Search

Background and Aims: Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes., Methods: Gene mutation analysis for BA transporter deficiencies was performed using Next Generation/Sanger sequencing, with analysis for gene deletions/duplications., Results: Intrahepatic cholestasis of pregnancy was early-onset (9-32 weeks gestation) and severe (peak BA 74-370 μmol/L), with premature delivery (28 +1 -37 0 weeks gestation) in 7/8 pregnancies, in utero passage of meconium in 4/8, but overall good perinatal outcomes, with no stillbirths. There was generally no response to ursodeoxycholic acid and variable responses to rifampicin and chelation therapies; naso-biliary drainage appeared effective in 2/2 episodes persisting post-partum in each of the two sisters. Episodic jaundice occurring spontaneously or provoked by non-specific infections, and OCS-induced cholestasis, had previously occurred in 3/5 women. Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4 mutation and a fourth case was heterozygous for another ABCB4 mutation., Conclusions: Early-onset or recurrent ICP, especially with previous spontaneous or OCS-induced episodes of cholestasis and/or familial cholestasis, may be attributable to transporter mutations, including biallelic mutations of one or more transporters. Response to standard therapies for ICP is often incomplete; BA sequestering therapy or naso-biliary drainage may be effective. Optimized management can produce good outcomes despite premature birth and evidence of fetal compromise., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables., Design: The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models' predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates., Results: The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up., Conclusion: The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans that can be activated in a TCR-independent manner by inflammatory and antiviral cytokines. In humans, the capacity for TCR-independent activation is functionally linked to a transcriptional program that can be identified by the expression of the C-type lectin receptor, CD161. In addition to MAIT cells, it has been demonstrated that a subset of γδT cells expresses CD161 and can be activated by TCR-independent cytokine stimulation. In this study, we sought to clarify the nature of cytokine-responsive human γδT cells. We could link CD161 expression on Vδ2 + versus Vδ1 + γδT cells to the observation that Vδ2 + γδT cells, but not Vδ1 + γδT cells, robustly produced IFN-γ upon stimulation with a variety of cytokine combinations. Interestingly, both CD161 + and CD161 - Vδ2 + γδT cells responded to these stimuli, with increased functionality within the CD161 + subset. This innate-like responsiveness corresponded to high expression of PLZF and IL-18Rα, analogous to MAIT cells. Vδ2 + γδT cells in human duodenum and liver maintained a CD161 + IL-18Rα + phenotype and produced IFN-γ in response to IL-12 and IL-18 stimulation. In contrast to MAIT cells, we could not detect IL-17A production but observed higher steady-state expression of Granzyme B by Vδ2 + γδT cells. Finally, we investigated the frequency and functionality of γδT cells in the context of chronic hepatitis C virus infection, as MAIT cells are reduced in frequency in this disease. By contrast, Vδ2 + γδT cells were maintained in frequency and displayed unimpaired IFN-γ production in response to cytokine stimulation. In sum, human Vδ2 + γδT cells are a functionally distinct population of cytokine-responsive innate-like T cells that is abundant in blood and tissues with similarities to human MAIT cells.

Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62)., Conclusion: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system-incorporating features of chronic biliary disease-again showed the strongest predictive value. (Hepatology 2017;65:907-919)., (© 2016 by the American Association for the Study of Liver Diseases.)

Purpose of Review: Cholangiocarcinoma is a devastating, unpredictable complication of large duct primary sclerosing cholangitis (PSC), which occurs in 5-15% of patients. The aim of this review is to discuss whether dominant strictures (DS) occurring in the larger bile ducts in PSC are a risk factor for the development of cholangiocarcinoma., Recent Findings: The development of DS is related to specific genetic polymorphisms affecting the innate immune system and the microbiome. In a recent study, the mean survival of PSC patients with DS was much worse (13.7 years) than for those without a DS (23 years). Survival difference was related to a 26% risk of cholangiocarcinoma, which developed only in those with DS. Half of the patients with cholangiocarcinoma presented within 4 months of the diagnosis of PSC. In another study, the risk of developing cholangiocarcinoma was directly related to the presence of underlying IBD, although this remains controversial. Efforts are being made towards surveying for cholangiocarcinoma including magnetic resonance imaging, endoscopic surveillance and serum tumour markers, but so far, an effective surveillance strategy has not been identified. DS should be treated endoscopically in the setting of symptoms, and there is limited evidence to suggest this may impact protectively on progression to cholangiocarcinoma., Summary: It is established that the presence of symptomatic DS occurring in the larger bile ducts in PSC can be the first presentation of cholangiocarcinoma. There is an increasing body of evidence that even when proven to be benign, dominant biliary strictures predispose to the future development of cholangiocarcinoma. Regular surveillance should be targeted at this selected high-risk group of PSC patients.

