Utilization of baclofen in maintenance of alcohol abstinence in patients with alcohol dependence and alcoholic hepatitis with or without cirrhosis.

AIM: To report the efficacy and safety of baclofen in improving clinical state in patients with alcoholic hepatitis. METHOD: Single center, open, retrospective study analyzing the effects of baclofen utilized over 12 months in patients with alcoholic hepatitis with or without cirrhosis and alcohol dependence on these liver parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (Tbili), prothrombin time (PT), international normalized ratio (INR), albumin and Model for End-Stage Liver Disease (MELD) score. RESULTS: Out of 40 patients, 35 were treated with baclofen. On average, baclofen was used for 5.8 months. A significant decrease in the mean AST, ALT, Tbili, INR, PT and MELD score was seen when comparing pre-baclofen use compared with post-baclofen use. Of the 35 patients who were started on baclofen, 34 (97%) remained abstinent. There were no serious adverse events. CONCLUSIONS: Baclofen's safety and efficacy in improving the clinical condition patients with alcoholic liver disease has been supported. Randomized prospective studies with longer duration of baclofen in this population may further optimize its use and corroborate efficacy.

Detemir vs Glargine: Comparison of Inpatient Glycemic Control.

CONTEXT: Hyperglycemia in the hospital setting is associated with increased morbidity and mortality. In an attempt to cut costs, some hospitals implement policies to substitute all glargine orders with detemir. OBJECTIVE: To examine how the substitution of glargine with detemir affects inpatient blood glucose control. METHODS: Medical records were retrospectively analyzed to investigate the effect of a hospital formulary change at a semi-urban underserved hospital that substituted detemir for glargine on a 1:1 dosing basis. The study evaluated blood glucose control from September 6, 2015, to September 5, 2016, before substitution and from September 6, 2016, to September 5, 2017, after the substitution began. Patients were included in the study if they were older than 18 years, received glargine before admission, and had type 1 or 2 diabetes mellitus. Patients were excluded if they were pregnant, did not receive long-acting insulin, or lacked regular blood glucose testing. The medical records were analyzed for mean glucose levels, hypoglycemic events, and short-acting insulin administration amounts. RESULTS: A total of 318 patients met criteria and were included in the retrospective analysis-134 patients received detemir and 184 patients received glargine. The mean glucose levels in the morning were 133.8 mg/dL for patients receiving detemir and 145.8 mg/dL for patients receiving glargine (95% CI, 126.972-140.753; P=.013). The mean blood glucose levels in the afternoon were 171.6 mg/dL for patients receiving detemir and 172.1 mg/dL for patients receiving glargine (95% CI, 162.955-180.344; P=.938). The mean blood glucose levels in the evening were 162.5 mg/dL for patients receiving detemir and 163.3 mg/dL for patients receiving glargine (95% CI, 153.654-171.315; P=.897). The mean blood glucose levels at night were 176.1 mg/dL for patients receiving detemir and 174.7 mg/dL for patients receiving glargine (95% CI, 167.797-184.474; P=.788). No significant difference in sliding scale insulin was required between the patient groups (0.16 U/kg insulin aspart in detemir group vs 0.18 U/kg aspart in glargine; 95% CI, 0.154-0.189; P=.297). There was no significant difference between the patient groups in regard to hypoglycemic events (45% glargine vs 49% detemir; P=.59). CONCLUSION: Substituting detemir for glargine did not adversely affect inpatients' blood glucose control.

Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis.

BACKGROUND: CD4+CD25+ regulatory T cells (TR) can prevent or treat experimental murine colitis but little is known about their potential role in human inflammatory bowel disease (IBD). FOXP3 is a transcription factor that plays a critical role in the development and function of CD4+CD25+ TR. The aim of this study was to examine the presence and functional characteristics of TR cells in colonic lymphoid tissues in patients with ulcerative colitis (UC). METHODS: FOXP3 expression was assessed by flow cytometry, immunohistochemistry, and reverse-transcriptase polymerase chain reaction (RT-PCR). Functional characterization of CD4+CD25+ cells was analyzed by suppression of proliferation and secretion of cytokines by cocultured effector CD4+CD25- T cells. RESULTS: FOXP3 +CD4+ T cells are increased in the lamina propria (LP) of inflamed and noninflamed areas of UC colon compared to normal colon. CD4+CD25+ T cells in UC mesenteric lymph nodes (MLN) express FOXP3 mRNA and protein and suppress the proliferation of autologous MLN CD4+CD25 T cells. The suppressor activity of MLN CD4+CD25+ T cells is cell contact-dependent but cytokine-independent. In addition, CD4+CD25+ T cells potently suppress the production of both Thl (IFN-gamma, IL-2) and Th2 (IL-5, IL-13) cytokines by cocultured CD4+CD25 T cells. FOXP3' cells localized in the T-cell-rich areas of MLN and occasionally present in the follicles. CONCLUSIONS: There is an expansion of FOXP3+CD4+ T cells in mucosal lymphoid tissues in UC. CD4+CD25+ isolated from UC MLN express FOXP3 and display features of TR cells in spite of active mucosal inflammation. These data suggest that their suppressor activity may be abrogated in vivo or they are unable to counterbalance the chronic mucosal inflammation in UC.

Cyclooxygenase-2 deficiency enhances Th2 immune responses and impairs neutrophil recruitment in hepatic ischemia/reperfusion injury.

Cyclooxygenase-2 (COX-2) is a prostanoid-synthesizing enzyme that is critically implicated in a variety of pathophysiological processes. Using a COX-2-deficient mouse model, we present data that suggest that COX-2 has an active role in liver ischemia/reperfusion (I/R) injury. We demonstrate that COX-2-deficient mice had a significant reduction in liver damage after I/R insult. The inability of COX-2(-/-) to elaborate COX-2 products favored a Th2-type response in these mice. COX-2(-/-) livers after I/R injury showed significantly decreased levels of IL-2, as well as IL-12, a cytokine known to have a central role in Th1 effector cell differentiation. Moreover, such livers expressed enhanced levels of the anti-inflammatory cytokine IL-10, shifting the balance in favor of a Th2 response in COX-2-deficient mice. The lack of COX-2 expression resulted in decreased levels of CXCL2, a neutrophil-activating chemokine, reduced infiltration of MMP-9-positive neutrophils, and impaired late macrophage activation in livers after I/R injury. Additionally, Bcl-2 and Bcl-x(L) were normally expressed in COX-2(-/-) livers after injury, whereas respective wild-type controls were almost depleted of these two inhibitors of cell death. In contrast, caspase-3 activation and TUNEL-positive cells were depressed in COX-2(-/-) livers. Therefore, our data support the concept that COX-2 is involved in the pathogenic events occurring in liver I/R injury. The data also suggest that potential valuable therapeutic approaches in liver I/R injury may result from further studies aimed at identifying specific COX-2-derived prostanoid pathways.

Phenotype and effector function of CC chemokine receptor 9-expressing lymphocytes in small intestinal Crohn's disease.

CCL25/CCR9 chemokine ligand/receptor pair has been reported to play an important role in small bowel (SB) immunity and inflammation. We have previously reported an aberrant SB expression of CCL25 in Crohn's disease (CD) and an increased frequency of CCR9(+) T cells in the peripheral blood of patients with SB inflammatory diseases such as CD and celiac disease. In this study, we have characterized the phenotype and effector function of CCR9(+) T cells in mucosal lymphoid tissues in CD. We show that CCR9(+) T cells isolated from mesenteric lymph nodes (MLN) draining CD SB express a more activated phenotype compared with MLN draining normal SB. Stimulation of CCR9(+) T cells isolated from CD SB lamina propria produced more IFN-gamma and IL-17 in response to anti-CD3 or IL-12/IL-18 stimulation compared with those isolated from normal SB. The addition of TL1A to the cytokine combination markedly augmented the secretion of IFN-gamma, but not IL-17, by CD lamina propria CCR9(+) T cells. CCL25 incubation of CD SB lamina propria lymphocytes and MLN lymphocytes increased their adhesion to VCAM-1/Fc in vitro. Finally, the TCRVbeta analysis of CCR9(+) T cells revealed a diverse TCRVbeta repertoire among MLN CCR9(+) T cells in patients with SB CD. Our data indicate that CCR9(+) T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.

Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes.

The TNF-like cytokine TL1A augments IFN-gamma production by anti-CD3 plus anti-CD28 and IL-12/IL-18-stimulated peripheral blood (PB) T cells. However, only a small subset of PB T cells respond to TL1A stimulation with IFN-gamma production. PB CCR9+ T cells represent a small subset of circulating T cells with mucosal T cell characteristics and a Th1/Tr1 cytokine profile. In the current study, we show that TL1A enhanced IFN-gamma production by TCR- or CD2/CD28-stimulated CCR9(+)CD4+ PB T cells. However, TL1A had the most pronounced effect on augmenting IFN-gamma production by IL-12/IL-18-primed CCR9(+)CD4+ PB T cells. TL1A enhanced both the percentage and the mean fluorescence intensity of IFN-gamma in CCR9(+)CD4+ T cells as assessed by intracellular cytokine staining. IL-12 plus IL-18 up-regulated DR3 expression in CCR9(+)CD4+ T cells but had negligible effect on CCR9(-)CD4+ T cells. CCR9(+)CD4+ T cells isolated from the small intestine showed a 37- to 105-fold enhancement of IFN-gamma production when TL1A was added to the IL-12/IL18 cytokine combination. Cell membrane-expressed TL1A was preferentially expressed in CCR9(+)CD4+ PB T cells, and a blocking anti-TL1A mAb inhibited IFN-gamma production by cytokine-primed CCR9(+)CD4+ T cells by approximately 50%. Our data show that the TL1A/DR3 pathway plays a dominant role in the ultimate level of cytokine-induced IFN-gamma production by CCR9+ mucosal and gut-homing PB T cells and could play an important role in Th1-mediated intestinal diseases, such as Crohn's disease, where increased expression of IL-12, IL-18, TL1A, and DR3 converge in the inflamed intestinal mucosa.