Long-Term Mortality of Patients with Septic Ocular or Central Nervous System Complications from Pyogenic Liver Abscess: A Population-Based Study

Background: Taiwan is endemic for pyogenic liver abscess (PLA). Septic ocular or central nervous system (CNS) complications derived from PLA can result in catastrophic disability. We investigated the epidemiology and long-term prognosis of PLA patients with septic ocular or CNS complications over an 8-year period. Methodology/Principal Findings: We extracted 21,307 patients with newly diagnosed PLA from a nationwide health registry in Taiwan between 2000 and 2007. The frequency of and risk factors for PLA with septic ocular or CNS complications were determined. The 2-year survival of these patients was compared between those with and without septic ocular or CNS complications. Septic ocular or CNS complications accounted for 2.1 % of all PLA patients. Age and the Charlson comorbidity index were significantly lower in PLA patients with ocular or CNS complications than those without. Diabetes and age,65 years were independent predictors of septic ocular or CNS complications. The 2-year mortality of patients with septic ocular or CNS complications was similar to those without complications (24.8 % vs. 27.5%, p = 0.502). However, among patients,65 years old and a Charlson index #1, the 2-year mortality was significantly higher in those with than without complications (18.6 % vs. 11.8%, p = 0.001). Conclusions/Significance: Physicians should recognize that catastrophic disability due to ocular or neurologica

Verbal Autopsy: Reliability and Validity Estimates for Causes of Death in the Golestan Cohort Study in Iran

BACKGROUND: Verbal autopsy (VA) is one method to obtain valid estimates of causes of death in the absence of valid medical records. We tested the reliability and validity of a VA questionnaire developed for a cohort study in Golestan Province in northeastern Iran. METHOD: A modified version of the WHO adult verbal autopsy was used to assess the cause of death in the first 219 Golestan Cohort Study (GCS) subjects who died. The GCS cause of death was determined by two internists who independently reviewed all available medical records. Two other internists ("reviewers") independently reviewed only the VA answers and classified the cause of death into one of nine general categories; they repeated this evaluation one month later. The reliability of the VA was measured by calculating intra-reviewer and inter-reviewer kappa statistics. The validity of the VA was measured using the GCS cause of death as the gold standard. RESULTS: VA showed both good validity (sensitivity, specificity, PPV, and NPV all above 0.81) and reliability (kappa>0.75) in determining the general cause of death independent of sex and place of residence. The overall multi-rater agreement across four reviews was 0.84 (95%CI: 0.78-0.89). The results for identifying specific cancer deaths were also promising, especially for upper GI cancers (kappa = 0.95). The multi-rater agreement in cancer subgroup was 0.93 (95%CI: 0.85-0.99). CONCLUSIONS: VA seems to have good reliability and validity for determining the cause of death in a large-scale adult follow up study in a predominantly rural area of a middle-income country

Violent Deaths of Iraqi Civilians, 2003–2008: Analysis by Perpetrator, Weapon, Time, and Location

Madelyn Hsiao-Rei Hicks and colleagues provide a detailed analysis of Iraqi civilian violent deaths during 2003-2008 of the Iraq war and show that of 92,614 deaths, unknown perpetrators caused 74% of deaths, Coalition forces 12%, and Anti-Coalition forces 11%

TNFAIP3 Maintains Intestinal Barrier Function and Supports Epithelial Cell Tight Junctions

Tight junctions between intestinal epithelial cells mediate the permeability of the intestinal barrier, and loss of intestinal barrier function mediated by TNF signaling is associated with the inflammatory pathophysiology observed in Crohn's disease and celiac disease. Thus, factors that modulate intestinal epithelial cell response to TNF may be critical for the maintenance of barrier function. TNF alpha-induced protein 3 (TNFAIP3) is a cytosolic protein that acts in a negative feedback loop to regulate cell signaling induced by Toll-like receptor ligands and TNF, suggesting that TNFAIP3 may play a role in regulating the intestinal barrier. To investigate the specific role of TNFAIP3 in intestinal barrier function we assessed barrier permeability in TNFAIP3−/− mice and LPS-treated villin-TNFAIP3 transgenic mice. TNFAIP3−/− mice had greater intestinal permeability compared to wild-type littermates, while villin-TNFAIP3 transgenic mice were protected from increases in permeability seen within LPS-treated wild-type littermates, indicating that barrier permeability is controlled by TNFAIP3. In cultured human intestinal epithelial cell lines, TNFAIP3 expression regulated both TNF-induced and myosin light chain kinase-regulated tight junction dynamics but did not affect myosin light chain kinase activity. Immunohistochemistry of mouse intestine revealed that TNFAIP3 expression inhibits LPS-induced loss of the tight junction protein occludin from the apical border of the intestinal epithelium. We also found that TNFAIP3 deubiquitinates polyubiquitinated occludin. These in vivo and in vitro studies support the role of TNFAIP3 in promoting intestinal epithelial barrier integrity and demonstrate its novel ability to maintain intestinal homeostasis through tight junction protein regulation

