AIM: To investigate the association between cholecystectomy and gastro-intestinal tract(GIT) cancers.METHODS: We conducted a systematic review according to the PRISMA guidelines. A MEDLINE search was performed with pr...AIM: To investigate the association between cholecystectomy and gastro-intestinal tract(GIT) cancers.METHODS: We conducted a systematic review according to the PRISMA guidelines. A MEDLINE search was performed with predefined search criteria for English Language articles on the association between cholecystectomy and GIT cancers. Additional articles were retrieved by manual search of references. All relevant articles were accessed in full text. Data onstudy type; cases; controls; country; effect estimate; adjustments for confounders and quality of publication were extracted. The quality of the publications were scored by adherence to the STROBE checklist. The data for each part of the GIT were presented in separate tables.RESULTS: Seventy-five studies and 5 meta-analyses satisfied the predefined criteria for inclusion and were included in this review. There were inconsistent reports and no strong evidence of an association between cholecystectomy and cancers of the oesophagus(Adenocarcinoma), pancreas, small bowel and rightsided colon cancers. In squamous cancer of the oesophagus, cancers of the stomach, liver, bile ducts, small bowel and left sided colon cancers, good quality studies suggested a lack of association with cholecystectomy. Equally, distal colon and rectal cancers were found not to be associated with cholecystectomy. Several mechanisms for carcinogenesis/promotion of carcinogensis have been proposed. These have focused on a role for bile salts in carcinogenesis with several potential mutagenic molecular events and gut metabolic hormones signaling cell proliferation or initiation of carcinogenesis.CONCLUSION: This is a comprehensive review of the association between GIT cancers and cholecystectomy. This review found no clear association between cholecystectomy and GIT cancers.展开更多
Non-alcoholic fatty liver disease(NAFLD)is a widely prevalent hepatic disorder that covers wide spectrum of liver pathology.NAFLD is strongly associated with liver inflammation,metabolic hyperlipidaemia and insulin re...Non-alcoholic fatty liver disease(NAFLD)is a widely prevalent hepatic disorder that covers wide spectrum of liver pathology.NAFLD is strongly associated with liver inflammation,metabolic hyperlipidaemia and insulin resistance.Frequently,NAFLD has been considered as the hepatic manifestation of metabolic syndrome.The pathophysiology of NAFLD has not been fully elucidated.Some patients can remain in the stage of simple steatosis,which generally is a benign condition;whereas others can develop liver inflammation and progress into non-alcoholic steatohepatitis,fibrosis,cirrhosis and hepatocellular carcinoma.The mechanism behind the progression is still not fully understood.Much ongoing proteomic researches have focused on discovering the unbiased circulating biochemical markers to allow early detection and treatment of NAFLD.Comprehensive genomic studies have also begun to provide new insights into the gene polymorphism to understand patientdisease variations.Therefore,NAFLD is considered a complex and mutifactorial disease phenotype resulting from environmental exposures acting on a susceptible polygenic background.This paper reviewed the current status of proteomic and genomic studies that have contributed to the understanding of NAFLD pathogenesis.For proteomics section,this review highlighted functional proteins that involved in:(1)transportation;(2)metabolic pathway;(3)acute phase reaction;(4)antiinflammatory;(5)extracellular matrix;and(6)immune system.In the genomic studies,this review will discuss genes which involved in:(1)lipolysis;(2)adipokines;and(3)cytokines production.展开更多
The skin facilitates a number of key roles but its functioning can be impaired by disease. Atopic eczema is a chronic inflammatory disease where the skin barrier has become leaky, and inflammation occurs. It affects u...The skin facilitates a number of key roles but its functioning can be impaired by disease. Atopic eczema is a chronic inflammatory disease where the skin barrier has become leaky, and inflammation occurs. It affects up to 20% of children and 3% of adults worldwide, manifesting as red itchy patches of skin with varying severity. This review aims to investigate the leaky skin barrier and immune mechanisms from the perspective of potential novel treatments. The complexity of atopic eczema as a disease is what makes it difficult to treat. Genome-wide association studies have highlighted possible genetic variations associated with atopic eczema, however in some cases, individuals develop the disease without these genetic risk factors. Loss of function mutations in the filaggrin gene are one of these associations and this is plausible due to its key role in barrier function. The Th2 immune response is the link with regards to the immune mechanisms as atopic inflammation often occurs through increased levels of interleukin(IL)-4 and IL-13. Eczematous inflammation also creates susceptibility to colonisation and damage by bacteria such as Staphylococcus aureus. Potential novel treatments are becoming ever more specific, offering the hope of fewer side effects and better disease control. The best new treatments highlighted in this review target the immune response with human beta defensin 2, phosphodiesterase-4 inhibitors and monoclonal antibodies all showing promise.展开更多
