The Perfect Way to Predict the Severity of Acute Pancreatitis: The Search Continues

This study was designed to determine the clinical utility of three rating scales (Ranson's, Acute Physiology And Chronic Health Evaluation [APACHE] II and Glasgow) in predicting the severity of acute pancreatitis experienced by patients known to have human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). A retrospective analysis identified 73 patients with both acute pancreatitis and HIV who had been admitted to two Canadian hospitals between 1989 and 1999. Of those 73, 11 (15%) went on to have a clinical course consistent with a diagnosis of severe pancreatitis. For the purposes of the study, severe pancreatitis was defined by the occurrence of death, intensive care unit admission, surgical intervention or significant symptomatic local complications (necrosis, abscess or pseudocyst). The authors found that the APACHE II and Ranson's scores had a sensitivity of 100% and specificities of 70% and 33% for severe pancreatitis, respectively. The Glasgow score had a statistically poorer diagnostic performance

Case Report A Case Study of Severe Esophageal Dysmotility following Laparoscopic Sleeve Gastrectomy

Following bariatric surgery, a proportion of patients have been observed to experience reflux, dysphagia, and/or odynophagia. The etiology of this constellation of symptoms has not been systematically studied to date. This case describes a 36-year-old female with severe esophageal dysmotility following LSG. Many treatments had been used over a course of 3 years, and while calcium channel blockers reversed the esophageal dysmotility seen on manometry, significant symptoms of dysphagia persisted. Subsequently, the patient underwent a gastric bypass, which seemed to partially relieve her symptoms. Her dysphagia was no longer considered to be associated with a structural cause but attributed to a "sleeve dysmotility syndrome." Considering the difficulties with managing sleeve dysmotility syndrome, it is reasonable to consider the need for preoperative testing. The question is whether motility studies should be required for all patients planning to undergo a LSG to rule out preexisting esophageal dysmotility and whether conversion to gastric bypass is the preferred method for managing esophageal dysmotility after LSG

Prospective Study of Biliary Strictures to Determine the Predictors of Malignancy

BACKGROUND: There have been few prospective studies regarding the investigation of biliary strictures, principally because of rapid technological change. The present study was designed to determine the sensitivity of various imaging studies for the detection of biliary strictures. Serum biochemistry and imaging studies were evaluated for their role in distinguishing benign from malignant strictures

Prospective study of biliary strictures to determine the predictors of malignancy

