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Introduction: The ventrolateral (VL) nucleus of the thalamus is the commonly chosen target for deep brain stimulation (DBS) to alleviate tremor. However, it has a poor efficacy in alleviating proximal tremor and patients may develop tolerance to the action component of tremor. We performed bilateral stimulation of the caudal or motor part of the zona incerta nucleus (cZI) to determine its safety and efficacy in alleviating tremor. Methods: 5 patients with parkinsonian tremor and 13 with a range of tremors (Holmes (HT), cerebellar (CT), essential (ET), multiple sclerosis (MS) and dystonic tremor (DT)) affecting both the proximal and distal body parts underwent MRI guided, bilateral cZI DBS. Tremor was assessed by the Fahn-Tolosa-Marin (FTM) tremor scale at baseline and at a mean follow-up of 12 months. Results: Resting PD tremor improved by 94.8% and postural tremor by 88.2%. The total tremor score improved by 75.9% in 6 patients with ET. HT improved by 70.2%, proximal CT by 60.4% and proximal MS tremor by 57.2% in the total tremor rating score. In the single patient with DT, there was improvement in both the dystonia and the tremor. Patients required low voltages of high-frequency stimulation and did not develop tolerance to it. Stimulation-related side effects were transient. Conclusion: This prospective study shows that the cZI may be an alternative target for the treatment of tremor with DBS. In contrast to bilateral DBS of the VL nucleus, it improves all components of tremor affecting both the distal and proximal limbs as well as the axial musculature. [ABSTRACT FROM AUTHOR]

Background: The importance of antinucleolar antibodies seen by indirect immunofluorescence on HEp-2 cells, although associated with systemic sclerosis (SSc), in unselected patients is unknown. Arms: To determine the true clinical significance of antinucleolar antibodies in an unselected patient population. Methods: Antinucleolar antibody (ANoA) positive samples were identified in the immunology laboratory during routine autoimmune screening tests; case notes were using a standard proforma. reviewed Results 104 patients with ANoA were identified and ANoA samples were subclassified into homogeneous clumpy and .speckled antinucleolar types. SSc was evident in only two (1.8%) patients. Other connective tissue diseases were identified in 33 patients (32%); 22 patients (21%) had evidence of various malignancies. Both disordered liver function and anaemia were seen in 22 patients And were the commonest laboratory abnormalities. Conclusions: Neither the presence nor subtype of ANoA is specific four systemic sclerosis. Laboratory comments appended, to results should reflect this fact. [ABSTRACT FROM AUTHOR]

Background: The TIMI risk score is a well-validated scoring system used to predict mortality in patients following an ST-segment elevation myocardial infarction (STEMI). N-terminal pro-B-type natriuretic peptide (NTpr0BNP) has also been found to be useful in predicting mortality following STEMI. Objective: To investigate the utility of the TIMI score and NTproBNP levels at predicting risk of death in patients with acute myocardial infarction (AMI). Methods: 473 patients (352 men, mean (SD) age 63.7 (12.3) years) with AMI were studied. Blood was drawn within 24 hours after the onset of chest pain and the plasma concentration of NTpr0BNP was determined using an in-house non-competitive immunoassay. Patients TIMI risk score was measured and patients stratified into low- (0 to 2), intermediate- (3-7) and high-risk (>8) groups. Results: Mortality was 8.9% and was related to higher TIMI risk scores (p = 0.029 for trend). Higher NTproBNP levels were also related to increased mortality (median (range) fmol/ml, survivors 700.2 (0.3-11485.3) vs dead 5781.3 (1.4-10835.9), p<0.001). In a multivariate binary logistic regression model, independent predictors of mortality were NTproBNP levels in the first 24 hours (odds ratio (OR) = 4.21, 95% Cl 1.96 to 9.07, p<0.001) together with drug treatments. The receiver operating curve for NTpr0BNP in the first 24 hours yielded an area under the curve (AUC) of 0.79 (95% Cl 0.70 to 0.88), p<0.001, for TIMI risk score the AUC was 0.67 (95% Cl 0.58 to 0.76), p = 0.001. Conclusion: In the first 24 hours following an AMI, NTpr0BNP is better than the TIMI risk score at predicting mortality. A simple NTproBNP blood test is more easily applicable and is more accurate than a clinical risk score. [ABSTRACT FROM AUTHOR]