There has long been a recognised association between non-alcoholic fatty liver disease(NAFLD)and the composite aspects of the metabolic syndrome.Part of this association highlighted the supposed co-existence of elevat...There has long been a recognised association between non-alcoholic fatty liver disease(NAFLD)and the composite aspects of the metabolic syndrome.Part of this association highlighted the supposed co-existence of elevated uric acid levels in those with NAFLD.There is interest in exploitation of this as a putative diagnostic and prognostic biomarker in NAFLD.Given the increased economic and health burden associated with the NAFLD epidemic,improved methods of population-based,minimally-invasive methods and biomarkers are clearly highly sought and necessary.In this opinion review we review the proposed role of uric acid in the pathogenesis of NAFLD and its potential utilisation in the diagnosis and monitoring of the disease process.展开更多
AIM: To the look at the current strength of evidence and the potential application of anti-oxidants in this setting.METHODS: Two electronic databases(Pub Med and Web of Knowledge) were searched to January 2013 to find...AIM: To the look at the current strength of evidence and the potential application of anti-oxidants in this setting.METHODS: Two electronic databases(Pub Med and Web of Knowledge) were searched to January 2013 to find studies addressing serum bilirubin levels in nonalcoholic fatty liver disease(NAFLD). The search used key word combinations in relation to NAFLD and serum bilirubin specific to human adults only. After screening selected studies were reviewed in depth by two independent reviewers. Data synthesis with further metaanalysis was planned but not possible due to the heterogeneity of the outcome measures in these studies.RESULTS: Out of 416 studies screened only seven studies were considered suitable for inclusion. All seven studies consistently reported an inverse association of bilirubin with NAFLD despite the heterogeneous sample of studies. Only two studies were prospective. No negative studies were found. CONCLUSION: Most studies suggest a correlationbetween high bilirubin levels of any type are inversely correlated with NAFLD. But to date most of these studies have been poorly designed to allow meaningful conclusions, except one cohort study. There is a need for a large prospective cohort study in multiple populations to test this hypothesis fully before mechanistic associations can be established and therapeutic options of the apparent anti-oxidant effect of bilirubin be explored in NAFLD. Furthermore these studies should include analysis of UGT1A1 gene to expound upon underlying cause of unconjugated hyperbilirubinaemia.展开更多
Pancreatic neuroendocrine neoplasms are a rare and complex group of neoplastic lesions that develop from pancreatic islet cells.Their incidence has dramatically increased during the last two decades.Due to its complex...Pancreatic neuroendocrine neoplasms are a rare and complex group of neoplastic lesions that develop from pancreatic islet cells.Their incidence has dramatically increased during the last two decades.Due to its complex nature and pathophysiological behaviour,surgical management continues to evolve.Surgery remains the cornerstone of treatment for most non-functional and functional pancreatic neuroendocrine tumours,while lymphadenectomy remains a controversial subject.Different techniques,such as pancreas-preserving and minimally invasive approaches,continue to evolve and offer the same overall outcomes as open surgery.This comprehensive review describes in detail the current and most up-todate classification and staging of pancreatic neuroendocrine tumours,explores the rationale for nonsurgical and surgical management,and focuses on surgical treatment and more specifically,on minimally invasive approaches.展开更多
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and is associated with significant morbidity and mortality. It is becoming increasingly evident diabetes is a significant risk factor for the deve...Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and is associated with significant morbidity and mortality. It is becoming increasingly evident diabetes is a significant risk factor for the development of AF. The reason for this link is not clearly understood, however it is clear that other co-morbid diseases associated with diabetes such as hypertension and obesity may be implicated or there may be direct arrthymogenic affects of glucose dysregulation on the myocardium. The development of AF in patients with diabetes may be an ominous sign given the increased risk of death from cardiovascular disease and we propose this is an under researched area where treatments may bring benefits over and above those patients without diabetes in terms of morbidity or death from cardiovascular disease.展开更多
