Cylindrical spirals in two families: Clinical and genetic investigations.

Cylindrical spirals are a rare ultrastructural finding on muscle biopsy, with fewer than 20 reported cases since its first description in 1979. These structures are sometimes observed with tubular aggregates and are thought to comprise longitudinal sarcoplasmic reticulum. While mutations in genes encoding key components of Ca2+ handling (ORAI1 and STIM1) underlie tubular aggregate myopathy, no causative genes have been associated with cylindrical spirals. Here we describe two families with cylindrical spirals on muscle biopsy with a suspected genetic cause. In one family we identified a known truncating variant in EBF3, previously associated with a neurodevelopmental disorder. The affected individuals in this family present with clinical features overlapping with those described for EBF3 disease. An isolated proband in the second family harbours bi-allelic truncating variants in TTN and her clinical course and other features on biopsy are highly concordant for titinopathy. From experimental studies, EBF3 is known to be involved in Ca2+ regulation in muscle, thus EBF3 dysregulation may represent a novel mechanism of impaired Ca2+ handling leading to cylindrical spirals. Additional cases of EBF3 disease or titinopathy with cylindrical spirals need to be identified to support the involvement of these genes in the pathogenesis of cylindrical spirals.

Prognostic Value of the Burden of Cytomegalovirus Colonic Reactivation Evaluated by Immunohistochemical Staining in Patients with Active Ulcerative Colitis.

BACKGROUND: Colonic cytomegalovirus [CMV] reactivation has been involved in steroid refractoriness in patients with active ulcerative colitis [UC]. The benefits of antiviral therapy in this clinical setting are still under debate, but the burden of viral reactivation has been associated with a poorer outcome in some studies. Our aim was to assess whether the burden of CMV reactivation measured by the number of viral inclusions by immunohistochemistry [IHC-CMV] is associated with a risk of colectomy. METHODS: Biopsy sets of UC patients with positive IHC-CMV were identified from the Pathology departments of three university hospitals. All biopsies were reviewed by expert pathologists, and the maximum number of IHC-CMV-positive cells in each biopsy set was re-assessed. Epidemiological and clinical features and clinical outcomes were recorded. RESULTS: Forty-six positive IHC-CMV cases with UC were included. At the time of CMV reactivation, 70% were receiving corticosteroids, 33% azathioprine, and 24% anti-tumour necrosis factor [TNF] agents. Thirty-two patients [70%] were treated with antiviral therapy. The median number of IHC-CMV-positive cells was 2 cells/biopsy [IQR 1-4]. Fourteen patients [30%] underwent colectomy, and 4 of them [29%] showed persistence of CMV in the surgical specimen. In the multivariate analysis, colectomy was only associated with >2 positive cells/biopsy [p = 0.048] and younger age [p = 0.023]. CONCLUSIONS: The burden of CMV colonic reactivation in patients with active UC, as measured by IHC, seems to be related to the risk of colectomy, and more data is needed to understand whether antiviral therapy guided by CMV burden will alter the clinical outcome.

CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78).

CD5-like (CD5L) is a soluble scavenger cysteine-rich protein that modulates inflammatory responses. We studied the involvement of CD5L in liver cancer. Immunohistochemistry (IHC) of CD5L in 60 hepatocellular carcinomas and 34 adjacent nontumor livers, showed that CD5L staining was higher in tumor than in nontumor tissue (Mann-Whitney test; P = 0.0039). High CD5L correlated with elevated proliferation (Ki67, linear regression; P < 0.0001) and lower patient event-free survival (log-rank; P = 0.0185). Accordingly, CD5L expression was detected in the liver cancer cell lines Huh7, HepG2, and SNU-398. In vitro technologies using these cell lines, including small interfering RNA (siRNA) and cDNA transfection, showed that CD5L promoted colony formation and cell proliferation and protected against cisplatin-induced apoptosis. To find a molecular explanation for these roles, novel CD5L-interacting protein ligands in liver cancer cells were identified by immunoprecipitation followed by mass spectrometry. Among these, the molecular chaperone of the unfolded protein response (UPR), heat shock protein (HSP)-A5, was selected for validation. The interaction was confirmed by confocal microscopy in the Huh7 and HepG2 cell lines. Furthermore, functional experiments revealed that CD5L activates the UPR and autophagy mechanisms in Huh7 cells, thereby providing a novel molecular link between the UPR and autophagy in liver cancer.-Aran, G., Sanjurjo, L., Bárcena, C., Simon-Coma, M., Téllez, É., Vázquez-Vitali, M., Garrido, M., Guerra, L., Díaz, E., Ojanguren, I., Elortza, F., Planas, R., Sala, M., Armengol, C., Sarrias, M.-R. CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78).