Background and purpose: Posterior circulation stroke accounts for 20% of ischaemic strokes. Recent data suggest that the early stroke recurrence risk is high and comparable with carotid artery disease. Vertebral artery stenosis accounts for approximately 20% of posterior circulation stroke, and with endovascular treatment available accurate diagnostic imaging is important. We performed a systematic literature review to validate the accuracy of the non-invasive imaging techniques Duplex ultrasound (DUS), magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) in detecting severe vertebral artery stenosis, with intra-arterial angiography (IAA) as the reference standard. Methods: We identified studies that used non-invasive imaging and IAA as the reference standard to determine vertebral artery stenosis and provided adequate data to calculate sensitivity and specificity. We analysed the quality of these studies, looked for evidence of heterogeneity and performed subgroup analysis for different degrees of stenosis. Results: 11 studies categorised stenosis into 50-99%. The sensitivity of CIA (single study) and pooled sensitivities of contrast enhanced MRA (CE-MRA) and colour duplex were 100% (95% CI 15.8 to 100), 93.9% (79.8 to 99.3) and 70.2% (54.2 to 83.3), respectively. The specificities for CIA, CE-MRA and colour duplex were 95.2% (83.8 to 99.4), 94.8% (91 .1 to 97.3) and 97.7% (95.2 to 99.1). However, specificities for CE-MRA and colour duplex demonstrated significant heterogeneity (p=0.003 and p=0.002, respectively). Conclusions: CE-MRA and possibly CIA may be more sensitive in diagnosing vertebral artery stenosis than DUS. However, data are limited and further high quality studies comparing DUS, MRA and CIA with IAA are required. [ABSTRACT FROM AUTHOR]

Aims: To demonstrate the expression patterns of two fibroblast growth factor receptors (FGFR-2 and FGFR-3) in the normal human fetal orbit. Methods: 6 μm orbital slide sections were prepared from 12 week old human fetal material obtained within established ethical guidelines. Radioactive in situ hybridisation techniques were used to demonstrate the expression patterns of FGFR-2 and FGFR-3 within these sections. Only one foetus had appropriate orbital sections taken. Results: FGFR-2 was expressed within the extraocular muscles (EOMs) and the optic nerve sheath and to a lesser degree within the orbital periosteal margins and the cranial sutures. FGFR-3 was expressed a lot within the periosteal margins and cranial sutures but not within either the EOMs or the optic nerve sheath. Conclusions: FGFR-2 and FGFR-3 are differentially expressed within different orbital components. FGFR-2 gene mutations may be responsible for craniosynostotic syndromes such as Crouzon, Pfeiffer, and Apert, while those in the FGFR-3 gene may cause isolated unicoronal synostosis. EOMs may be histologically abnormal in cases of Apert, Pfeiffer, and Crouzon syndromes but not isolated unicoronal synostosis. The pattern of expression of FGFR-2 in the normal human fetal orbit may explain some of the EOM histological findings seen in some cases of Apert, Pfeiffer, and Crouzon syndromes. [ABSTRACT FROM AUTHOR]

AIMS: To determine the visual outcome and prevalence of amblyogenic risk factors in children with craniosynostotic syndromes. METHODS: The case notes of 141 children seen within the craniofacial unit were reviewed and information retrieved on date of birth, age at first and last examination, cycloplegic refraction at last visit, best corrected visual acuity at last visit, horizontal ocular deviation in primary position at first visit, and alphabet pattern if any. The presence of astigmatism, its magnitude, and orientation of axis were determined. RESULTS: 40.3% of patients had 1 dioptre (D) of astigmatism or greater and, of these, 64% had oblique astigmatism in at least one eye. Anisometropia of 1D or more was found in 18% of patients (age matched normals 3.5%). Horizontal strabismus was found in 70% (38% exotropia, 32% esotropia). Visual outcome results showed 39.8% of patients (45 of 113) had visual acuity of 6/12 or worse in their better eye. CONCLUSION: In the largest study to date a poor visual outcome was shown in children with Crouzon's, Pfeiffer's, Apert's, and Saethre-Chotzen syndromes (39.8% with 6/12 or worse in the better eye) together with significant prevalence of amblyogenic risk factors. [ABSTRACT FROM AUTHOR]

The article offers introduction to the online tutorial entitled "Cholangiocarcinoma and its management" offered by the magazine. It states that cholangiocarcinoma develops in the biliary epithelium and contributes to the growth of mortality rates in Great Britain. In addition, it shows that cholangiocarcinoma leads to the development of sclerosing cholangitis. It reveals that magnetic resonance imaging (MRI) can be utilized for the disease's diagnosis.

As ageing is an upcoming issue in low-income countries, an increase dependence on familial support is expected. Yet, traditional familial support mechanisms are threatened by declining family size, urban migration and globalisation. Our aim for this qualitative study was to explore the personal experiences and perception of elderly Pakistani patients about social and family support dynamics. The study was nested in a larger quantitative study. Patients attending the outpatient department of a tertiary care hospital were interviewed. Content analysis of data resulted in identification of one main theme, “Ageing exposes limitations in the support systems to address disability, reliance and vulnerabilities” and two sub-themes, (1) Disability and Vulnerability; (2) Support and Expectation. The driving forces behind limitation in the support systems were functional disability, illness, inability to pay for healthcare, and disobedience and expectations from children. In addition, due to lack of old age social benefit systems elderly became dependent on their children for their physical and emotional care. They perceived old age as a tough stage of life, and felt themselves as a financial burden on their children. The elderly cited the concern regarding deteriorating social support system due to a crumbling value system of the society. Further, looking after the elderly was a value and responsibility of the children, society and government. Most of the participants refused to avail alternative accommodation like old homes, as they wanted to live with their loved ones in the current setup even with all difficulties. Strengthening of systems could enable elderly to cope. [ABSTRACT FROM PUBLISHER]

As ageing is an upcoming issue in low-income countries, an increase in the prevalence of functional disability among older citizens is expected, paralleled with increase dependence on familial support. The study examines the occurrence of functional disabilities among older people in a low-income setting and its association with individual familial support. Data were gathered from a sample of 136 patients aged 60+ years attending a tertiary healthcare hospital in Islamabad. Assessments of functional disability (ADL and IADL) and familial support were made using a standardised questionnaire. Disability (yes/no) was assessed for each of 15 functional disability items. Thereafter, the association between disability (on any item) and each (also dichotomised) component of three dimensions of familial support (instrumental; social and emotional) was measured using Fisher exact test (a total of 15 components). 69% of the subjects qualified as disabled. Disability was more common in IADL than ADL activities. There was a significant difference between disabled and non-disabled persons as regards several forms of instrumental support they received, to the benefit of the disabled. There was not much difference in social and emotional support. The fact of being disabled seems to be associated with individual sociodemographic status, to the detriment of women, illiterate and non earners. Disability is prevalent among older people in Pakistan, occurs at an early age and is associated with the familial support received, particularly instrumental support. There is a need to understand these associations better to allow older people to realise their healthy life potential. [ABSTRACT FROM PUBLISHER]

Introduction Tuberculosis (TB) is prevalent in over a third of the world's population, with Asia (31%) and Africa (55%) accounting for most cases. The rising UK incidence of TB is partly due to increasing immigration from these regions. The UK prevalence of Hepatitis B virus (HBV) is estimated at 0.1% and the prevalence of Hepatitis C Virus (HCV) at 0.4%. HBV & HCV are treatable, but are largely asymptomatic until advanced liver disease has occurred. Therefore, HBV and HCV screening are recommended in high risk groups. Patients with TB do not currently undergo routine screening for these viruses, but are offered screening for HIV. HBV & HCV share similar epidemiological hotspots with TB and studies from Asia suggest HBV/HCV are significantly associated with TB infection and Drug-Induced Liver Injury (DILI) from anti-TB therapy. Currently, no studies have investigated the prevalence of viral hepatitis in TB patients in Western Europe, and the risk this poses to DILI. Aim To assess (1) the prevalence of viral hepatitis in patients undergoing anti-TB therapy in West London; (2) if patients with serological evidence of viral hepatitis are at increased risk of DILI. Method This was a prospective study of 245 newly diagnosed active (n=167) and latent (n=78) TB patients embarking on anti-TB therapy. Liver Function Tests (LFTs) were performed prior to & 2 weeks after initiation of anti-TB therapy. Patients were offered both HIV and viral hepatitis screening. All patients were tested for viral markers, including HBsAg, HBeAg, HBcAg, anti-HBc, seropositivity to HCV, and to HIV. DILI was defined as ALT elevated twice above the upper limit of normal (2x >ULN (40 IU/L)) any time following normal pre-treatment LFTs. Results 149 (61%) TB patients were from the Asian Subcontinent and Sub-Saharan Africa, while only 15 (6%) were from the UK, mimicking global TB prevalence. 49 (20%) patients had serological markers for HBV or HCV, of whom 7 (3%) were HBsAg positive (one patient was Asian, two South East Asian and four Sub-Saharan African). 37 patients (15%) had isolated antibody to HBcAg. Five (2.0%) patients were HCV positive (one Asian, two Sub-Saharan African and two UK Caucasian). 17% of those with viral markers had raised pre-treatment ALT. 2.6% of patients tested for HIV were positive for viral hepatitis. 18% of active TB patients and 23% of latent TB patients had markers for viral hepatitis. Ten (5.4%) patients were diagnosed with DILI, of whom only 1 (0.5%) had markers for viral hepatitis. Four (2.2%) patients required treatment interruption due to elevated LFTs, none of whom had serological markers of viral hepatitis. Conclusion In our West London cohort, TB patients are a high risk group for HBV and HCV carriage. We found no increased risk of DILI in patients with markers of viral hepatitis undergoing anti-TB therapy. Screening for viral hepatitis in high risk groups is advocated by several international associations. However, testing for HBV and HCV in TB patients is not routine practice in the UK. Larger studies are required to identify the highest risk groups within TB populations. Until then, we recommend that screening for viral hepatitis is considered in all patients with TB. [ABSTRACT FROM PUBLISHER]

A prospective study of 489 consecutive outpatient image-guided percutaneous lung biopsies was conducted to determine whether early discharge, incorporating ambulatory Heimlich valve drain, is potentially advantageous to the National Health Service. Patients were discharged at 30 or 60 min, with significant pneumothoraces treated using Heimlich valve. 485 (99.2%) patients were successfully discharged early, 402 at 30 min. 87 (17.8%) patients developed pneumothorax: 52 required Heimlich valve; 5 proceeded to biopsy with Heimlich valve in situ. All drains were removed within 48 h, 38/52 (73.1%) at 24 h. Our results provide evidence for a paradigm shift in UK practice: early discharge lung biopsy, facilitated by ambulatory Heimlich valve, is safe with significant clinical and economic benefits. [ABSTRACT FROM AUTHOR]

Aim: The primary aim of the study was to evaluate two different methods of communicating information on cardiopulmonary resuscitation (CPR) to patients admitted to general medical and elderly care wards. The information was either in the form of a detailed information leaflet (appendix I) or a summary document (appendix II). The study examined the willingness of patients in seeking detailed information on cardiopulmonary issues.Setting: The study was conducted over three months on a general medical ward and an acute elderly care ward in two district general hospitals.Methods: A detailed information leaflet on CPR was provided to the nursing staff on the wards. An A4 summary document summarising the CPR decision making process and basic information on cardiopulmonary issues was placed in a folder at the foot of each bed on the elderly care ward. On the general medical ward it was displayed prominently over the head of all beds.Results: Out of the 274 patients admitted to the general medical ward only two requests were received for the detailed information leaflet. On the elderly care ward there were 182 admissions but no patients or their relatives requested the leaflet.Conclusions: Availability of basic information on cardiopulmonary resuscitation to all patients is practical and does not lead to unnecessary distress or offence to patients or their carers. It makes the decision making process more transparent. Detailed information leaflets are of value for a minority of hospitalised patients. [ABSTRACT FROM AUTHOR]

Aim: The primary aim of the study was to evaluate two different methods of communicating information on cardiopulmonary resuscitation (CPR) to patients admitted to general medical and elderly care wards. The information was either in the form of a detailed information leaflet (appendix I) or a summary document (appendix II). The study examined the willingness of patients in seeking detailed information on cardiopulmonary issues. Setting: The study was conducted over three months on a general medical ward and an acute elderly care ward in two district general hospitals. Methods: A detailed information leaflet on CPR was provided to the nursing staff on the wards. An A4 summary document summarising the CPR decision making process and basic information on cardiopulmonary issues was placed in a folder at the foot of each bed on the elderly care ward. On the general medical ward it was displayed prominently over the head of all beds. Results: Out of the 274 patients admitted to the general medical ward only two requests were received for the detailed information leaflet. On the elderly care ward there were 182 admissions but no patients or their relatives requested the leaflet. Conclusions: Availability of basic information on cardiopulmonary resuscitation to all patients is practical and does not lead to unnecessary distress or offence to patients or their carers. It makes the decision making process more transparent. Detailed information leaflets are of value for a minority of hospitalised patients. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate HIV seroprevalence estimates from demographic and health surveys (DHS) and AIDS indicator surveys (AIS) for potential bias because of non-response and exclusion of non-household population groups.Methods: Data are from 14 DHS/AIS surveys with HIV testing, conducted during 2003-6. Blood samples were collected and analysed for HIV using standard laboratory and quality control procedures. HIV prevalence among non-tested adults was predicted based on multivariate statistical models of HIV for those who were interviewed and tested, using a common set of predictor variables. Estimates of the size of non-household populations in national censuses were used to assess potential bias because of their exclusion in the household surveys under different assumptions about proportion of adults and HIV prevalence in non-household populations.Results: Non-tested men had significantly higher predicted HIV prevalence than those tested in eight of the 14 countries, while non-tested women had significantly higher predicted prevalence than those tested in seven of the 14 countries. Effects of non-response were somewhat stronger in lower-prevalence countries. The overall effect of non-response on observed national HIV estimates was small and insignificant in all countries. Estimated effects of exclusion of non-household population groups were generally small, even in concentrated epidemics in India and Cambodia under the scenario that 75% of the non-household population was adults having 20 times greater HIV prevalence than adults in household surveys.Conclusions: Non-response and the exclusion of non-household population groups tend to have small, insignificant effects on national HIV seroprevalence estimates obtained from household surveys. [ABSTRACT FROM AUTHOR]

An abstract of the article "Recovery From Fixed Dystonia in Complex Regional Pain Syndrome Type 1 (CRPS-1) Following Deep Brain Stimulation (DBS) Surgery," by S. Javed and colleagues is presented.

Background One-third of the world's population is thought to be infected with Mycobacterium tuberculosis (Mtb); the highest incidence rates for active disease are found in the WH' s South-East Asian and African regions. Hepatitis B virus (HBV) and Hepatitis C virus (HCV) each infect about 0.3% of the UK population. HBV/HCV are treatable but largely asymptomatic until advanced liver disease and/or cancer. Screening for HBV/HCV is recommended in high-risk individuals but is not routinely performed in TB patients. HBV/HCV share similar epidemiological "hotspots" to TB, and several studies, primarily in South America and East Asia, have shown an increased prevalence of HBV/HCV in TB patients and an association between HBV/HCV and Drug Induced Liver Injury (DILI) following anti-TB therapy. No such analysis has been performed in the UK. Aims To assess 1. The prevalence of markers of HBV and HCV infection in patients undergoing anti-TB therapy. 2. Whether serological evidence of HBV/HCV increases risk of DILI. Method A prospective study on 429 TB patients receiving anti-TB therapy in a diverse urban TB clinic. Serological markers of HBV/HCV/HIV infection were documented. ALT was measured prior to treatment and 2-4 weeks after treatment initiation. DILI was defined as an ALT rise of greater than 2-times upper limit of normal following a normal pre-treatment level (<40 IU/ml). Results 58.7% of patients were from either South-East Asia or Africa. 61 (14.2%) patients were isolated anti-HBc antibody positive (Anti-HBc), 11 (2.6%) were Hepatitis B surface antigen positive (HBsAg) and 7 (1.6%) were HCV antibody positive. The prevalence of active HBV/HCV infection was significantly higher than the estimated UK prevalence in this urban TB clinic. Three (5.3%) patients with serological evidence of HBV/HCV had DILI compared to 25 (9.5%) of those without. Conclusion HBV/HCV prevalence is higher among TB patients and routine screening for viral hepatitis should be considered in this group. DILI was not increased in patients with serological markers of HBV/HCV . [ABSTRACT FROM AUTHOR]

This article focuses on a study related to coronary heart disease (CHD) in patients with intermittent claudication. CHD is common among patients with peripheral arterial disease (PAD), and death and major morbidity in PAD are often due to coronary events. Risk factor management should be similar in CHD and PAD. Patients with claudication and evidence of CHD appear to receive more evidence-based treatments than non-CHD patients, but overall patients with claudication referred from primary care in Great Britain are not receiving optimal medical risk factor management.

Introduction Sporadic cholangiocarcinoma (CC) occurs in subjects with no known risk factor for the disease. Its pathogenesis is likely to involve complex interaction of environmental and human factors, including genetic variation. Polymorphisms in natural killer cell receptor protein G2D (NKG2D) have been associated CC in subjects with primary sclerosing cholangitis (PSC). In a recent study, comparing 49 subjects with CC to 316 subjects with PSC and no CC, two single nucleotide polymorphisms (SNPs) in were associated with an increased risk of CC: rs11053781 (OR 2.08, p value 0.011) and rs2617167 (OR 2.32, p value 0.0020). We aimed to test whether variation in also modifies susceptibility to sporadic CC. Methods DNA was collected from 172 subjects with sporadic CC and a matched control cohort of 256. Haploview v 4.2 was used to select SNPs capturing common genetic variation around the gene (MAF >0.05, pair-wise comparisons). This identified 7 SNPs to be genotyped, including rs11053781 and rs2617167. Genotyping was performed with a PCR based, robotic system. Hardy–Weinberg equilibrium testing, Armitage trend testing and haplotype frequency comparisons were undertaken. Correction for multiple testing was performed using a permutation method. Results All genotypes were in Hardy–Weinberg equilibrium. None of the individual SNPs were significantly associated with altered susceptibility to CC. Haplotype analysis revealed that no haplotypes significantly modified risk of CC. Conclusion This is the first study to examine polymorphisms in sporadic CC. The study was well powered. We found no relationship between variation in and susceptibility to CC, in contrast to prior findings in PSC patients with CC. This finding may reflect an important difference between the pathogenesis of sporadic CC and that of PSC related CC. It might point to a false-positive result in the prior study of PSC related CC, but it was well executed and produced strong, positive results. This could be elucidated in an additional candidate-gene validation study. However, with increasing availability and affordability, a genome wide association study (GWAS) may prove a more efficient method for further exploring genetic factors in cholangiocarcinoma. [ABSTRACT FROM PUBLISHER]

