Autoantibody and human leukocyte antigen profiles in children with autoimmune liver disease and their first-degree relatives.

OBJECTIVE: Familial clustering of juvenile autoimmune liver disease (AILD), including autoimmune hepatitis and autoimmune sclerosing cholangitis (ASC), is rare, despite a high prevalence of autoimmune disorders in AILD families. METHODS: To investigate this discrepancy, we measured autoantibodies diagnostic for AILD, anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-liver cytosol type 1, and anti-soluble liver antigen antibodies, and human leukocyte antigen profiles in 31 patients and 65 of their first-degree relatives (FDR). The autoantibody profile was compared with that of 42 healthy subjects (HS). RESULTS: Autoantibodies were detected in 71% (22/31) patients. Anti-nuclear antibody or anti-smooth muscle antibody were present in 4/65 FDR (6.2%). HS were negative for all autoantibodies. The frequencies of homozygous HLA DRB1*0301 (DR3) genes and haplotype A1-B8-DR3 were higher in the patients (25% and 43%) than in FDR (9% and 27%) and HS (0% and 16%). The frequencies of disease-protective genes DR4 and/or DR15 were lower in the patients (25%) than in FDR (42%) and HS (42%). Only 1 family contained 2 patients with AILD, 1 with ASC and 1 with primary sclerosing cholangitis. Both patients possessed A1-B8-DR3 genes, the ASC being homozygous and the primary sclerosing cholangitis heterozygous. Six FDR had nonhepatic autoimmune disorders, none being autoantibody positive. CONCLUSIONS: Homozygosity for DR3 plays a major role in the predisposition to juvenile AILD. Diagnostic autoantibodies for AILD are rare among patients' FDR and not linked to clinical manifestation of AILD.

The management of treatment-resistant biliary calculi using percutaneous endourologic techniques.

BACKGROUND: Complicated choledocholithiasis cannot always be managed by standard surgical, radiologic or endoscopic methods. One additional approach is to use percutaneous techniques developed by endourologists to treat renal calculi. In this report, we present our experience over the past 10 years with this novel approach. METHODS: We conducted a retrospective review of all patients who underwent percutaneous, endoscopic treatment of biliary calculi at our institution between January 1997 and August 2007. Primary outcomes of interest were symptom- and stone-free rates, length of stay in hospital and complications. RESULTS: Nineteen patients underwent 21 percutaneous treatments for biliary calculi. All were dependent on external drainage for symptom control. The primary indications for treatment were cholangitis, retained stone, biliary colic and jaundice. Seventeen patients (89.5%) had failed prior endoscopic retrograde cholangiopancreatography (ERCP) or open attempts at treatment. The 2 remaining patients (10.5%) were deemed unfit for a general anesthetic. Patients had experienced a mean of 1.8 (standard deviation [SD] 1.0) prior failed attempts at stone removal. We used several treatment modalities, including holmium:yttrium-aluminum-garnet laser (61.9%), electrohydraulic lithotripter (19.0%), ultrasound (9.5%), basket extraction (9.5%) and balloon dilatation of the ampulla (19.0%). Overall, treatment led to successful removal of the biliary drainage tube in 94.7% of patients and 76.2% were stone-free. We performed cholangiograms an average of 21.8 (SD 13.7) days after treatment. The average length of stay in hospital was 1.9 (SD 1.1) days. One patient experienced a perioperative acute coronary syndrome and another experienced prolonged biliary drainage. Both had successful endoscopic treatment of their calculi. There were no cases of treatment-related sepsis, and we observed no other complications. CONCLUSION: Biliary calculi may be successfully treated using standard endourologic methods with high stone-free rates. This technique is generally well-tolerated even among high-risk patients.

Reduced monocyte HLA-DR expression: a novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure.

Acute liver failure (ALF) shares striking similarities with septic shock where a decrease in HLA-DR expression on monocytes is associated with disease severity and predicts outcome. We investigated monocyte HLA-DR expression in ALF in relation to inflammatory mediator levels and clinical outcome. Monocyte HLA-DR expression was determined in 50 patients with acetaminophen-induced ALF (AALF) and 20 non-acetaminophen-induced ALF (NAALF). AALF patients were divided into dead/transplanted (AALF-NS, n = 26) and spontaneous survivors (AALF-S, n = 24). Fifty patients with chronic liver disease (CLD) and 50 healthy volunteers served as controls. Monocyte HLA-DR expression was determined by double-color flow-cytometry with monoclonal antibodies detecting HLA-DR and monocyte specific CD14. Serum levels of interleukin (IL) -4, -6, -10, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were concomitantly measured by ELISA. Compared to healthy volunteers (75%) and CLD (67%) monocyte HLA-DR percentage expression was lower in AALF (15%, P < .001) and NAALF (22 %, P < .001). Compared to AALF-S, AALF-NS had lower monocyte HLA-DR % (11% vs. 36%, P < .001) and higher levels of IL-4, IL-6, IL-10 and TNF-alpha (P < .001). HLA-DR percentage negatively correlated with INR, blood lactate, pH and levels of encephalopathy (r = -0.8 to -0.5, P < .01), IL-10 (r = -0.8, P < .0001), TNF-alpha (r = -0.4, P = .02). HLA-DR percentage level