High Prevalence of Liver Fibrosis Among European Adults With Unknown Liver Disease: A Population-Based Study.

BACKGROUND & AIMS: Liver fibrosis is the main determinant of long-term outcome in chronic liver diseases. Little is known about the prevalence of liver fibrosis in the general population. The aim of the study was to investigate the prevalence of liver fibrosis in the general adult population with unknown liver disease. METHODS: This was a population-based, cross-sectional study performed in the Barcelona metropolitan area. Subjects aged 18 to 75 years old were identified randomly from citizens included in the primary health care registry. Of 4866 subjects invited, 3076 participated (63.2%). Liver fibrosis was estimated by measuring liver stiffness (LS) with transient elastography (TE). Liver histology was assessed in 92 subjects with increased LS. RESULTS: Prevalence estimates of increased LS (≥6.8, ≥8.0, and ≥9.0 kPa) were 9.0%, 5.8%, and 3.6%, respectively. The etiology of liver disease was mainly nonalcoholic fatty liver disease (NAFLD), followed by alcohol risk consumption (consumption of ≥21 standard drinking units/wk in men and ≥14 standard drinking units/wk in women). Factors independently associated with increased LS were male sex, abdominal obesity, type 2 diabetes, serum glucose, high-density lipoprotein, and triglyceride levels. Subjects without risk factors for NAFLD or without alcohol risk consumption had a very low prevalence of increased LS. The best cut-off value of LS for significant liver fibrosis (F2-F4) was 9.2 kPa, with high sensitivity and specificity. TE was more accurate than alanine aminotransferase, NAFLD fibrosis score, or Fibrosis 4. An algorithm for screening for liver fibrosis using TE in the community setting is proposed. CONCLUSIONS: These findings show a high prevalence of silent liver disease with advanced fibrosis mainly related to NAFLD in adult European subjects without known liver disease. An LS value less than 9.2 kPa predicts the absence of significant liver fibrosis with high accuracy and could be used for screening purposes.

Acute histological inflammatory activity is associated with clinical relapse in patients with ulcerative colitis in clinical and endoscopic remission.

BACKGROUND: It has been suggested that acute histological activity has a prognostic value in the outcome of ulcerative colitis (UC) patients in clinical and endoscopic remission. Our aim was to assess the role of histology as a risk factor for clinical relapse (CR) in patients in both clinical and endoscopic remission. METHODS: Patients with left-sided or extensive UC in clinical and endoscopic remission (Mayo endoscopic subscore ≤1) undergoing colonoscopy for dysplasia surveillance with random colonic biopsies between 2005-2015 were included. Basal plasmacytosis, acute (AHA), and the chronic (CHA) histological inflammatory activity of all biopsy sets were evaluated. RESULTS: One hundred and thirteen patients were included. Median time in clinical remission at inclusion was 27 months (IQR 15-56). Eight percent of patients relapsed within the first year and 33% during the whole follow-up period. In the univariate analysis, the presence of AHA, alone (P=0.048) or together with a past flare within the previous 12 months (P=0.01), was associated with CR within the first year of follow-up. In the multivariate analysis, AHA, together with a flare within the previous 12 months, remained the only risk factor for relapse (RR=7.5; IC95%; 1.8-29.9; P=0.005). CONCLUSIONS: In UC patients in clinical and endoscopic remission, the presence of AHA is a risk factor for clinical relapse.

Comparative Effect of the I3.1 Probiotic Formula in Two Animal Models of Colitis.