Atopic dermatitis(AD) is a chronic inflammatory skin disorder which can precede asthma and allergic rhinitis in a disease trajectory known as the atopic march. The pathophysiology of AD includes cutaneous inflammation...Atopic dermatitis(AD) is a chronic inflammatory skin disorder which can precede asthma and allergic rhinitis in a disease trajectory known as the atopic march. The pathophysiology of AD includes cutaneous inflammation, disrupted epidermal barrier function, xerosis and propensity to secondary infections. AD had previously been thought to arise from the systemic atopic immune response and therapies are therefore directed towards ameliorating Th2-mediated inflammation. However in recent years the focus has shifted towards primary defects in the skin barrier as an initiating event in AD. Links between loss-of-function variants in the gene encoding filaggrin and disrupted activity of epidermal serine proteases and AD have been reported. Based on these observations, a mechanism has been described by which epidermal barrier dysfunction may lead to inflammation and allergic sensitization. Exogenous and endogenous stressors can further exacerbate inherited barrier abnormalities to promote disease activity. Pathways underlying progression of the atopic march remain unclear, but recent findings implicate thymic stromal lymphopoietin as a factor linking AD to subsequent airway inflammation in asthma. This new appreciation of the epidermis in the development of AD should lead to deployment of more specific strategies to restore barrier function in atopic patients and potentially halt the atopic march.展开更多
Background: St John s wort (SJW) is widely used as a treatment for depression. A phototoxic reaction, due to its content of hypericin, can occur in animals and in cell culture, and has been reported in humans. Hyper...Background: St John s wort (SJW) is widely used as a treatment for depression. A phototoxic reaction, due to its content of hypericin, can occur in animals and in cell culture, and has been reported in humans. Hypericin displays absorption within the ultraviolet (UV) A1 spectrum and there may therefore be a potential for phototoxicity if taken during high-dose UVA1 therapy. Objectives: To assess the phototoxicity risk of SJW ingestion. Methods: Eleven adult volunteers of skin types I and II were exposed to a geometric dose series of UVA1 irradiation from a high-output source (Dermalight Ultra 1; Dr H nle, Martinsreid, Germany; irradiance 70- 77 mW cm- 2) on the photoprotected lower back skin at eight 1.5-cm2 test areas. Irradiation was carried out at baseline and after 10 days of SJW extract 1020 mg (equivalent to 3000 μ g of hypericin) daily. Four, 8, 24 and 48 h after each exposure, the minimal erythema dose (MED) and the presence or absence of pigmentation were recorded visually and erythema was assessed objectively with an erythema meter. Results: The median MED and D0.025, an objective measure of MED, were lower at all time-points after SJW ingestion. The visual erythemal peak (lowest median MED), which was seen at 8 h postirradiation, was lower after SJW (median 14 J cm- 2, range 10- 56) than at baseline (median 20 J cm- 2, range 14- 56) (P = 0.047). Similarly, the median D0.025 at 8 h postirradiation was lower after SJW(median 22.0 J cm- 2, range 15.2- 53.9) than at baseline (median 33.7 J cm - 2, range 22.9- 136.0) (P = 0.014). The MED and D0.025 were also significantly different at the 48-h and 4-h time-points, respectively. Significance was not reached at the 24-h time-point. Median intensity of postirradiation erythema increased at all time-points after ingestion of SJW. Despite these differences, the maximum slope of the dose-response curve was not increased after SJW ingestion. Conclusions: These data suggest that SJW extract has the potential to lower the erythemal threshold to UVA1 irradiation in a significant proportion of individuals and highlight the importance of ascertaining a full drug history, including herbal remedies, before initiating UVA1 phototherapy.展开更多
Background:High-dose ultraviolet (UV) A1 therapy (doses in the order of 130 J cm-2) is effective for atopic dermatitis and scleroderma. UVA1 has been shown to induce a dose-dependent increase in p53 expression in kera...Background:High-dose ultraviolet (UV) A1 therapy (doses in the order of 130 J cm-2) is effective for atopic dermatitis and scleroderma. UVA1 has been shown to induce a dose-dependent increase in p53 expression in keratinocytes. Objectives:To examine the effect of UVA1 on the activation of p53 by phosphorylation, which has not yet been studied. Methods:Five adult volunteers were exposed to dose series of UVA1 (10-100 J cm-2) and, for comparison, narrowband UVB (TL-01) (25-550 mJ cm-2) and solar-simulated radiation (SSR) (5.6-30 J cm-2)on photoprotected buttock skin and the minimal erythema dose (MED) for each was determined at 24 h. Separate sites on the buttock were subsequently irradiated with a 3-MED dose of