Background: Alcoholic liver disease (ALD) carries a significant cost burden and often leads to inpatient care. It is unclear whether inpatient care for ALD is any more costly than admission for other reasons., Aims: To compare the costs and outcomes of inpatient care for ALD to two groups: a control group of matched cases admitted in the same time frame and people admitted for other chronic liver diseases (CLD)., Methods: All admissions for ALD and other CLD in a 3-month period were retrospectively identified. Five randomly identified gender- and age-matched contemporaneously admitted controls were allocated. Length of stay (LoS), mortality, inpatient costs, blood product utilisation and discharge destination were compared., Results: Of the 71 admissions due to CLD, ALD was the most frequent cause (53/71, 75%). ALD admissions cost more (median $10 100 vs $5294; P = 0.0012) and had greater LoS (median LoS 7.2 days (interquartile range (IQR) 0.2-40.7)) than controls (2.6 days (IQR 1.1-6.8); P = 0.0001). A larger proportion of the ALD cohort required blood transfusion and had a higher mortality than controls (24.5 vs 6.4%, P = 0.002 and 13.2 vs 0.2%; P < 0.0001 respectively). Self-discharge was more common in the ALD group (13.2 vs 1.1%, P < 0.0001)., Conclusions: ALD inpatient hospital admissions have greater median total cost, longer LoS, greater blood product utilisation, higher mortality and greater rate of discharge against medical advice than age- and gender-matched controls. These data emphasise the large inpatient care burden, high mortality and suboptimal engagement in those with ALD, which justifies the more active provision of services for ALD., (© 2016 Royal Australasian College of Physicians.)

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, which in the majority of patients progresses to liver transplantation or death. To date, no medical treatment has been proven to be of benefit, although ursodeoxycholic acid is widely used. The etiopathogenesis of PSC is unclear, although it is associated with inflammatory bowel disease. Various hypotheses have been suggested, which have led to different therapeutic strategies. Recent studies have suggested that the microbiome may play a role in PSC, raising the possibility of efficacy of antibiotics and fecal microbiota transplantation. Gut-homing T cells may be important in the pathogenesis of PSC, and several agents are in development, targeting various receptors, integrins, and ligands on this pathway, including VAP-1, MAdCAM-1, α4β7, and CCR9. Nuclear receptor agonists such as obeticholic acid and fibrates hold promise, as do other therapies that alter bile acid composition such as norUDCA. Antifibrotic agents such as Loxl2 inhibitors are also being assessed. In conclusion, it is likely that an effective drug therapy for PSC will become available over the next decade., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Introduction: Primary sclerosing cholangitis (PSC) is a progressive cholestatic disorder that ultimately can lead to cirrhosis, liver failure, malignancy and death. It is strongly associated with inflammatory bowel disease (IBD), and though a rare disease, its incidence is increasing. There are no proven medical therapies for PSC., Sources of Data: Ovid Medline was utilised to search for articles with keywords 'sclerosing cholangitis' and 'cholangiocarcinoma' and containing titles 'primary sclerosing cholangitis', and references of these papers were cross-referenced for further relevant manuscripts., Areas of Agreement: PSC is a rare disease, and there is a strong association with risk loci within the major histocompatibility complex and other genes common to other autoimmune diseases. PSC is a premalignant condition, associated with higher rates of hepatobiliary and colorectal cancer in patients with ulcerative colitis (UC)., Areas of Controversy: The pathogenesis is unclear, and competing theories exist surrounding toxic bile acids, enhanced homing of particular T cells from the gut to the liver and increased passage of toxins to the liver through a permeable bowel wall. It is unclear whether the higher rate of colonic cancer in PSC/UC occurs in PSC/Crohn's disease. Ursodeoxycholic acid therapy reduces liver enzymes but has not been shown to improve survival. It may reduce the prevalence of bowel cancer., Growing Points: Recent genetic studies have revealed new risk loci, pointing to the importance of the immune system and its interaction with the biome., Areas Timely for Developing Research: On the basis of the genetic studies discussed earlier, novel agents are being developed and trialled in the treatment of PSC., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Colonoscopy is an invasive procedure and a limited resource. It is therefore desirable to restrict its use to those in whom it yields an important diagnosis, without missing pathology in others., Aim: The aim of this study was to determine whether standard clinical criteria can be used to reliably distinguish when colonoscopy is advisable in women 30 years and younger., Methods: A retrospective audit was performed at a single centre of 100 consecutive colonoscopies performed in women 30 years old and younger. The indications for the colonoscopy were recorded, and divided into clear and relative indications. The primary outcome of whether an endoscopic diagnosis was made was compared between the two groups. Clear indications for colonoscopy included overt rectal bleeding, elevated inflammatory markers, anaemia, iron deficiency and strong family history of colorectal cancer. Relative indications included abdominal pain or discomfort, bloating and altered bowel habit/motions., Results: The average age was 23 years. Sixty women had both relative and clear indications. Eleven had only clear indications and 28 only relative indications. Altogether, 58 colonoscopies were normal, and 17 showed inflammatory bowel disease. No subject with only relative indications had an abnormal finding (0/28). The diagnostic yield was significantly different between those with only relative indications (0%) versus those with at least one clear indication (59%; P < 0.0001)., Conclusions: Standard clinical criteria can be used to restrict safely the use of colonoscopy in young women. This will avoid performing procedures in people without clear indications, saving costs, resources and complications., (© 2015 Royal Australasian College of Physicians.)