Use of probiotic therapy is an active area of investigation to treat intestinal disorders. The clinical benefits of the I3.1 probiotic formula (Lactobacillus plantarum (CECT7484, CECT7485) and P. acidilactici (CECT7483)) were demonstrated in irritable bowel syndrome (IBS) patients in a randomized, double-blind, placebo-controlled clinical trial. The aim of this study was to evaluate the therapeutic effects of I3.1 in two experimental models of colitis, a dextran sulfate sodium (DSS)-induced colitis model and an interleukin (IL)-10-deficient mice model. Colitis was induced in 32 8-week-old Balb/c mice by administering 3% (w/v) DSS in drinking water for 5 days. Probiotics were administered orally (I3.1 or VSL#3, 1 × 109 CFU daily) for 10 days before the administration of DSS. Also, probiotics (I3.1 or VSL#3, 1 × 109 CFU daily) were administered orally to 36 6-week-old C57B6J IL-10(-/-) mice for 10 weeks. Body weight was recorded daily. Colon samples were harvested for histological examination and cytokine measurements. Body weight after DSS administration did not change in the I3.1 group, whereas the VSL#3 group had weight loss. Also, I3.1 normalized IL-6 to levels similar to that of healthy controls and significantly increased the reparative histologic score. In the IL-10-deficient model, both VSL#3 and I3.1 reduced the severity of colitis compared to untreated controls, and I3.1 significantly reduced the levels of IFN-γ compared to the other two groups. In conclusion, I3.1 displays a protective effect on two murine models of experimental colitis. Results suggest that the mechanism of action could be different from VSL#3.

Interleukin-10 Enhances the Intestinal Epithelial Barrier in the Presence of Corticosteroids through p38 MAPK Activity in Caco-2 Monolayers: A Possible Mechanism for Steroid Responsiveness in Ulcerative Colitis.

Glucocorticosteroids are the first line therapy for moderate-severe flare-ups of ulcerative colitis. Despite that, up to 60% of patients do not respond adequately to steroid treatment. Previously, we reported that low IL-10 mRNA levels in intestine are associated with a poor response to glucocorticoids in active Crohn's disease. Here, we test whether IL-10 can favour the response to glucocorticoids by improving the TNFα-induced intestinal barrier damage (assessed by transepithelial electrical resistance) in Caco-2 monolayers, and their possible implications on glucocorticoid responsiveness in active ulcerative colitis. We show that the association of IL-10 and glucocorticoids improves the integrity of TNFα-treated Caco-2 cells and that p38 MAPK plays a key role. In vitro, IL-10 facilitates the nuclear translocation of p38 MAPK-phosphorylated thereby modulating glucocorticoids-receptor-α, IL-10-receptor-α and desmoglein-2 expression. In glucocorticoids-refractory patients, p38 MAPK phosphorylation and membrane desmoglein-2 expression are reduced in colonic epithelial cells. These results suggest that p38 MAPK-mediated synergism between IL-10 and glucocorticoids improves desmosome straightness contributing to the recovery of intestinal epithelium and reducing luminal antigens contact with lamina propria in ulcerative colitis. This study highlights the link between the intestinal epithelium in glucocorticoids-response in ulcerative colitis.

Hepatic glycogenosis: An underdiagnosed complication of diabetes mellitus?

Hepatic glycogenosis (HG) is characterized by excessive glycogen accumulation in hepatocytes and represents a hepatic complication of diabetes that particularly occurs in patients with longstanding poorly controlled type 1 diabetes (T1D). HG has been reported to be a very rare disease, although it is believed to be extremely underdiagnosed because it is not possible to distinguish it from non-alcoholic fatty liver disease (NAFLD) unless a liver biopsy is performed. In contrast to HG, NAFLD is characterized by liver fat accumulation and is the more likely diagnosis for patients with type 2 diabetes and metabolic syndrome. The pathogenesis of HG involves the concomitant presence of insulin and excess glucose, which increases glycogen storage in the liver. HG is characterized by a transient elevation in liver transaminases and hepatomegaly. Differentiating between these two conditions is of the utmost importance because HG is a benign disease that is potentially reversible by improving glycemic control, whereas NAFLD can progress to cirrhosis. Therefore, HG should be suspected when liver dysfunction occurs in patients with poorly controlled T1D. The aim of this article is to review the epidemiology, clinical characteristics, pathogenesis and histology of HG.

Nodular Mucinosis of the Breast in a Male: Reassessment of Diagnostic Criteria and Proposal for Its Classification as a Soft Tissue Tumor in the Myofibroblastoma and Spindle Cell Lipoma Spectrum.

Nodular mucinosis of the breast (NMB) is a rare entity with only a few cases described in the literature, most of them in young girls. All cases are located in the nipple and areolar area and microscopically consist of a multinodular myxoid mesenchymal proliferation. Bands of sclerotic collagen containing preexisting breast ducts and abundant vascularization are other features typical of NMB. No relation to Carney complex has been reported, and an indolent behavior is the rule in all patients. We present a case of NMB occurring in the nipple of a 46-year-old man and analyze the clinicopathological features of the other cases of NMB reported in the English literature, concluding that two of them most likely correspond to trauma-induced cutaneous focal mucinosis of the mammary areola. Finally, we review diagnostic criteria for NMB and elaborate an ontogenetic hypothesis based on both its morphological resemblance to myofibroblastoma and its immunohistochemical profile.

Biomarkers for diagnosis and monitoring of celiac disease.

Celiac disease (CD) is an autoimmune disorder, which damages the small intestine and is caused by ingestion of gluten in genetically susceptible individuals. The only known effective treatment is a lifelong gluten-free diet. Genetic risk factors have been identified and nearly all patients are HLA-DQ2 and/or HLA-DQ8 positive. Specific autoantibodies, IgA antitissue transglutaminase-2, antiendomysium, and antideaminated forms of gliadin peptide antibodies, are widely used as diagnostic aids in celiac patients. However, the discovery of new biomarkers may help in the diagnosis and follow-up of the disease. Recently, the molecule REG Iα, involved in tissue regeneration, has been proposed as a new biomarker of CD. REG Iα expression is increased in the target tissue and in the sera of celiac patients during damage and inflammation, decreasing after gluten-free diet. In this article we review the main biomarkers for diagnosis and monitoring of CD, focusing on the immune response-related mechanisms.

Effect of liver fibrosis on long-term mortality in HIV/hepatitis C virus-coinfected individuals who are evaluated to receive interferon therapies in the highly active antiretroviral therapy era.

The factors associated with overall mortality and liver decompensation in HIV and hepatitis C virus (HCV)-coinfected patients who are evaluated to receive HCV antiviral therapy with a known liver histological fibrosis stage were evaluated in a prospective cohort study. A total of 387 consecutive HIV/HCV-coinfected patients attending an outpatient clinical unit between January 1997 and December 2007 who fulfilled criteria to be treated with interferon and to whom liver biopsy was performed were included and followed every 6 months from time of liver biopsy to death or to December 2008. The follow-up period was 6.2 years (IQR: 3.5-9.2). The median age at time of liver biopsy was 38 years. This included 73% men; 28% had advanced liver fibrosis (F3-F4) and a CD4 cell count of 556 cells/mm(3), 72% had HIV RNA <400 copies/ml and a mean CD4 nadir of 207 cell/mm(3), 21% had a previous diagnosis of AIDS, and 92% were on antiretroviral therapy. During follow-up 48% underwent HCV antiviral therapy, with a sustained virological response in 33%. The overall mortality rate and the incidence of liver decompensation or liver-related death were 1.17 and 0.72 per 100 patients-year, respectively. End stage liver disease (9/28 patients) and non-AIDS-related cancer (6/28) were the main causes of death. F3-F4 (HR: 3.74, 95% CI: 1.69-8.26, p=0.001) and previous AIDS diagnosis (HR: 3.04, 95% CI: 1.36-6.81) were the factors independently associated with death. Mortality rates in patients who received and who did not receive HCV antiviral therapy were 0.44 and 2.04 per 100 patients-year, respectively (p=0.003). In addition to the low mortality rate observed, HIV/HCV-coinfected patients with poor predictors of survival are candidates for intensive clinical management.

Bacteria and spontaneous experimental colitis: immunological changes.