ORIGINAL ARTICLE BACKGROUND: There have been few prospective studies regarding the investigation of biliary strictures, principally because of rapid technological change. The present study was designed to determine the sensitivity of various imaging studies for the detection of biliary strictures. Serum biochemistry and imaging studies were evaluated for their role in distinguishing benign from malignant strictures. METHODS: Thirty-one patients with suspected noncalculus biliary obstruction were enrolled consecutively in the study. A complete biochemical profile, ultrasound, Disida scan and cholangiogram (endoscopic retrograde cholangiopancreatography [ERCP] or percutaneous cholangiogram) were obtained at study entry. Stricture etiology was determined based on cytology, biopsy and/or clinical follow-up at one year. RESULTS: Twenty-nine of 31 patients had biliary strictures, of which 15 were malignant. The mean age of the malignant cohort was 73.9 years versus 53.9 years in the benign cohort (P<0.001). Statistically significant differences between the malignant and benign groups, respectively, were as follows: alanine transaminase 235.2 versus 66.9 U/L (P=0.004), aspartate transaminase 189.8 versus 84.5 U/L (P=0.011), alkaline phosphatase 840.2 versus 361.1 U/L (P=0.002), bilirubin 317.8 versus 22.1 µmol/L (P<0.001) and bile acids 242.5 versus 73.2 µmol/L (P=0.001). Threshold analysis using receiver operative characteristic (ROC) curves demonstrated that a bilirubin level of 75 µmol/L was most predictive of malignant strictures. Intrahepatic duct dilation was present in 93% of malignant strictures versus 36% of benign strictures (P=0.002). Common hepatic duct dilation was less discriminatory (malignant 13.5 versus benign 9.6 mm; P=0.11). Ultrasound was highly sensitive (93%) in the detection of the primary tumour in the bile duct or pancreas, or in the visualization of nodal or liver metastases. In benign disease, ultrasound failed to detect evidence of intrahepatic or extrahepatic biliary dilation in most cases. Disida scans were not able to distinguish between malignant or benign strictures and could not accurately localize the level of obstruction. The sensitivity of Disida scan for the diagnosis of obstruction was 50%. Cholangiographic characterization of strictures revealed an equal distribution of smooth (eight of 13) and irregular (five of 13) strictures in the malignant group. Ten of 13 benign strictures were characterized as smooth. Malignant strictures were significantly longer than benign ones -30.3 versus 9.2 mm (P=0.001). Threshold analysis using ROC curves showed that strictures greater than or equal to 14 mm were predictive of malignancy (sensitivity 78%, specificity 75%, log odds ratio 11.23). CONCLUSIONS: A serum bilirubin level of 75 µmol/L or higher, or a stricture length of greater than 14 mm was highly predictive of malignancy in patients with a biliary stricture. Ultrasound was useful in predicting malignant strictures by detecting either intrahepatic duct dilation or by visualizing the tumour (primary or metastases). Strictures with a 'benign' cholangiographic appearance are frequently malignant. Disida scan did not add additional information. ERCP is necessary to diagnose benign strictures, which tend to be less extensive at presentation. B iliary strictures are a challenging problem for the clinician. By the time that patients with biliary strictures are referred to a specialist, the diagnosis is usually already known or strongly suspected because clinical evaluation and noninvasive investigations alone have a high specificity and sensitivity (1-4). The job of the medical or surgical specialist is not only to confirm the diagnosis of biliary stricture but also, importantly, to define the etiology and the exact anatomic location, which is vital to therapeutic planning. The differentiation between benign and malignant strictures can be difficult but is of obvious importance in regard to prognosis and optimal therapy. Numerous imaging modalities are available for the investigation of biliary strictures, including abdominal ultrasound, computed tomographic (CT) scanning, nuclear imaging, percutaneous transhepatic cholangiography (PTC), endoscopic retrograde cholangiopancreatography (ERCP) and most recently magnetic resonance cholangiopancreatography (MRCP). Comparative and descriptive studies in this area are lacking, primarily because rapid technological improvements and developments outdate them. We, therefore, embarked on a prospective descriptive trial with the following aims: · Determine the predictive value of liver enzymes, serum bilirubin, serum bile acids, ultrasound and diethyl-iminodiacetic acid (Disida) nuclear imaging for the presence of malignant biliary strictures. · Measure the ability of ultrasound and nuclear imaging to localize the level of obstruction using direct cholangiography as the gold standard. · Determine the sensitivity of abdominal ultrasound and Disida nuclear scanning for the detection of biliary strictures. · Investigate the utility of various cholangiographic features to distinguish malignant from benign strictures. PATIENTS AND METHODS Patients: All patients with biliary strictures referred to the Division of Gastroenterology at the University of Alberta Hospitals for investigation between January 1, 1995 and December 31, 1995 were prospectively entered into the trial. The inclusion criteria were age 16 years or older and noncalculus biliary obstruction. Patients were excluded if subsequent evaluation did not show a stricture. Ethics committee approval was obtained. sente dans 93 % des sténoses malignes par rapport à 36 % des sténoses béni-gnes (P = 0,002). Une dilatation du canal hépatique commun était moins discriminatoire (13,5 mm en cas de malignité par rapport à 9,6 mm en cas de bénignité, P = 0,11). L'échographie était hautement sensible (93 %) pour déceler la tumeur primaire dans le canal biliaire ou le pancréas, ou pour visualiser les nodules ou les métastases hépatiques. Dans le cas d'une maladie bénigne, l'échogra-phie n'a pas réussi à déceler la présence d'une dilatation biliaire intra-hépa-tique ou extra-hépatique dans la plupart des cas. Les scintigraphies au disida n'ont pas pu différencier les sténoses malignes des sténoses bénignes ou localiser précisément le niveau de l'obstruction. La sensibilité des scintigraphies au disida pour établir un diagnostic d'obstruction était de 50 %. La caractérisation cholangiographique des sténoses a révélé une distribution égale de sténoses lisses (huit sur 13) et irrégulières (cinq sur 13) dans le groupe des sténoses malignes. Dix des 13 sténoses bénignes ont été qualifiées de lisses. Les sténoses malignes étaient nettement plus longues que les sténoses bénignes, soit 30,3 mm par rapport à 9,2 mm (P=0,001). L'analyse des seuils au moyen des courbes ROC a révélé que des sténoses supérieures ou égales à 14 mm étaient un prédicteur de malignité (sensibilité de 78 %, spécificité de 75 %, risque relatif logarithmique de 11,23). CONCLUSIONS : Un niveau de bilirubine sérique de 75 µmol/L ou une longueur de sténose de 14 mm étaient fortement prédictifs de malignité chez les patients atteints d'une sténose biliaire. L'échographie était utile pour prédire les sténoses malignes en décelant soit une dilatation du canal intra-hépatique ou en visualisant la tumeur (primaire ou métastases). Les sténoses d'apparence « bénigne » à la cholangiographie s'avèrent souvent malignes. La scintigraphie au disida n'apportait pas d'informations supplé-mentaires. Une CPRE est nécessaire pour diagnostiquer des sténoses bénignes, qui ont tendance à être moins étendues à l'examen. · Abdominal ultrasound examination with particular attention to intrahepatic biliary dilation, extrahepatic duct calibre, presence or absence of gallbladder and other relevant pathology such as tumour mass or ductal stones. · Disida scan. Patients were examined after a 4 h fast. Opiates were withheld for the proceeding 24 h. In addition to the standard scan, data were collected for deconvolutional analysis to determine hepatic extraction fraction and time activity curve so that the half-life of biliary excretion and time to peak activity could be analyzed. · Cholangiography. ERCP was attempted first in all patients with failures proceeding to PTC. Cefazoline 1 g was administered intravenously 30 to 60 mins before cholangiography. The biliary system was filled as completely as possible using 50% Conray 60 (Mallenchrodt, St Louis, Missouri) contrast injected under low pressure. The information obtained from each cholangiogram included site of stricture, multiplicity, character (smoothly tapered versus irregular or shouldered), stricture(s) length, minimal stricture width, maximal proximal biliary dilation and other information (ampullary mass, primary sclerosing cholangitis, cancer of the pancreas). All data were to be collected within five working days so that the different imaging modalities tested would be comparable. All imaging studies were interpreted by radiologists blinded to the results of the patients' other diagnostic studies. The ERCP data were obtained last so that a biliary stent could be inserted if indicated. The cholangiographic measurements were confirmed by two independent observers. Stricture etiology was defined by cytology or biopsy histology or by clinical outcome after one year. Statistical analysis: Statistical analysis was performed using SPSS. Between-groups differences in mean values of continuous variables were tested by independent samples t tests or by nonparametric Mann-Whitney Rank Sum tests when the distributions were not normal. The differences in frequencies of categorical variables were tested by c 2 test with Yates' correction for continuity or by Fisher's exact test when the expected number of observations per cell was less than five. Associations between continuous variables were assessed by Pearson correlation coefficient. Logistic regression analysis was used to analyze the association of dichotomous outcome variable (malignant versus benign) with continuous and categorical predictor variables. The statistical inferences were based on the level of significance P<0.05. Receiver operating characteristic (ROC) curves were constructed for the biochemical variables. To determine optimal threshold levels for each diagnostic parameter, ROC plots were constructed using the observed true and false positive rates at each potential threshold level. A best fit ROC curve was constructed according to methods published elsewhere (5,6). The threshold value providing the best compromise between true and false positive rates was estimated from the ROC plot. Likelihood ratios were calculated from the fitted ROC curve. RESULTS Thirty-one patients were enrolled in the study. Two patients were excluded -one because he did not have a stricture and one whose suspected stricture was unevaluable because of previous biliary bypass and contraindication for PTC as a result of coagulopathy. Of the remaining 29 patients, 15 were diagnosed with malignant strictures and 14 with benign strictures. Two patients had primary sclerosing cholangitis, both of whom had multiple strictures. Patient demographics and underlying diagnosis are shown i

