A mixture of Lactobacillus plantarum CECT 7315 and CECT 7316 enhances systemic immunity in elderly subjects. A dose-response, double-blind, placebo-controlled, randomized pilot trial.

BACKGROUND & AIM: Immunosenescence can increase morbi-mortality. Lactic acid producing bacteria may improve immunity and reduce morbidity and mortality in the elderly. We aimed to investigate the effects of a mixture of two new probiotic strains of Lactobacillus plantarum--CECT 7315 and 7316--on systemic immunity in elderly. METHODS: 50 institutionalized elderly subjects were randomized, in a double-blind fashion, to receive for 12 weeks 1) 5·10(8) cfu/day of L. plantarum CECT7315/7316 ("low probiotic dose") (n = 13), 2) 5·10(9) cfu/day of the probiotic mixture ("high probiotic dose") (n = 19), or 3) placebo (n = 15). Leukocyte subpopulations, and cytokine levels (IL-1 , IL-10, TGF-ß1) were measured in venous blood at baseline, end of treatment (week 12), and end of follow-up (week 24). Infection and survival rates were recorded. RESULTS: After treatment, high probiotic dose resulted in significant increases in the percentages of activated potentially T-suppressor (CD8+CD25+) and NK (CD56+ CD16+) cells, while low probiotic dose increased activated T-helper lymphocytes (CD4+CD25+), B lymphocytes (CD19+), and antigen presenting cells (HLA-DR+). Also, plasma TGF-ß1 concentration significantly decreased after treatment with both probiotic doses. Most of these changes remained 12 weeks after probiotic discontinuation. Incidence of infections during treatment showed a significant trend to be lower in the high probiotic dose group. In addition, there was a significant trend for mortality to be greater in the placebo group vs. both probiotic groups. CONCLUSIONS: Depending on the dose, L. plantarum CECT7315/7316 have different immune-enhancing effects in elderly subjects. These effects might result in a better clinical outcome.

Clinical outcome of newly diagnosed Crohn's disease: a comparative, retrospective study before and after infliximab availability.

BACKGROUND: Infliximab (IFX) could change the course of Crohn's disease (CD) by reducing steroid use, surgery or prompting earlier introduction of immunomodulators (IMM). AIM: To evaluate the impact of IFX availability on the course of early CD. METHODS: Two cohorts of newly diagnosed CD patients were identified: The first cohort included patients diagnosed from January 1994 to December 1997 and the second from January 2000 to December 2003. All patients were diagnosed, treated and followed up in the same centre until December 1999 (first cohort) or December 2005 (second cohort). Development of disease-related complications, steroid, IMM or IFX requirements and intestinal resections during follow-up were registered. RESULTS: A total of 328 patients were included (146 first cohort, 182 second cohort). A similar proportion of patients in both cohorts received steroids, but steroid exposure resulted significantly more intense in the first cohort (P = 0.001). In the second cohort, 14% of patients received IFX. Thiopurines were used more (P = 0.001) and earlier (P = 0.012) in the second cohort. No differences in surgical requirements or the development of disease-related complications were found. CONCLUSIONS: Following a step-up therapeutic algorithm, IFX availability did not reduce surgical requirements or the development of disease-related complications.

Infliximab safety profile and long-term applicability in inflammatory bowel disease: 9-year experience in clinical practice.

BACKGROUND: Most available data on infliximab therapy come from large, short-term, pivotal RCTs and concerns about long-term safety profile still remain. AIM: To evaluate the long-term safety profile of infliximab in inflammatory bowel disease (IBD) in a clinical practice setting. METHODS: Since 1999, all IBD patients treated with infliximab were registered and clinical outcomes prospectively recorded up to March 2008, loss of follow-up or patient's death. Infliximab regimens and preventive measures were in accordance with the prevalent guidelines or with the manufacturer's recommendations. RESULTS: One hundred fifty-two patients were included (121 Crohn's disease, 24 ulcerative colitis, 7 indeterminate colitis), with a median of 5 infliximab infusions (IQR 3-8) and 87% of patients received at least three infusions. Seventy-nine per cent of them received concomitant immunomodulators and 70% were pre-medicated with hydrocortisone from the first infusion. After a median follow-up of 142 weeks, 13% presented infusion reactions, 13% viral or bacterial infections and two patients developed neoplasia. The mortality rate was 2.6% (four patients). CONCLUSIONS: Infliximab therapy is safe when the recommended preventive measures are implemented, with a rate of serious adverse events less than 10%. No new safety signals were found.

TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort.

OBJECTIVES: Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. METHODS: A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. RESULTS: The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A. CONCLUSIONS: This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

Reduced liver injury in the interleukin-6 knockout mice by chronic carbon tetrachloride administration.

BACKGROUND: Interleukin-6 has been involved in restoration of liver function after partial hepatectomy and toxic liver injury. However, normal liver regeneration in interleukin-6 knockout mice has also been reported. The aim of this work was to investigate the effect of interleukin-6 deficiency on liver injury and its regeneration in a model of long term carbon tetrachloride (CCl4) administration. DESIGN: Serum and whole livers from wild type and interleukin-6 knockout mice treated with carbon tetrachloride (0.25 mL kg(-1)) twice a week were obtained after 4, 6 and 8 weeks (n = 4-6). Sections were assessed for liver regeneration, liver injury and hepatocyte apoptosis whereas sera were assayed for aminotransferase levels. Nuclear extracts and total liver lysates were assayed for transcription factor activation and apoptosis related proteins, respectively. RESULTS: When compared to wild type, interleukin-6 knockout mice showed reduced liver damage scores, lower aminotransferase levels and diminished apoptosis, as well as reduced nuclear factor kappa B activation. Although the level of active protein was lower, activation of signal transducer and activator of transcription 3 still takes place in knockout mice. Furthermore, liver regeneration measured by bromodeoxyuridine incorporation showed no differences between wild type and knockout animals after 6 and 8 weeks of treatment. CONCLUSIONS: Compared to the wild type mice liver regeneration after chronic treatment with carbon tetrachloride proceeds at a slower rate in interleukin-6 deficient mice. However, this low recovery rate is accompanied by a reduction not only in hepatocyte apoptosis, but also in activation of nuclear factor kappa B and liver injury.

Efficacy and safety of short-term adalimumab treatment in patients with active Crohn's disease who lost response or showed intolerance to infliximab: a prospective, open-label, multicentre trial.

BACKGROUND: The use of tumour necrosis factor antagonists has changed the therapeutic approach to Crohn's disease. AIM: To determine response and remission rates associated with the 4-week induction phase of adalimumab treatment in patients with luminal and/or fistulizing Crohn's disease, who have lost response to or become intolerant of infliximab. METHODS: In this multicentre, prospective, open-label, observational, 52-week study, 50 adults received an induction dose of adalimumab (160 mg at baseline followed by 80 mg at week 2). RESULTS: Of the 36 patients with luminal Crohn's disease, 83% achieved clinical response [> or =70-point reduction in the Crohn's Disease Activity Index (CDAI) score] and 42% achieved clinical remission (CDAI score <150) at week 4. Of the 22 patients with fistulizing disease, five (23%) experienced fistula remission (complete closure of all fistulas that were draining at baseline), and nine (41%) experienced fistula improvement (> or =50% decrease in the number of fistulas that were draining at baseline) at week 4. Of the 19 adverse events, most [13 (68%)] were mild, and no serious or infectious adverse events occurred. CONCLUSIONS: Adalimumab may be an effective alternative in patients with luminal and/or fistulizing Crohn's disease who have lost response to or become intolerant of infliximab.

Review article: the intestinal lumen as a therapeutic target in inflammatory bowel disease.

Undigested carbohydrates reaching the colon can act as competitors for epithelial bacterial receptors, making it difficult for noncommensal bacteria to adhere to them. On the contrary, fermentation of these carbohydrates by anaerobic flora produces - among other substrates - butyrate that is involved in numerous important metabolic processes. These include the provision of energy to the colonocytes, the enhancement of sodium and water absorption and the synthesis of mucus and cell membranes. In addition, butyrate inhibits the nuclear translocation of the transcription factor NFkappaB, which exerts a potent anti-inflammatory activity. Clinical experience with probiotics in inflammatory bowel disease (IBD) is controversial. Whereas some probiotic preparations appear to be useful in ulcerative colitis (UC) and pouchitis, most attempts to use probiotics for treating or preventing recurrence in Crohn's disease have failed. It should be pointed out that - unlike in the small bowel - the colon and ileal pouches are well-established microbiological ecosystems with increasing amounts of a wide variety of bacterial strains. These bacterial strains have a high degree of metabolic interaction with luminal nutrients and a greater probability of developing dysbiosis. With this in mind, the rationale for using pre- and probiotics appears to be stronger for colonic IBD (UC or Crohn's colitis) and pouchitis than for IBD mostly involving the small bowel.

European evidence based consensus on the diagnosis and management of Crohn's disease: special situations.

This third section of the European Crohn's and Colitis Organisation (ECCO) Consensus on the management of Crohn's disease concerns postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy. The first section on definitions and diagnosis reports on the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn's disease. The second section on current management addresses treatment of active disease, maintenance of medically induced remission, and surgery of Crohn's disease.

Clinical evolution of luminal and perianal Crohn's disease after inducing remission with infliximab: how long should patients be treated?

BACKGROUND: Few data are available regarding the evolution of Crohn's disease after discontinuing a successful course of infliximab. AIM: To evaluate clinical outcome of Crohn's disease after induction of remission with three infliximab infusions (luminal disease) and after maintenance of remission with 1-year course of infliximab every 8 weeks (luminal and perianal). METHODS: Twenty-three patients with active luminal Crohn's disease who responded to three infusions of infliximab (0, 2, and 6 weeks), and 23 patients with sustained response to infliximab every 8 weeks during 1 year, were included. Patients were followed-up until relapse or for at least 6 months after infliximab discontinuation. Clinical outcomes and factors associated to relapse were evaluated. RESULTS: In luminal Crohn's disease, a three-infusion infliximab regimen achieved a sustained response in most patients, especially if a complete response occurred at the time of the third infusion. In patients treated for 1-year, infliximab discontinuation was also successful, with a cumulative probability of being free of relapse of 69% at 12 months. In perianal disease, early relapse was the rule after stopping infliximab treatment, with only 34% of patient maintaining remission at 1 year. CONCLUSIONS: Short regimens of infliximab might be evaluated in patients with luminal Crohn's disease. However, infliximab discontinuation is not recommended in perianal Crohn's disease, because of a high rate of early relapse.

[Gasometric alterations in hospitalized cirrhotic patients]. / Alteraciones gasométricas en pacientes cirróticos hospitalizados.

BACKGROUND AND OBJECTIVES: Gas exchange alterations have been described in cirrhotic patients; but by the moment, a few prospective studies have focused in them. The aim of this study was to describe the frequency and severity of gasometric alterations in hospitalized cirrhotic patients, a their correlation with hepatocellular disfunction. PATIENTS AND METHODS: 50 consecutive cirrhotic patients (41 males) admitted for liver decompensation (ascites, liver encephalopathy, alcoholic hepatitis and upper gastrointestinal bleeding) without acute or chronic cardiopulmonary disfunction were included in the study. Patients were classified according with Child-Pugh score (A, n = 13; B, n = 21; C, n = 16). Severe alcoholic hepatitis (SAH) was confirmed in 7 patients. Arterial gasometry was performed in all patients before discharge. Contrast echocardiography was performed in any case of suspicion of hepatopulmonary syndrome (HPS). RESULTS: Light hypoxemia was observed (80.9 mmHg), without differences with Child-Pugh. Hypocapnia was significantly more evident in Child C than in A and B (31.2 +/- 3.1 vs. 38.1 +/- 4.3 y 36.3 +/- 5 mmHg; p < 0,05), respectively. Cirrhotic patients with SAH showed a significantly higher hypocapnia by comparison with others (31.2 +/- 3.1 vs. a 36.3+/-5 mmHg; p < 0.05). In multivariate analysis, independent prognostic variables for hypocapnica were plasmatic levels of protrombin time, albumin and sodium. HPS was confirmed in 8 patients (16%). CONCLUSIONS: The most prevalent gas exchange abnormality in cirrhosis was the alteration of alveolar-arterial oxygen tension gradient, directly correlated with hepatocellur disfunction. Hypocapnia could be a compensatory mechanism or the result of the activation of central respiratory centres by non-depurated substances by the liver.

[Autoimmune hemolytic anemia associated with ulcerative colitis]. / Anemia hemolítica autoinmunie asociada a colitis ulcerosa.

The incidence of immunological disorders has been reported to be greater in patients with inflammatory bowel disease than among the general population. The association of ulcerative colitis (UC) and autoimmune hemolytic anemia (AIHA) was first described in the early 1950s but no more than 50 cases have been described in the international literature. Detailed description of the pathogenic mechanisms involved in this association is lacking. The clinical course of AIHA and treatment response in these patients seems to be independent of UC, sometimes requiring immunosuppressive treatment and even surgery. We present 2 cases of AIHA associated with UC with distinct response to conventional treatment. We also review the literature on the subject.