BACKGROUND: Intestinal commensal flora seems to be a requisite for both human and experimental intestinal inflammation. Our aim was to assess the immunological changes in the colon of IL-10(-/-) mice depending on the environmental conditions. MATERIALS AND METHODS: Twelve wild-type (WT) and 24 IL-10(-/-) 4-week-old mice were kept under specific pathogen-free (SPF) conditions for 4 weeks. Half of them were transferred to a conventional environment. Mice were sacrificed at 12 weeks of age, and the incidence and severity of colitis was assessed. Intraepithelial (IEL) and lamina propria (LPL) lymphocytes were assessed for phenotype and apoptosis by flow cytometry. Toll-like receptors 2 (TLR2) and TLR9 expression was assessed by real-time PCR. Immunohistochemical analyses for cell apoptosis, TLR2 and MyD88 were also performed. RESULTS: IL-10(-/-) mice shifted to conventional conditions showed a greater incidence (66% vs. 50%) and severity of colitis than animals kept under SPF conditions (P = 0·009). The number of CD3+ IEL was higher and their apoptosis rate lower in IL-10(-/-) than in their WT counterparts, regardless of the environment. In LPL, however, these differences were only observed in mice shifted to conventional conditions. TLR2 expression was significantly increased in SPF-housed IL-10(-/-) mice when compared to WT controls. Immunohistochemistry demonstrated the loss of TLR2 and MyD88 in damaged areas. CONCLUSIONS: In SPF conditions, IL-10 deficiency appears to be compensated by an increased epithelial TLR2 expression, thus resulting in a milder colonic damage. However, in conventional conditions, this compensatory mechanism would be exceeded inducing a more severe colonic damage with activation of LPL immune cells.

Therapeutic effect of antisecretory factor-rich egg yolk on the late phases of 2,4,6-trinitrobenzenesulphonic acid colitis in mice.

Antisecretory factor (AF) is expressed in all tissues of mammals, inhibits intestinal hypersecretion and has anti-inflammatory properties as well. Endogenous AF synthesis may be stimulated by feeding hydrothermally processed cereals. Alternatively, freeze-dried egg yolk can be used as a source of exogenous AF. Several reports have suggested that AF from freeze-dried egg yolk may be useful in inflammatory bowel disease. We assessed the effect of freeze-dried, AF-rich egg yolk intake on 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis. Balb/c mice were randomised to receive (1) AF in sterile drinking-water (4 g/l, n 38) and (2) sterile drinking-water alone (vehicle, n 38) from TNBS or saline administration onwards. Different subsets of mice were killed at weeks 1-3 after TNBS or saline administration. Macroscopic and microscopic damage was assessed in colonic specimens. Eicosanoid and cytokine production was evaluated in supernatants of 24 h-incubated colonic explants. Myeloperoxidase activity was measured in frozen colonic samples, while apoptosis was assessed in paraffined samples by the in situ oligoligation method. AF-treated mice showed a milder colonic damage compared with the vehicle group, which became statistically significant at week 3. This was accompanied by decreased IL-2, IL-1 and leukotriene B4 production at weeks 2 and 3, as well as increased interferon-γ at week 1, in AF-treated mice compared with vehicle-treated mice. AF-treated mice had significantly increased counts of apoptotic cells in the lamina propria at weeks 1 and 2 post-TNBS. In conclusion, the administration of AF-rich egg yolk has a therapeutic effect in the late phases of TNBS colitis in Balb/c mice.

Idiopathic myointimal hyperplasia of mesenteric veins and pneumatosis intestinalis: a previously unreported association.

Idiopathic myointimal hyperplasia of mesenteric veins is a very rare disease occurring in young male patients, with no more than eight cases reported in the world literature. It causes venous ischemia in the sigmoid colon and rectum that clinically resembles inflammatory bowel disease. Pneumatosis intestinalis is also a rare condition usually associated to a wide range of diseases including bowel ischemia. We herein report on a case of pneumatosis intestinalis associated to idiopathic myointimal hyperplasia of mesenteric veins. To our knowledge, this is the first report of such an association, and the first one of idiopathic myointimal hyperplasia of mesenteric veins occurring in a female patient as well.