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Developmental history and stress responsiveness are related to response inhibition, but not judgement bias, in a cohort of European starlings (Sturnus vulgaris)

Judgement bias tasks are designed to provide markers of affective states. A recent study of European starlings (Sturnus vulgaris) demonstrated modest familial effects on judgement bias performance, and found that adverse early experience and developmental telomere attrition (an integrative marker of biological age) both affected judgement bias. Other research has shown that corticosterone levels affect judgement bias. Here, we investigated judgement bias using a modified Go/No Go task in a new cohort of starlings (n = 31) hand-reared under different early-life conditions. We also measured baseline corticosterone and the corticosterone response to acute stress in the same individuals. We found evidence for familial effects on judgement bias, of a similar magnitude to the previous study. We found no evidence that developmental treatments or developmental telomere attrition were related to judgement bias per se. We did, however, find that birds that experienced the most benign developmental conditions, and birds with the greatest developmental telomere attrition, were significantly faster to probe the learned unrewarded stimulus. We also found that the birds whose corticosterone levels were faster to return towards baseline after an acute stressor were slower to probe the learned unrewarded stimulus. Our results illustrate the potential complexities of relationships between early-life experience, stress and affectively mediated decision making. For judgement bias tasks, they demonstrate the importance of clearly distinguishing factors that affect patterns of responding to the learned stimuli (i.e. response inhibition in the case of the Go/No Go design) from factors that influence judgements under ambiguity

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson's disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors. The D2 dopamine receptor (DRD2) is the primary target for both typical and atypical antipsychotic drugs, and for drugs used to treat Parkinson's disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors. Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2-risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved