Diagnostic criteria in predicting a biliary origin of acute pancreatitis in the era of endoscopic ultrasound: multicentre prospective evaluation of 213 patients.

BACKGROUND: No study on bioclinical criteria predicting a biliary origin for acute pancreatitis has included endosonography as a reference examination. Re-examination of bioclinical parameters deserves consideration in the era where other causes are known (e.g. hereditary, autoimmune). AIM AND METHODS: To determine the performance of bioclinical markers in predicting a biliary origin of acute pancreatitis where the diagnosis of biliary lithiasis was established or ruled out using endosonography. Only patients with a first acute episode of pancreatitis were included. RESULTS: 213 patients (male: 55%; median age: 56 years) were prospectively included in 14 centres. Causes of acute pancreatitis were: biliary (62%), alcoholic (25%), other (13%). Delay between symptom-onset and admission was <48 h in 80%. Endosonography was the sole method establishing the diagnosis of biliary pancreatitis in 15% of patients. At univariate analysis, age, female sex, declared alcohol consumption, elevated aspartate and alanine transaminases on admission, gammaglutamyl transferase, alkaline phosphatase, total bilirubin, lipase, mean corpuscular volume were predictive of a biliary origin. Only age (p < 0.0001), sex (p < 0.0008) and alanine transaminase (p < 0.0004) remained significant at multivariate analysis. At age 50, the respective sensitivity and specificity were 73 and 65%. With an elevated alanine transaminase at 2 times the upper limit of normal range, the respective sensitivity and specificity were 74 and 84%. The probability of a biliary origin of acute pancreatitis could be estimated by the following formula: = 1/1 + exp(4.6967 - 0.0656 x age + 1.1208 x sex - 0.6909 x alanine transaminase). CONCLUSION: When endosonography is performed to confirm or exclude a biliary origin of acute pancreatitis, age, sex and alanine transaminase at admission are the only factors predictive of a biliary cause.     

Compound heterozygosity for unstable hemoglobin Genova and beta(o)-thalassemia associated with early onset of thalassemia major syndrome

We described the case of an infant with compound heterozygozity for a b0-thalassemic mutation and Hemoglobin (Hb) Genova, an unstable Hb variant. He has required regular transfusions as early as the second month of life and since then, behaves like a thalassemia major patient. This association leads to the most severe clinical course involving an unstable variant, reported so far.     

Hb Montfermeil [beta 130(H8) Tyr-->Cys]: suggests a key role for the interaction between helix A and H in oxygen affinity of the hemoglobin molecule

Hb Montfermeil [beta130(H8) Tyr-->Cys] is a high oxygen affinity variant causing erythrocytosis. The cysteine replacement is buried in the inside of the beta chain where it alters the interactions between helix A and H, with a further effect on helix E. This position has already been proposed to contribute to the difference in oxygen affinity between human and bovine hemoglobins. Three dimensional structural considerations and comparison of the functional behavior of other variants suggest that this region is an important determinant of the intrinsic oxygen affinity of the hemoglobin molecule.     

Comparison of Direct Interview and Family History Diagnoses of Alcohol Dependence

Using data from The Collaborative Study on the Genetics of Alcoholism, we compare direct interview diagnoses of alcohol dependence to those obtained by history from family members. Using a requirement of three or more positive implications by history, the specificity, sensitivity, and positive predictive values are 98%, 39%, and 45%, respectively.
A logistic analysis found the gender of the relative and alcoholism in the informant to be significant, but not the gender of the informant. The partial odds ratio of a diagnosis at interview associated with a positive family history diagnosis was 13.6. The relationship between the informant and relative was significant, with negative reports from an offspring or mate more influential than a negative report from a parent or second-degree relative.
We derived a recursive equation to combine a variable number of family history reports, wherein the probabilities associated with a single report are computed from the logistic analysis. This permits the use of family history information both as a proxy for an uninterviewed relative, as well as a second source of information to be used in the analysis of genetic family data.     