Lactobacillus fermentum CECT 5716 prevents and reverts intestinal damage on TNBS-induced colitis in mice.

BACKGROUND: Probiotics attenuate gut inflammation when administered before experimental colitis, but data on their effect after colitis induction are scarce. We aimed to evaluate the effects of Lactobacillus fermentum CECT 5716 on gut injury when administered either before or after trinitrobencene sulfonic acid (TNBS) colitis in Balb/c mice. METHODS: In a preventive study, probiotic or vehicle was administered for 2 weeks before colitis. Then mice were allocated to: probiotic + TNBS, probiotic + sham, vehicle + TNBS, or vehicle + sham, and sacrificed 72 hours later. In a therapeutic study, mice were allocated into the same groups as before. Probiotic or vehicle were administered for 3 weeks. Mice were sacrificed at weeks 1, 2, and 3 after TNBS. Histological score, myeloperoxidase activity, and eicosanoid and cytokine production in colonic explant cultures were measured. Immunohistochemistry for nitrotyrosine and MyD88 was also performed. RESULTS: In the preventive study, colitis was milder with probiotic than with vehicle (P = 0.041). This was associated with increased PGE(2), IL-2, and IL-4 production, as well as attenuated nitrotyrosine staining in the former. In the therapeutic study, histological score at week 1 post-TNBS was higher in probiotic than in vehicle fed mice (P = 0.018). However, at weeks 2 and 3 the histological score was significantly lower-with decreased IL-6 production and increased MyD88 staining-in mice receiving the probiotic. CONCLUSIONS: Pretreatment with L. fermentum CECT 5716 attenuates TNBS colitis, an effect that seems to be due to its antioxidant abilities. When administered after TNBS, this probiotic is also effective in accelerating colitis recovery, and this is associated with an enhanced Toll-like receptor function.

Partial replacement of dietary (n-6) fatty acids with medium-chain triglycerides decreases the incidence of spontaneous colitis in interleukin-10-deficient mice.

Enteral nutrition has a primary therapeutic effect in active Crohn's disease. It is unknown which nutrient(s) account for this action, but a role for both the amount and type of dietary fat has been postulated. Some clinical and experimental data suggest that medium-chain triglycerides (MCT) may reduce intestinal inflammation. We aimed to assess the effect of replacing part of the dietary fat with MCT on the incidence and severity of colitis in interleukin (IL)-10(-/-) mice under specific pathogen-free conditions. Twenty-four IL-10(-/-) 4-wk-old mice were randomized to receive a control diet based on sunflower oil [(n-6) fatty acids (FA)] and an experimental isocaloric, isonitrogenous diet with 50% sunflower and 50% coconut oil (MCT diet). When the mice were 12 wk old, they were killed and the colon was examined for the presence of colitis, lymphocyte subpopulations and apoptosis, ex vivo cytokine production in supernatant of colon explants, toll-like receptor (TLR)-2 and TLR-9 mRNA, and FA profile in colonic tissue homogenates. Colitis incidence was lower in the IL-10(-/-) mice fed the MCT diet (1/12) than in the mice fed the control diet (8/12; P = 0.03). The histological damage score was also lower in the former (P < 0.0005). Feeding the MCT diet resulted in fewer total and apoptotic intraepithelial CD3+ and lamina propria CD3+CD4+ lymphocytes, as well as downregulated production of IL-6 and interferon-gamma, and reduced TLR-9 mRNA. We conclude that partial replacement of dietary (n-6) FA with MCT decreases the incidence of colitis in a model of spontaneous intestinal inflammation and provide experimental arguments for a possible primary therapeutic effect of MCT in human Crohn's disease.

Accuracy of simple biochemical tests in identifying liver fibrosis in patients co-infected with human immunodeficiency virus and hepatitis C virus.