Since the early 2000s concern has increased that college students might feign ADHD in pursuit of academic accommodations and stimulant medication. In response, several studies have validated tests for use in differentiating feigned from genuine ADHD. Although results have generally been positive, relatively few publications have addressed the possible impact of the presence of psychological disorders comorbid with ADHD. Because ADHD is thought to have accompanying conditions at rates of 50% and higher, it is important to determine if the additional psychological disorders might compromise the accuracy of feigning detection measures. The present study extended the findings of Jasinski et al. (2011) to examine the efficacy of various measures in the context of feigned versus genuine ADHD with comorbid psychological disorders in undergraduate students. Two clinical groups (ADHD only and ADHD + comorbid psychological disorder) were contrasted with two non-clinical groups (normal controls answering honestly and normal participants feigning ADHD). Extending previous research to individuals with ADHD and either an anxiety or learning disorder, performance validity tests such as the Test of Memory Malingering (TOMM), the Letter Memory Test (LMT), and the Nonverbal Medical Symptom Validity Test (NV-MSVT) were effective in differentiating both ADHD groups from normal participants feigning ADHD. However, the Digit Memory Test (DMT) underperformed in this study, as did embedded validity indices from the Wechsler Adult Intelligence Scale-IV (WAIS-IV) and Woodcock Johnson Tests of Achievement-III (WJ-III).

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease caused by diffuse inflammation and fibrosis that can involve the entire biliary tree. It is a progressive disorder which can ultimately lead to biliary cirrhosis, portal hypertension and hepatic failure. PSC is a complex genetic disorder with male predominance. Environmental predisposing factors include non-smoking. It is closely associated with inflammatory bowel disease (IBD), particularly ulcerative colitis, which occurs in about two thirds of PSC cases. Recent studies have suggested that PSC-IBD is a separate disease entity from IBD alone with distinctive genetic and phenotypic characteristics. Most PSC patients are asymptomatic at presentation; clinical symptoms include fatigue, jaundice, weight loss, right upper quadrant pain and pruritis. Serum biochemical tests indicate cholestasis, and diagnosis is usually established by cholangiography. In symptomatic patients, median survival from presentation to death or liver transplantation is about 12 years. It is a premalignant condition, and the majority of deaths are from malignancy, particularly cholangiocarcinoma or colonic cancer. PSC has no curative treatment. Medical treatment with ursodeoxycholic acid may slow progression of the disease and reduce colonic dysplasia, though trials lack statistical significance. Liver transplantation is the only option in young patients with PSC and advanced liver disease., (© 2014 S. Karger AG, Basel.)