UVA1, TL-01 and SSR. At 24 h, punch biopsies (4 mm) were taken from each irradiated site and from an adjacent unirradiated control site, and immunohistochemical staining for p53 (Do-1), activation of p53 (assessed by phosphorylation at serine 12 and serine 392) and p21 was performed. Cell staining was expressed as the mean number of cells stained per three high-power fields (HPFs) and as a percentage of 1000 cells. Sunburn cells (SBCs)were also counted per HPF. Results UVA1 produced negligible numbers of SBCs, relatively little p53 (Do-1) staining (mean±.SD cell count per HPF 16±10),no p53 activation and very little evidence of p21 expression (mean±SD cell count per HPF 5.3±7), in contrast to TL-01 (mean±SD cell count per HPF of 11.83±2.1 SBCs, 146.3±38 for Do-1, 26.6±15 for serine 15, 14.9±12 for serine 392 and 77.9±30 for p21) or SSR irradiation (mean±SD cell count per HPF of 3.5±1.2 SBCs, 147.5±62 for Do-1, 54±50 for serine 15, 38.9±18 for serine 392 and 56.7±30 for p21). Conclusions:These data indicate that there are fundamental differences in the effects of UVA1 on p53 and its activation pathways compared with TL-01 and SSR, and may in part explain the differential effects of these phototherapies.展开更多
Background: Accumulation of molecular alterations, including mutations in Kirsten-ras (K-ras), p53, and adenomatous polyposis coli (APC), contribute to colorectal carcinogenesis. Our group has previously characterised...Background: Accumulation of molecular alterations, including mutations in Kirsten-ras (K-ras), p53, and adenomatous polyposis coli (APC), contribute to colorectal carcinogenesis. Our group has previously characterised a panel of sporadic colorectal adenocarcinomas for mutations in these three genes and has shown that p53 and K-ras mutations rarely occur in the same colorectal tumour. This suggests that mutations in these genes are on separate pathways to colorectal cancer development and may influence patient prognosis independently. Aims: To correlate the presence or absence of mutations in K-ras, p53, and APC with survival in a cohort of colorectal cancer patients. Patients: A series of 107 inpatients treated surgically for colorectal cancer in Tayside, Scotland between November 1997 and December 1999. Methods: Colorectal tumours were characterised for mutations in K-ras, p53, and APC. Kaplan-Meier survival curves were constructed using overall survival and disease specific survival as the primary end points. Patient survival was analysed using the log rank test and Cox proportional hazards model. Results: Patients with K-ras mutations had significantly poorer overall survival than patients without K-ras mutations (p = 0.0098). Multivariate analysis correcting for Dukes’ stage, age, and sex confirmed this (hazard ratio 2.9 (95% confidence interval 1.4-6.2); p = 0.0040). K-ras mutations were also significantly associated with poorer disease specific survival. The presence of APC and p53 mutations did not affect survival in this cohort of patients (p = 0.9034 and p = 0.8290, respectively). Conclusions: Our data indicate that the presence of K-ras mutations predicts poor patient prognosis in colorectal cancer, independently of tumour stage.展开更多
Objective: To determine the time course and dose-response characteristics of UV-A1 erythema in the Tayside region of Scotland. Design: Adult volunteers (skin types I and II [n=13]- and III and IV [n=11])were exposed t...Objective: To determine the time course and dose-response characteristics of UV-A1 erythema in the Tayside region of Scotland. Design: Adult volunteers (skin types I and II [n=13]- and III and IV [n=11])were exposed to geometric dose series of UV-A1 irradiation from a high-output source on photoprotected lower back and inner forearm skin. Setting: Photobiology unit in a university hospital. MainOutcomeMeasures: The minimal erythema dose (MED) was recorded visually and erythema was assessed objectively by erythema meter at 4, 8, 24, and 48 hours after exposure. Results: Peak erythema (lowest visual MED) was seen at 8 hours on the back and arm in 11 subjects with skin types I and II and on the back at 8 hours in 9 subjects and on the arm at 4 hours in 10 subjects with skin types III and IV. The lowest median (range) MED was 20 J/cm2 (14- 56 J/cm2) on the back and 42 J/cm2 (20 to >80 J/cm2) on the arm at 8 hours for subjects with skin types I and II and 28 J/cm2 (20- 112 J/cm2) at 8 hours on the back and 56 J/cm2 (28- 80 J/cm2) at 4 hours on the arm for subjects with skin types III and IV. The D0.025, an objective measure that corresponds approximately to the visual MED, demonstrated a broad peak from 8 to 24 hours. Conclusions: Our local population is more erythemally sensitive to UV-A1 radiation than reports suggest. Daily dose regimens may risk cumulative erythema. Lower starting doses should be used in this population. The wide range of MEDs highlights the need for MED testing.展开更多