BACKGROUND & AIMS: We assessed the ability of 3 simple biochemical tests to stage liver fibrosis in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). METHODS: We analyzed liver biopsy samples from 324 consecutive HIV/HCV-positive patients (72% men; mean age, 38 y; mean CD4+ T-cell counts, 548 cells/mm(3)). Scheuer fibrosis scores were as follows: 30% had F0, 22% had F1, 19% had F2, 23% had F3, and 6% had F4. Logistic regression analyses were used to predict the probability of significant (>or=F2) or advanced (>or=F3) fibrosis, based on numeric scores from the APRI, FORNS, or FIB-4 tests (alone and in combination). Area under the receiver operating characteristic curves were analyzed to assess diagnostic performance. RESULTS: Area under the receiver operating characteristic curves analyses indicated that the 3 tests had similar abilities to identify F2 and F3; the ability of APRI, FORNS, and FIB-4 were as follows: F2 or greater: 0.72, 0.67, and 0.72, respectively; F3 or greater: 0.75, 0.73, and 0.78, respectively. The accuracy of each test in predicting which samples were F3 or greater was significantly higher than for F2 or greater (APRI, FORNS, and FIB-4: >or=F3: 75%, 76%, and 76%, respectively; >or=F2: 66%, 62%, and 68%, respectively). By using the lowest cut-off values for all 3 tests, F3 or greater was ruled out with sensitivity and negative predictive values of 79% to 94% and 87% to 91%, respectively, and 47% to 70% accuracy. Advanced liver fibrosis (>or=F3) was identified using the highest cut-off value, with specificity and positive predictive values of 90% to 96% and 63% to 73%, respectively, and 75% to 77% accuracy. CONCLUSIONS: Simple biochemical tests accurately predicted liver fibrosis in more than half the HIV/HCV co-infected patients. The absence and presence of liver fibrosis are predicted fairly using the lowest and highest cut-off levels, respectively.

Evolution of foamy macrophages in the pulmonary granulomas of experimental tuberculosis models.

The chronic phase of Mycobacterium tuberculosis infection in mouse experimental models is characterized by the accumulation of foamy macrophages (FM)--which shape the outer ring of the granuloma - in the alveolar spaces, as detected in paraffin-embedded tissues stained with hematoxylin-eosin. In this study, the use of semi- and ultra-thin sections offers more detailed information about the origin of FM both in mouse and guinea-pig experimental models. Lipid bodies (LB) are present in macrophages from the beginning of infection and accumulate in the chronic phase. LB progress from an early (ELB) to a late (LLB) stage, defined according to their progressive capacity to generate cholesterol crystals, resembling atherosclerotic lesions. FM arise from massive accumulation of LLB. Electronic microscopy reveals intracellular lipophilic inclusions (ILIs) in those M. tuberculosis bacilli inside FM. It is our hypothesis that the accumulation of lipids in M. tuberculosis concomitant to the establishment of the non-replicating state prepares the bacilli for future reactivation and for facing future stressful environments.

Cytomegalovirus infection in ulcerative colitis: a prospective, comparative study on prevalence and diagnostic strategy.

BACKGROUND: Cytomegalovirus (CMV) infection has been reported in ulcerative colitis (UC), especially in severe, steroid-refractory disease. However, its role in steroid-refractoriness remains unknown. Our goals were to evaluate the prevalence of CMV disease in UC, the best diagnostic strategy, and the influence of disease activity and/or treatment in its development. METHODS: Prospective, observational study including 114 subjects with active UC requiring intravenous steroids, steroid-refractory UC, inactive UC on mesalamine, inactive UC on azathioprine, and healthy controls. CMV antibodies, pp65-antigenemia, and rectal biopsies for hematoxylin and eosin staining, immunohistochemistry, and CMV-pp67 mRNA were performed. These procedures were repeated after medical treatment only in patients with active UC. CMV disease was defined by the presence of inclusion bodies and/or positive immunohistochemistry in colonic biopsies. RESULTS: CMV disease was found in 6 steroid-refractory, CMV-IgG-positive UC patients but not among controls, inactive UC, or steroid-responding UC patients. In 5 out of the 6 patients, CMV disease was diagnosed after 7-10 days on cyclosporine. CONCLUSIONS: CMV disease in UC only affects seropositive, steroid-refractory UC patients. Steroid/cyclosporine treatment together with disease activity may predispose to latent colonic CMV reactivation. The impact of antiviral therapy on the clinical outcome of these patients remains to be elucidated.