The Minnesota Multiphasic Personality Inventory-2-RF (MMPI-2-RF) validity scales were evaluated to determine accuracy when differentiating honest responding, random responding, genuine posttraumatic stress disorder (PTSD), and feigned PTSD. Undergraduate students (n = 109), screened for PTSD, were randomly assigned to 1 of 4 instructional groups: honest, feign PTSD, half random, and full random. Archival data provided clinical MMPI-2-RF profiles consisting of 31 veterans diagnosed with PTSD. Veterans were diagnosed with PTSD using a structured interview and had passed a structured interview for malingering. Validity scales working as a group had correct classification rates of honest (96.6%), full random (88.9%), genuine PTSD (80.7%), fake PTSD (73.1%), and half random (44.4%). Results were fairly supportive of the scales' ability to discriminate feigning and full random responding from honest responding of normal students as well as veterans with PTSD. However, the RF validity scales do not appear to be as effective in detecting partially random responding.

Archival, paraffin-embedded, pathology specimens representing pretreatment tissue biopsies from 73 patients with epidermoid carcinoma of the head and neck were analyzed for DNA Index and %S-phase cells by flow cytometry and were scored for quantitative histomorphology. The DNA fluorescence/light scatter size patterns derived from paraffin-embedded specimens were shown to be essentially the same as those from mechanically disaggregated, ethanol-fixed cells obtained from the same tissue specimen. Patterns ranged from lymphocyte-like to highly abnormal DNA Index cytokinetic patterns. The DNA Index values ranged from 0.70 to 3.50 (median 1.42), with an aneuploidy frequency of 63/73 (86%). DNA distribution %S ranged from 4% to 45% (mean 19), with the microscopic malignancy grading showing broad heterogeneity (mean 2.1, range 1.0-3.0, where 1.0-1.7 = well differentiated, 1.8-2.3 = moderately differentiated, 2.4-3.0 = poorly differentiated). Cross-comparison of these data showed that (1) the tumor %S was dependent on DNA Index (higher %S at higher ploidy), (2) low to high malignancy tumors were randomly distributed between diploid/near diploid tumors and high-degree DNA abnormality tumors, and (3) proliferative activity values broadly overlapped between low to high malignancy scored tumors. However, those carcinomas characterized by high DNA Index (greater than or equal to 1.50) and high %S-phase fractions (greater than or equal to 20) had a five fold higher incidence of high-degree malignancy, invasive tumors than diploid/near diploid (%S less than or equal to 19) tumors.

Helium, resident in relatively high concentrations in certain natural gas fields in the United States, can be lost to the atmosphere when the natural gas is burned as fuel. In 1960, Congress amended the Helium Act of 1925 to provide for stripping natural gas of its helium, for purchase of the separated helium by the government, and for its long-term storage. In 1971, after about 28 billion cubic feet had been stored, the purchase program was terminated by the government, an action that unleashed several lawsuits and not a little acrimony. After more than a decade of controversy, much of the litigation has been concluded, much of the helium that could have been saved has been wasted to the atmosphere, and the gas fields supplying the helium are almost depleted. A new rich source of helium has been discovered in southwestern Wyoming that could ensure adequate supplies for many decades if an appropriate new federal policy on helium is developed and implemented.

The flow cytometric measured DNA content (i.e., DNA index), S-fractions, and histopathologic malignancy grades were studied for ninety uterine cervical squamous cell carcinomas using tissue biopsies taken prior to radiotherapy. The DNA aneuploidy frequency for low S-phase tumors (%S less than 14) was only 9/29 (31%) compared to 22/30 (73%) for intermediate (%S 15-23) and 30/31 (97%) for high (%S greater than 24) tumors. An overall mean %S of 20 +/- 7 (range 2-45%) was observed for these cervical cancers, with the S-fraction significantly increasing (P = less than 0.01) from 12 +/- 5, to 18 +/- 8, and 26 +/- 7 for diploid/near diploid, low-degree DNA aneuploidy, and high-degree DNA aneuploidy tumors, respectively. Broad heterogeneity was observed for the microscopic scored malignancy grades within DNA index and the cell-cycle S-fraction subgroups. Generally, multifactorial histopathology scoring was not significantly correlated with either the tumor DNA index or %S variables. Based on statistical analysis, the malignancy grades more closely reflected the tumor proliferative activity than the DNA index, with nuclear polymorphism, mitotic frequency, and the invasion pattern showing the lowest P values (which were not significant at P = 0.05). High tumor S-fraction was associated with high malignancy grade, as evidenced by 19/25 (75%) of high S-fraction, high degree DNA aneuploidy tumors having greater than average malignancy grade compared to only 2/14 (14%) low to moderate S-fraction tumors having similar DNA index. The results indicate that more reliable identification of biologically different cervical cancers can be achieved by evaluating the tumor DNA index in relationship to the cell-cycle %S and malignancy grading.

In an attempt to achieve more biologically meaningful subclassification of squamous cell cervical cancers and ultimately more reliable prediction of tumor behavior, we have studied the tumor pretreatment DNA content (i.e., DNA index), cell-cycle S-fraction, and histomorphologic malignancy grading properties for tumors having similar and different clinical staging. The tumor DNA index, %S-phase cells, and average malignancy grades were statistically tested against known clinical predictive variables for 90 primary squamous cell carcinomas of the uterine cervix studied prior to radiotherapy. We observed that the biological and morphological tumor properties of cervical cancers broadly overlapped between different stages of disease and for other clinical criteria including the gross morphology, lymph node status, and intravenous positivity. No significant differences were detected in the DNA indices, %S, or malignancy grades between the stages of disease or the other clinical criteria. It was concluded that: the gross clinical staging criteria inadequately reflected the tumor biological properties; and that the possibility exists for refining prognosis by use of the biological and morphological noncodependent tumor parameters to supplement staging criteria; and the use of cell-cycle cytokinetic and malignancy grading criteria in addition to tumor DNA index is superior to DNA index (or DNA content) alone for identifying biologically different cervical cancers.

Flow cytometrically (FCM) derived DNA and RNA profiles were studied in acridine orange (AO)-stained body cavity fluid (BCF) specimens obtained from 78 patients with various solid tissue and hematologic malignancies. The ploidy (DNA index), RNA content (RNA index), proliferative activity (% S + G2M) and DNA and RNA scattergram patterns were tested "double-blind" against the cytologic scoring of specimens as malignant, benign or reactive. It was determined that expression of an "abnormal" RNA index (greater than or equal to 2.8) and an elevated proliferative activity (% S + G2M greater than or equal to 7.4) was dependent on the presence of malignancy; 21 of 22 specimens having those abnormal indices had DNA aneuploidy and were cytologically scored as positive. The AO FCM sensitivity and specificity for detecting malignant cells (when measured against cytology scoring) were 61% and 90%, respectively, using the "abnormal" RNA index and % S + G2M cut-offs together with the cellular DNA aneuploidy marker. By supplementing the cytologic scoring with AO FCM DNA and RNA features, the sensitivity for detecting malignant cells was 94%, as compared to 72% for cytology alone. Two specimens gave false-positive FCM results: a tuberculous effusion with a tetraploid subpopulation and a reactive mesothelial proliferation that was diploid and negative cytologically. Scoring for malignancy based on the visual pattern of the DNA and RNA FCM scattergrams, while showing good correlation for aneuploid specimens, in some cases failed to identify diploid disease. The results demonstrate the usefulness of FCM DNA and RNA analysis for supplementing cytologic examination of BCF specimens for the purpose of detecting malignant cells.(ABSTRACT TRUNCATED AT 250 WORDS)

A far-infrared radiometer, cooled to 1.6 K by superfluid helium, has been flown in a Terrier-Sandhawk rocket. The instrument was designed to measure night-sky radiation in three wavelength passbands between 6 mm and 0.1 mm at altitudes between 120 km and 350 km. A failure in the rocket nose cone separation system prevented the measurement of this radiation, but the performance of the instrument during flight was generally satisfactory. Design features and operational characteristics of the cryogenic, optical, detection, and electronic systems are presented.