Occupational exposure to ionizing radiation is associated with autoimmune thyroid disease

CONTEXT: The thyroid gland is a potential target organ for radiation-related damage. OBJECTIVE: The aim of the analysis was to investigate the association between occupational exposure to ionizing radiation and autoimmune thyroid disease (AITD). DESIGN: Our design was the cross-sectional Study of Health in Pomerania. SETTING: The setting was the general community. SUBJECTS: Analyses were performed in a population-based sample of 4299 subjects. Among them, 160 persons reported a history of occupational exposure to ionizing radiation. MAIN OUTCOME MEASURE: AITD was defined as the combined presence of hypoechogenicity in thyroid ultrasound and antithyroxiperoxidase antibodies greater than 200 IU/ml. RESULTS: Females with occupational exposure to ionizing radiation had more often AITD than nonexposed females (10.0 vs. 3.4%; P < 0.05). This association persisted after adjustment for relevant confounders (odds ratio, 3.46; 95% confidence interval, 1.16-10.31; P < 0.05). In males, there were too few subjects who fulfilled the criteria of AITD, but the association between the exposure to radiation and hypoechogenicity of the thyroid gland barely missed statistical significance (odds ratio, 2.20; 95% confidence interval, 0.92-5.26; P = 0.08). In both females and males, subjects who reported a length of exposure of more than 5 yr exhibited the highest risk of the endpoints. CONCLUSIONS: We conclude that occupational exposure to ionizing radiation is related to the risk of AITD. The usage of thyroid protection shields by radiation workers is strongly recommended.     

Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

BACKGROUND/AIMS: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. METHODS: In 28 liver transplant recipients, bile samples were collected daily posttransplantation for determination of bile composition. Hepatic expression of bile transporters was studied before and after transplantation. Histopathological criteria as well as biliary concentrations of alkaline phosphatase (ALP) and gamma-glutamyltransferase (gamma-GT) were used to quantify bile duct injury. RESULTS: Early after transplantation, bile salt secretion increased more rapidly than phospholipid secretion, resulting in high biliary bile salt/phospholipid ratio (BA/PL). In parallel with this, mRNA levels of the bile salt transporters NTCP and BSEP increased significantly after transplantation, whereas phospholipid translocator MDR3 mRNA levels remained unchanged. Bile duct injury correlated significantly with bile salt secretion and was associated with a high biliary BA/PL ratio. CONCLUSIONS: Bile salt secretion after human liver transplantation recovers more rapidly than phospholipid secretion. This results in cytotoxic bile formation and correlates with bile duct injury. These findings suggest that endogenous bile salts have a role in the pathogenesis of bile duct injury after liver transplantation.     

Activins and activin antagonists in hepatocellular carcinoma

In many parts of the world hepatocellular carcinoma （HCC） is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β （TGFβ） superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homoor heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic coreceptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.     

Gab1, SHP2, and protein kinase A are crucial for the activation of the endothelial NO synthase by fluid shear stress

Fluid shear stress enhances NO production in endothelial cells by a mechanism involving the activation of the phosphatidylinositol 3-kinase and the phosphorylation of the endothelial NO synthase (eNOS). We investigated the role of the scaffolding protein Gab1 and the tyrosine phosphatase SHP2 in this signal transduction cascade in cultured and native endothelial cells. Fluid shear stress elicited the phosphorylation and activation of Akt and eNOS as well as the tyrosine phosphorylation of Gab1 and its association with the p85 subunit of phosphatidylinositol 3-kinase and SHP2. Overexpression of a Gab1 mutant lacking the pleckstrin homology domain abrogated the shear stress-induced phosphorylation of Akt but failed to affect the phosphorylation or activity of eNOS. The latter response, however, was sensitive to a protein kinase A (PKA) inhibitor. Mutation of Gab1 Tyr627 to phenylalanine (YF-Gab1) to prevent the binding of SHP2 completely prevented the shear stress-induced phosphorylation of eNOS, leaving the Akt response intact. A dominant-negative SHP2 mutant prevented the activation of PKA and phosphorylation of eNOS without affecting that of Akt. Moreover, shear stress elicited the formation of a signalosome complex including eNOS, Gab1, SHP2 and the catalytic subunit of PKA. In isolated murine carotid arteries, flow-induced vasodilatation was prevented by a PKA inhibitor as well as by overexpression of either the YF-Gab1 or the dominant-negative SHP2 mutant. Thus, the shear stress-induced activation of eNOS depends on Gab1 and SHP2, which, in turn, regulate the phosphorylation and activity of eNOS by a PKA-dependent but Akt-independent mechanism.     

Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium

Uridine diphospho-glucuronosyltransferases (UGTs) inactivate and facilitate the excretion of estrogens to glucuronides (-G), the most abundant circulating estrogen conjugates. The identity of the conjugated estrogens formed by all known overexpressed UGTs (n = 16) was analyzed by comparison with retention time and mass fragmentation of authentic standards by HPLC tandem mass spectrometry methods. Six UGTs, namely 1A1, 1A3, 1A8, 1A9, 1A10, and 2B7, were found to glucuronidate estradiol (E(2)) and estrone (E(1)), their hydroxyls (OH), and their methoxy derivatives (MeO). Addition of glucuronic acid was catalyzed by specific UGTs at positions 2, 3, and 4 of the estrogens, whereas only E(2) was conjugated at position 17 by UGT2B7. Kinetic parameters indicate that the conjugation of E(2) at position 3 was predominantly catalyzed by 1A1, 1A3, and 1A8 and by 1A8 for E(1). Conjugation of 2-OHE(1)/E(2) and 2- and 4-MeOE(1)/E(2) was selective at position 3, mostly catalyzed by 1A1 and 1A8. Of all UGTs, UGT2B7 demonstrated the highest catalytic activities for estrogens and at least 10- to 50-fold higher activity for the conjugation of genotoxic 4-hydroxycatecholestrogens at position 4, compared with the conjugation of E(2), E(1), and 2-hydroxycatecholestrogens. Its presence was further shown in the endometrium by RT-PCR and immunohistochemistry, localizing in the same cells expressing CYP1B1, involved locally in the formation of 4-hydroxycatecholestrogens. Data show that several UGT enzymes detected in the endometrium are involved in the glucuronidation of E(2) and its 2-OH, 4-OH, and 2-MeO metabolites that exert various biological effects in the tissue.     

Constant vs auto-continuous positive airway pressure in patients with sleep apnea hypopnea syndrome and a high variability in pressure requirement

STUDY OBJECTIVES: Auto-continuous positive airway pressure (CPAP) has been reported to have no more efficacy than constant CPAP in unselected patients with sleep apnea hypopnea syndrome (SAHS). The aim of this study was to evaluate patients judged to be good candidates for auto-CPAP because of a high within-night variability in pressure requirement. DESIGN: Single-blind, randomized, cross-over study (2 x 8 weeks) to compare auto-CPAP with constant CPAP. PATIENTS: Outpatients with moderate-to-severe SAHS attending the chest clinic. INTERVENTIONS: Patients were equipped at home in the auto-CPAP mode (model GK418A; Malinckrodt; Nancy, France), using a 4- to 14-cm H(2)O pressure range. Those individuals having a high within-night variability in pressure requirement, assessed at the end of a 14-day run-in period, were included in the cross-over study. Auto-CPAP was compared with constant CPAP (according to a titration night in the sleep laboratory) in terms of compliance, efficacy on apneas (assessed from the pressure monitor), and sleepiness (assessed on the Epworth sleepiness scale). MEASUREMENTS AND RESULTS: Of 90 consecutive patients with SAHS, 27 patients were selected for a within-night variability in pressure requirement exceeding a given threshold. After completion of the cross-over, 24 patients were evaluable. The median percentage of nights the machine was used was 95.5% (range, 45 to 100%) on constant CPAP, and 96.5% (range, 40 to 100%) on auto-CPAP; the median apnea index recorded by the device was 0.40/h (range, 0 to 2.40/h) on constant CPAP, and 0.45/h (range, 0 to 5.80/h) on auto-CPAP (differences not significant). The mean Epworth sleepiness score was significantly (p < 0.01) lower on auto-CPAP (5.1; SD, 2.8) than on constant CPAP (6.1; SD, 2.8). CONCLUSIONS: In patients selected for a high within-night variability in pressure requirement, auto-CPAP administered via a GK418A device was equivalent to constant CPAP based on a titration night in the sleep laboratory. Subjective ratings for sleepiness were slightly lower on auto-CPAP.