Intestinal permeability before and after ibuprofen in families of children with Crohn’s disease

BACKGROUND: Members of a subset of first-degree relatives of adults with Crohn's disease have been shown to have an increased baseline intestinal permeability and/or an exaggerated increase in intestinal permeability after the administration of acetylsalicylic acid. PURPOSE: To determine intestinal permeability in unaffected first-degree relatives of children with Crohn's disease before and after the administration of an ibuprofen challenge. METHODS: Lactulose-mannitol ratios, a measure of intestinal permeability, were determined in 14 healthy control families (41 subjects) and 14 families with a child with Crohn's disease (36 relatives, 14 probands) before and after ingestion of ibuprofen. An upper reference limit was defined using the control group as mean ± 2 SD. RESULTS: The proportion of healthy, first-degree relatives with an exaggerated response to ibuprofen (20%, 95% CI 7% to 33%) was significantly higher than controls (P=0.003). The exaggerated response was more common among siblings than among parents of pediatric probands. CONCLUSIONS: Members of a subset of first-degree relatives of children with Crohn's disease have an exaggerated increase in intestinal permeability after ibuprofen ingestion. These findings are compatible with there being a genetic link between abnormalities of intestinal permeability and Crohn's disease. Pediatrics, Health Science Centre, 3330 Hospital Drive NW, Calgary, Received for publication March 11, 1998. Accepted July 7, 1998 ORIGINAL ARTICLE T he etiology of Crohn's disease remains unknown; however, genetic and environmental factors are believed to contribute to the development of the disease. The familial aggregation of inflammatory bowel disease (Crohn's disease and/or ulcerative colitis), which may be attributed to either genetic or environmental factors, is well recognized, with a 5% to 20% likelihood of finding inflammatory bowel disease in relatives of a proband (1-5). A recent survey determining familial empirical risk of inflammatory bowel disease estimated that between 5% and 8% of first-degree relatives of affected patients will develop Crohn's disease in their lifetime (6). One approach to the identification of a genetic cause of a given disorder is to search for clinical or phenotypic markers, the occurence of which may mark the presence of specific candidate genes that might predispose to the development of the disorder -in this instance, Crohn's disease. Hollander et al The objectives of the present study were to measure intestinal permeability before and after an ibuprofen challenge in families (first-degree relatives) of children with Crohn's disease and to examine concordance in permeability results among family members. Children were studied because the familial aggregation of Crohn's disease has been shown to be associated with a lower age of onset in affected individuals of successive generations (19-22). Studies of affected parent-child pairs have shown that parents are between five and 15 years older than children at onset SUBJECTS AND METHODS Subjects: The study was approved by the Conjoint Medical Regional Ethics Board representing the University of Calgary and the Calgary Regional Health Association, and written informed consent was obtained from participating families. Of all the families of children with Crohn's disease followed at the Gastroenterology Clinic at Alberta Children's Hospital, 31 met the inclusion criteria of having a child with Crohn's disease in clinical remission, assessed by the attending pediatric gastroenterologist using a previously validated pediatric Crohn's disease activity index (25). Seven families refused to participate because the proband did not agree to do the test. Among the 24 remaining families who gave informed consent, 14 children (less than 18 years of age) with Crohn's disease and their complete families (36 first-degree relatives of children with Crohn's disease) completed the permeability studies. Fourteen healthy families (recruited from the out-patient fracture clinic and the families of staff at Alberta Children's Hospital) comprised the control group (41 family members). All relatives and controls were free of gastrointestinal symptoms. Asymptomatic relatives and controls were not investigated to identify undiagnosed Crohn's disease. Exclusion criteria for the families of healthy control children or families with an index child affected by Crohn's disease were regular use of ASA/NSAID (at least once a week), allergy or contraindication to ibuprofen, diabetes mellitus, renal insufficiency and, for children with Crohn's disease, clinical relapse. Study protocol: Subjects were instructed not to consume alcohol or NSAID for at least three days before permeabil- Technilab) and mannitol 2 g (BDH Chemicals Inc) in 100 mL of water (osmolarity 273 osmol/L). Children received 2 mL/kg (maximum 100 mL) of the test solution (lactulose 0.1 g/kg and mannitol 0.04 g/kg) and adults 100 mL. Subjects voided before drinking the test solution and then collected all urine including the first morning void in containers with 5 mL of 10% thymol in methanol. Subjects underwent two permeability tests -a baseline and a postibuprofen test. The second test was done one to five days after the baseline test. A pilot study in adults determined that an 800 mg dose of ibuprofen produced a percentage change in lactolose-mannitol (LM) ratio similar to that reported in response to ASA (18). On this basis, an oral dose of ibuprofen (adults: 800 mg; children 10 mg/kg to a maximum dose of 800 mg) was administered, and 1 h later subjects consumed the test solution and collected urine in an identical fashion to that for the baseline permeability test. One child with Crohn's disease and one subject in the relatives group had an intolerance to NSAID and did not perform the ibuprofen challenge. Analytical methods: Urine samples were kept refrigerated until analysis. Urine samples (10 mL) were deionized by adding 1 g of a 1:1.5 (wt/wt) mixture of Amberlite IR-120 and IRA-400 resin (BDH Chemicals Inc). Following centrifugation at 700 g for 10 mins, the supernatant was filtered through a 40 µm/L Millipore filter (Millipore, Massachusetts). Samples were separated on a Dionex MA-1 anion exchange column in a Dionex HPLC (Dionex) at room temperature using 500 mmol/L sodium hydroxide as the isocratic mobile phase. Peak identification was accomplished with the use of authentic standards and detected using pulsed amperometric electrochemical detection on a gold electrode. Samples were diluted as necessary after addition of cellobiose as an internal standard. Sample concentrations were quantified using linear interpolation between concentrations of known standards at multiple concentrations. All samples were diluted so that concentrations of interest fell within the range of the standards. The fractional excretion of each probe was determined by calculating the proportion of the ingested probe that was excreted in the urine. The LM ratio was obtained by dividing the fractional excretion of lactulose by the fractional excretion of mannitol. The LM ratio represents the measure of intestinal permeability. To account for the baseline level of intestinal permeability in each individual, the percentage change in LM ratio after ibuprofen was used as the main measure of interest, reflecting the response to the NSAID challenge. This ratio was calculated as follows: Percentage change in LM ratio Statistical analysis: Analyses were performed using the statistical software Stata 5.0 (Stata Corporation, Texas). All statistical tests are two-sided with an alpha level of 0.05. Descriptive statistics were performed on baseline characteristics of children with Crohn's disease and their firstdegree relatives, and controls. Baseline LM ratios did not appear to have a normal distribution and are, therefore, expressed as median and range. The percentage change in LM ratio postibuprofen was normally distributed, and data are means ± SE. Baseline LM ratios were compared among groups by using the Mann-Whitney U test. Changes in LM ratio postibuprofen were compared among study groups by using t tests. An upper reference limit was defined as mean ± 2 SD of the data from the control population. For baseCan J Gastroenterol Vol 13 No 1 January/February 1999 33 Intestinal permeability and Crohn's disease Percentage change in LM ratio, mean (SE) 38 RESULTS Permeability tests were well tolerated, and none of the children with Crohn's disease completing the ibuprofen challenge had a flare up of the disease attributable to the test. Demographic characteristics of study subjects are shown in Children in both the control and relative groups appeared to have higher baseline LM ratios than adults; however, this difference did not reach statistical significance. If children and adults were considered together, the median baseline LM ratio in relatives (0.0176) was similar to that in controls (0.0165). The median baseline LM ratio in children with Crohn's disease (0.0271) was significantly higher than in control children (P<0.001). One of 41 subjects in the control group (2%) and two of 36 in the relatives group (6%) had a baseline LM ratio above the upper reference limit. Baseline intestinal permeability was not significantly different between smokers and nonsmokers. No subject in the control group and one of 13 (8%) subjects in the group of children with Crohn's disease (8%) had a response to ibuprofen above the upper reference limit. Seven relatives (three parents and four siblings) had a percentage increase in LM ratio postibuprofen above the upper reference limit. Thus, the proportion of relatives with an exaggerated response to ibuprofen (seven of 35 [20%], 95% CI 7% to 33%) was significantly higher than that in controls (P=0.003). When smokers (four adults and no children in the group of relatives were current smokers) were excluded from the analysis, the proportion of relatives with an exaggerated response to ibuprofen remained higher than that in controls (16% versus 0%, respectively; Fisher's exact test P=0.06). In the group of relatives of children with Crohn's disease, the exaggerated response to ibuprofen was more frequent among siblings (four of 13 [31%]) than among their parents (three of 22 [14%]), and the children appeared to have a greater percentage change in LM ratio postibuprofen than adults (105% versus 44% respectively), but this difference did not reach statistical significance. The mean percentage change in LM ratio postibuprofen in relatives (mean 66%, SE 20%) and in children with Crohn's disease (mean 81%, SE 43%) was higher than in the control group (mean 35%, SE 7%); however, these differences did not reach statistical significance