Introduction Pancreatobiliary malignancies are amongst the commonest causes of cancer-related death worldwide and usually present with biliary obstruction. Accurate differentiation between benign and malignant causes of obstruction is likely to improve outcome in pancreatobiliary disease and reliable biomarkers are urgently needed. Bile is a potential source of such biomarkers due to its anatomical proximity to the site of pathology. Our aim was to apply a proteomic approach to identify potential biomarkers in bile which could differentiate between malignant and benign disease. Methods Bile, urine and serum were collected prospectively from 59 patients undergoing ERCP (endoscopic retrograde cholangiopancreatography) for benign (n = 36) or malignant (n = 23) pancreatobiliary disease at our centre. Initially, label-free proteomics and immunoblotting were performed in a sub-set of patients. Candidate biomarkers were selected on the basis of increased abundance of peptide fragments, and immunoblotting performed on an expanded cohort. ELISA was then performed for our potential biomarker on all samples in bile, blood and urine. Results Neutrophil gelatinase associated lipocalin (NGAL) levels were significantly raised in bile from the malignant disease group, compared to bile from the benign disease group (median 1839 ng/mL vs 472 ng/mL, p < 0.001). Biliary NGAL levels had an ROC-AUC of 0.76, specificity 56% and sensitivity 96% for distinguishing malignant from benign causes. Biliary NGAL was independent of serum biochemistry and CA 19-9 in differentiating between underlying benign and malignant disease. NGAL levels were then analysed in other body fluids in the same cohort. No significant differences in serum and urine NGAL levels were found between benign and malignant disease. Combining biliary NGAL and serum CA 19-9 improved diagnostic accuracy for malignancy (sensitivity 85%, specificity 82%, positive predictive value 79%, and negative predictive value 87%). Conclusion NGAL in bile is a novel potential biomarker to distinguish benign from malignant biliary obstruction, particularly in combination with serum tumour markers. [ABSTRACT FROM PUBLISHER]

Introduction Cholangiocarcinoma (CC) is increasing in incidence globally but its pathogenesis remains poorly understood. Chronic inflammation of the bile duct and cholestasis are major risk factors but most cases in the West are sporadic. Genetic polymorphisms in biliary transporter proteins have been implicated in benign biliary disease and, in the case of progressive familial cholestasis, have been associated with childhood onset of CC. A recent case-control study of a single nucleotide polymorphism c.3972C>T (rs3740066) in ABCC2, reported an association with CC. Aim To investigate five biologically plausible candidate genes as susceptibility factors for cholangiocarcinoma; ABCB11 (BSEP); ABCB4 (MDR3); ABCC2 (MRP2); ATP8B1 (FIC1) and NR1H4 (FXR). Method Germline DNA was collected from 172 Caucasian individuals with confirmed CC. A control cohort of 256 healthy Caucasian patients was included in the analysis. 73 SNPs were selected using the HapMap database in Haploview 4.1 (build 22; MAF >0.05, pair-wise comparisons only) to capture the majority of common genetic variation around the five candidate loci. Genotyping was undertaken with a competitive allele-specific PCR based robotic genotyping system. Confirmation of Hardy-Weinberg equilibrium and Cochran-Armitage trend testing were performed using PLINK v1.07. Haplotype frequencies were compared using haplo.stats v1.4.4. Results All 73 SNPs were in Hardy-Weinberg Equilibrium. Four SNPs in ABCB11 were associated with altered susceptibility to CC, including the V444A polymorphism (c.1331T>C, rs2287622, p<0.007) but these associations did not retain statistical significance after Bonferroni correction for multiple testing. Haplotype analysis of the genotyped SNPs in ATP8B1 identified significant differences in frequencies between cases and controls (global p value 0.005). None of the SNPs in ABCC2, including rs3 740 066, showed association with CC. Haplotype analysis in ABCC2 failed to detect significant association. Conclusion This is the largest study to date of biliary transporter polymorphisms as susceptibility factors for CC. The previously reported association between SNP rs3 740 066 in ABCC2 and CC was not replicated. Haplotypes in ATP8B1 demonstrated a significant difference between CC and control groups. There was also a trend towards significant association of V444A with CC. V444A has been strongly implicated in other cholestatic diseases. Given the biological plausibility of polymorphisms in ABCB11 and ATP8B1 as risk modifiers for CC, further study in a validation cohort is required. [ABSTRACT FROM PUBLISHER]