Visual-spatial ability, learning modality and surgical knot tying.

INTRODUCTION: The ability to mentally rotate an object in 3 dimensions has been shown with an individual's score on the Vandenberg and Kuse Mental Rotations Test. The was to determine whether this Mental Rotations Test could be used to predict performance complex surgical skill - the tying of a 1-handed surgical reef knot. In addition, we learning a spatially complex surgical skill could be achieved more effectively via a computer-based selfdirected learning approach than with a didactic lecture-based teaching method. METHODS: preclerkship medical students at the University of Western Ontario were randomized into computer-based self-directed learning group and a didactic lecture-style learning group. administration of the Mental Rotations Test, the students were taught how to tie a reef knot via the learning modality assigned to their respective group. RESULTS: Students Mental Rotations Test scores were able to tie more surgical knots in the allocated time Students learning how to tie the surgical knot via the computer-based self-directed showed improvement on their knot tying abilities more rapidly than their didactically trained colleagues. CONCLUSION: The ability to mentally rotate an object in 3 dimensions played an important initial learning of a spatially complex surgical technical skill. Our data demonstrated learning was as effective and more practical than traditional lecture-based learning.

The effect of anti-lymphocyte serum on subpopulations of blood and tissue leucocytes: possible supplementary mechanisms for suppression of rejection and the development of opportunistic infections.

Xenogeneic anti-lymphocyte serum (ALS) remains a major reagent for immunosuppression in clinical practice, but mechanisms of action and risks of opportunistic infection have not been considered in the context of innate immunity and its role in immune responsiveness. Rabbit anti rat ALS was administered intraperitoneally. Blood was taken for flow cytometry to establish absolute counts of leucocyte subsets. Tissues were harvested for immunohistology to evaluate interstitial dendritic cells and tissue macrophages. At day 2 of ALS therapy, T cells are completely depleted, as anticipated. B cells are undiminished and form approximately 90% of blood leucocytes. Monocytes and natural killer (NK) cells are substantially (approximately 80%), but not completely, depleted, and there is a trend for diminished numbers of putative dendritic cells. Neither interstitial dendritic cells nor tissue macrophages in heart are affected. The results at day 7 were very similar to day 2. Substantial depletion of blood monocytes and NK cells might attenuate the innate immune system, and represent a possible supplementary mechanism (in addition to T cell depletion) for suppression of rejection. It might be of particular importance in reducing defences against infections. Monitoring these parameters could be of clinical value.

Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis.

BACKGROUND/AIMS: Previous studies on patients with primary biliary cirrhosis (PBC) have shown extensive cross-reactivity between the dominant B- and T-cell epitopes of human pyruvate dehydrogenase complex-E2 (PDC-E2), and microbial mimics. Such observations have suggested microbial infection as having a role in the induction of anti-mitochondrial antibodies, through a mechanism of molecular mimicry. However the biological significance of these cross-reactivities is questionable, because PDC-E2 is so highly conserved among various species. METHODS: Interrogating protein databases, ten non-PDC-E2 microbial sequences with high degree of similarity to PDC-E2(212-226) were found in Escherichia coli (6), Helicobacter pylori, Pseudomonas aeruginosa, Cytomegalovirus, and Haemophilus influenzae. We report on a study testing reactivity and competitive cross-reactivity against these respective peptides, and in some cases the parent protein, using sera from 55 patients with PBC, compared to reactivity of 190 pathological and 28 healthy controls. RESULTS: Cross-reactivity to E. coli mimics was commonly seen in PBC, and in a subset of pathological controls except where there was no evidence of urinary tract infection and correlated with anti-mitochondrial reactivity. CONCLUSIONS: E. coli/PDC-E2 cross-reactive immunity characterizes primary biliary cirrhosis; the large number of E. coli immunogenic mimics may account for the dominance of the major PDC-E2 autoepitope.