1.94). Antibiotic exposure was significantly associated with CD (OR 1.74, 95% CI 1.35-2.23) but was not significant for UC (OR 1.08, 95% CI 0.91-1.27). Exposure to antibiotics most markedly increased the risk of CD in children (OR 2.75, 95% CI 1.72-4.38). All antibiotics were associated with IBD, with the exception of penicillin. Exposure to metronidazole (OR 5.01, 95% CI 1.65-15.25) or fluoroquinolones (OR 1.79, 95% CI 1.03-3.12) was most strongly associated with new-onset IBD.Exposure to antibiotics appears to increase the odds of being newly diagnosed with CD but not UC. This risk is most marked in children diagnosed with CD.

Corrigendum: Statins Associated with Decreased Risk of New Onset Inflammatory Bowel Disease

Chronic intestinal inflammation culminates in cancer and a link to Toll-like receptor-4 (TLR4) has been suggested by our observation that TLR4 deficiency prevents colitis-associated neoplasia. In the current study we address the effect of the aberrant activation of epithelial TLR4 on induction of colitis and colitis-associated tumor development. We take a translational approach to address the consequences of increased TLR signaling in the intestinal mucosa.Mice transgenic for a constitutively active TLR4 under the intestine-specific villin promoter (villin-TLR4 mice) were treated with dextran sodium sulfate (DSS) for acute colitis and azoxymethane (AOM)-DSS TLR4 expression was analyzed by immunohistochemistry in colonic tissue from patients with ulcerative colitis (UC) and UC-associated cancer. The effect of an antagonist TLR4 antibody (Ab) was tested in prevention of colitis-associated neoplasia in the AOM-DSS model.Villin-TLR4 mice were highly susceptible to both acute colitis and colitis-associated neoplasia. Villin-TLR4 mice had increased epithelial expression of COX-2 and mucosal PGE₂ production at baseline. Increased severity of colitis in villin-TLR4 mice was characterized by enhanced expression of inflammatory mediators and increased neutrophilic infiltration. In human UC samples, TLR4 expression was upregulated in almost all colitis-associated cancer and progressively increased with grade of dysplasia. As a proof of principle, a TLR4/MD-2 antagonist antibody inhibited colitis-associated neoplasia in the mouse model.Our results show that regulation of TLRs can affect the outcome of both acute colitis and its consequences, cancer. Targeting TLR4 and other TLRs may ultimately play a role in prevention or treatment of colitis-associated cancer.

BackgroundWe have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE2and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE2is the central factor downstream of TLR4 signaling that promotes intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE2in TLR4-/- mice to see if PGE2bypasses the protection from colitis-associated tumorigenesis.MethodMouse colitis-associated neoplasia was induced by azoxymethane (AOM) injection followed by two cycles of dextran sodium sulfate (DSS) treatment. Two different doses of PGE2(high dose group, 200 μg, n = 8; and low dose group, 100 μg, n = 6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE2during DSS treatment (200 μg, n = 5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.ResultsIn control mice treated with PBS, the average number of tumors was greater in WT mice (n = 13) than in TLR4-/- mice (n = 7). High dose but not low dose PGE2treatment caused an increase in epithelial proliferation. 28.6% of PBS-treated TLR4-/- mice developed dysplasia (tumors/animal: 0.4 ± 0.2). By contrast, 75.0% (tumors/animal: 1.5 ± 1.2, P < 0.05) of the high dose group and 33.3% (tumors/animal: 0.3 ± 0.5) of the low dose group developed dysplasia in TLR4-/- mice. Tumor size was also increased by high dose PGE2treatment. Endogenous prostanoid synthesis was differentially affected by PGE2treatment during acute and recovery phases of colitis. Exogenous administration of PGE2increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE2treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.ConclusionsThese results highlight the importance of PGE2as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.

Epiregulin (EPI) and amphiregulin (AR) are epidermal growth factor receptor (EGFR) ligands implicated in mucosal repair and tumorigenesis. We have shown that Toll-like receptor 4 (TLR4) induces intestinal epithelial cell (IEC) proliferation by activating EGFR through AR expression. We examined whether TLR4 differentially regulates expression of EGFR ligands in response to mucosal injury. The human IEC line SW480 was examined expression of EGFR ligands, EGFR phosphorylation, and proliferation in response to lipopolysaccharide (LPS). Small-interfering RNA (siRNA) was used to block TLR4. Neutralizing antibodies to EGFR ligands were used to examine inhibition of LPS-dependent EGFR activation. Acute colitis and recovery were examined in the mice given 2.5% dextran sodium sulfate (DSS). Colonic secretion of EPI and AR was analyzed by enzyme-linked immunosorbent assay. LPS selectively induces EPI and AR but not other EGFR ligands. LPS induced early EPI mRNA expression between 30 min and 24 h. The neutralizing antibodies to EPI and AR prevented activation of EGFR by LPS. LPS induces IEC proliferation (200%, P=0.01) in 24 h but blocking EPI and AR significantly decreased proliferation. In vivo, mucosal EPI and AR expression are significantly decreased in TLR4(-/-) mice (P=0.02) compared to wild-type mice during acute colitis. EPI and AR exhibit different kinetics in response to mucosal damage: EPI expression is upregulated acutely at day 7 of DSS, but falls during recovery at day 14. By contrast, a sustained upregulation of AR expression is seen during mucosal injury and repair. We show that TLR4 regulates EPI and AR expression and that both these EGFR ligands are necessary for optimal proliferation of IEC. The diverse kinetics of EPI and AR expression suggest that they function in distinct roles with respect to acute injury vs repair. Our results highlight the role of bacterial sensing for IEC homeostasis and may lead to targeted therapy for mucosal healing and prevention of tumorigenesis.

The human intestine has evolved in the presence of a diverse array of luminal microorganisms. In order to maintain intestinal homeostasis, mucosal immune responses to theses microorganisms must be tightly regulated. The intestine needs to be able to respond to pathogenic organisms while at the same time maintain tolerance to normal commensal flora. Toll-like receptors (TLRs) play an important role in this delicate balance. TLRs are transmembrane noncatalytic receptor proteins that induce activation of innate and adaptive immune responses to microorganisms by recognizing structurally conserved molecular patterns of microbes. Expression of TLRs by intestinal epithelial cell is normally down-regulated to maintain immune tolerance to the luminal microorganisms.One of the challenges of TLR research in the human intestine is that it is difficult for many experimental methods to detect very low expression of TLRs within the intestinal mucosa. Quantitative methods such as PCR are limited in their ability to detect TLR expression by specific cell types within a tissue sample, which can be important when studying the contribution of TLR signaling to pathological conditions. In this regard, immunohistochemistry (IHC) is advantageous in that one can visualize the distribution and localization of target proteins within both normal and pathologic parts of a given tissue sample. We found that a subset of human colorectal cancers over-express TLR4 by means of immunofluorescence (IF) and IHC methods. Localization of TLR4 within cancer tissue often appears to be patchy, making IHC an appropriate way to examine these changes. We will describe our current techniques to detect TLR4 in paraffin-embedded human large intestine sections. Establishing a practical IHC technique that may provide consistent results between laboratories will significantly enhance understanding of the role of TLRs in human intestinal health and disease.

Background: Prior studies suggest that medication exposures may be associated with new onset inflammatory bowel disease (IBD). The aim of this study was to determine the effect of specific medication classes on the risk of new onset IBD in a large United States health claims database. Methods: We conducted a matched case-control study with a national medical claims and pharmacy database from Source Healthcare Analytics LLC (SHA). This database included any patient age 18 or older with ICD-9 code 555.x for Crohn's disease (CD) or 556.x for ulcerative colitis (UC) between January 2008 and December 2012. Each IBD patient had up to 10 age, gender, race, and state matched controls using propensity scoring. Controls had no ICD-9 codes for CD, UC or IBD-associated diseases and no prescriptions for IBD-related medications. 12,544,273 patients were included in the database. New onset IBD patients were defined as having at least 3 separate CD or UC ICD-9 codes and at least 1 year with no IBD-related ICD-9 or prescription prior to index IBD ICD-9. 92,933 new IBD cases were matched with 929,330 controls. For this first analysis, we examined drug classes previously shown to modify established IBD or affect risk of new onset IBD. Drug class was defined by Uniform System of Classification (USC) level 5 code. To account for diagnostic delay, exposures within 6 months of index ICD-9 were excluded. Conditional logistic regression was used to identify medications associated with new onset IBD, CD, and UC. The Benjamini-Hochberg correction was applied to control the type I error rate at the 5% significance level. Results: Estimated odds ratios (OR) and 95% confidence intervals (CI) for new onset IBD, CD, and UC for medication classes of interest are shown in Table 1. Most classes of antibiotics were associated with an increased risk of IBD. The most strongly associated antibiotic classes were trichomonacides which include metronidazole and tinidazole and a USC 5 class which includes metronidazole as well as imipenam, ertapenam, polymyxin, and vancomycin. Prescriptions with estrogen alone were associated with an increased risk of IBD. However, progesterone or estrogen-progesterone combinations either had no association or demonstrated a protective effect against new IBD. Acne agents that do not contain anti-infectives, including isotretinoin, benzoyl peroxide, salicylic acid and tretinoin, did not increase the risk of IBD. The strongest protective effect against new onset IBD, and especially CD, was seen with statins. Conclusions: To our knowledge, this is the first study to suggest a protective effect of statins against new onset IBD. We also replicate prior findings that most antibiotics and estrogens are associated with new IBD. The acne medication class containing isotretinoin did not increase the risk of IBD. These findings should be confirmed in future studies. Table 1: Representative list of medication classes of interest with ORs for new onset IBD, CD, and UC

Background & Aims: Recently, the role of stromal cells such as inflammatory cells in tumor development has received much attention. Nuclear factor kappa B (NF-κB) is an important transcription factor in various biological processes and is involved in carcinogenesis. The exact mechanism how NF-κB activation contributes to inflammation-associated carcinogenesis is not clear.We conducted this study to investigate how colon cancer cells induced inflammatory response to link tumor growth. Methods: Mouse bone marrow macrophages (BMDMs) (wildtype, IKKβ-/-, TLR2-/-, TLR4-/and MyD88-/-), J774.1 and THP-1 cells were stimulated with the culture supernatant of several colon cancer cell lines. NF-κB activation was evaluated by EMSA, immunoblot of phosphorylated-IκBα and IκBα. Macrophage invasion assay were performed using chemotaxis chamber. In tumors of subcutaneously transplantation of the cells into nude mice, macrophage infiltration and IL-6 expression which is regulated NFκB activation were evaluated by immunostaining . Results: Six out of 10 (60%) of the supernatants prepared from colon cancer cells activated NF-κB in BMDMs and THP-1 cells (NF-κB activating colon cancer cells). This activation was observed in macrophages from wild-type and TLR4-/-, but not in TLR2-/-, MyD88-/and IKKβ-/-, suggesting that the activation is dependent on TLR2, MyD88 and IKKβ. Supernatant from NF-κB activating colon cancer cells also induces chemotaxis. In transplanted tumor tissue, macrophages accumulation and IL-6 expression were markedly increased in tumors of NF-κB activating colon cancer cells compared with non-activating ones. In addition, NF-κB activating colon cancer cells grewmore rapidly and aggressively than non-activating ones inmice. Surprisingly, NF-κB activating colon cancer cells had constitutive NF-κB activity. Conclusions: Colon cancer-derived certain factors induce accumulation of macrophages and activate NF-κB in macrophages through TLR2 and MyD88, eventually link tumor growth.

Background We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE 2 and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE 2 is the central factor downstream of TLR4 signaling that promotes intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE 2 in TLR4-/- mice to see if PGE 2 bypasses the protection from colitis-associated tumorigenesis.