Objectives: To determine whether the improved clinical status after newborn screening (NBS) for cystic fibrosis (CF) segregates with increased therapeutic intervention compared with presentation by clinical diagnosis ...Objectives: To determine whether the improved clinical status after newborn screening (NBS) for cystic fibrosis (CF) segregates with increased therapeutic intervention compared with presentation by clinical diagnosis (CD). Study design: In 2002, two populations (1 to 9 years of age) who presented (excluding meconium ileus) by NBS ≤ 3 months of age or by CD were compared in an observational, cross-sectional design. NBS and CD populations (184 and 950 patients, respectively) were divided into 3-year age groups (1 to 3, 4 to 6, and 7 to 9 years)-. Therapies of duration >3 months were compared together with Pseudomonas aeruginosa infection status. Results: NBS patients≤ 6 years of age received significantly fewer and less demanding therapies not explained by age, genotype, geography, or social deprivation. In 7-to 9-year-olds, significantly fewer NBS patients received intravenous antibiotics. NBS patients without P aeruginosa infection received significantly fewer therapies, but no differences were found between intermittently or chronically infected NBS and CD populations. Comparable results were found in Δ F508/Δ F508 subpopulations. Conclusions: CF populations diagnosed by NBS are associated with reduced treatment compared with age and genotype-matched CD control subjects.展开更多
Objectives: To determine whether early identification of babies with cystic fibrosis (CF) improves outcome in the current environment of new improved treatments, considering the criticism that there may be only margin...Objectives: To determine whether early identification of babies with cystic fibrosis (CF) improves outcome in the current environment of new improved treatments, considering the criticism that there may be only marginal benefit gained by CF newborn screening (NBS). Study design: We tested whether CF NBS in the setting of modern CF center care still afforded benefit using the UK CF Database (UKCFD; www.cystic-fi-brosis.org.uk) to compare clinical outcomes in infants who underwent NBS and control subjects who were clinically diagnosed (CD). With Mann-Whitney rank tests, 184 patients who underwent NBS aged 1 to 9 years in 2002 (excluding meconium ileus) were compared with matched patients who were CD in 3-year age groups (950 control subjects). Results: Patients as old as 6 years who underwent NBS had significantly greater median height z-scores, less severe Northern chest radiography scores, better Shwachman-Kulczycki scores, and lower rates of chronic Pseudomonas aeruginosa infection. No difference was found for weight z-score or % predicted forced expiratory value in 1 second or forced volume capacity. Nutritional benefit was demonstrated in patients who underwent NBS and were homozygous for the Δ F508 mutation. Conclusions: NBS segregates with better outcomes in patients as old as 6 years compared with age and gene-matched control subjects who are CD. This cross-sec-tional study shows that infants who undergo screening derive nutritional benefit in improved median height and reduced morbidity.展开更多
Background: Dead Sea (DS) salt solution soaks are used in combination with narrowband ultraviolet B (NB- UVB) to treat psoriasis in many centres, particularly in continental Europe. No previously published controlled ...Background: Dead Sea (DS) salt solution soaks are used in combination with narrowband ultraviolet B (NB- UVB) to treat psoriasis in many centres, particularly in continental Europe. No previously published controlled study has assessed DS salt + NB- UVB balneophototherapy. Objectives: To compareDS salt balneophototherapy with NB- UVB monotherapy for chronic plaque psoriasis. Methods: Sixty patients with chronic plaque psoriasis participated in this paired, controlled study, with pretreatment DS salt soaks randomly allocated to each participant’ s right or left study limb. Psoriasis severity was assessed with a Scaling, Erythema and Induration score by a blinded observer. Assessments were weekly during the therapy course, and thereafter 8- weekly until relapse or for up to 1 year after clearance. Results: The mean area under the psoriasis severity- time curves during treatment was not detectably lower with DS salt balneophototherapy than with NB- UVB monotherapy (P=0.099). The psoriasis severity score fell slightly more from beginning to end of courses with DS salt balneophototherapy than with NB- UVB monotherapy (P=0.019). There was no detectable difference in times to relapse. Conclusions: In this population the addition of pretreatment DS salt soaks to NB- UVB did not result in a clinically important improvement in clearance of psoriasis.展开更多
A 76-year-old man was commenced on carbamazepine for partial seizures. This was followed by the development of a rash in an apparently photodistributed pattern, fever, lymphadenopathy, eosinophilia, abnormal liver fun...A 76-year-old man was commenced on carbamazepine for partial seizures. This was followed by the development of a rash in an apparently photodistributed pattern, fever, lymphadenopathy, eosinophilia, abnormal liver function tests and atypical lymphocytosis fulfilling the criteria for drug-induced hypersensitivity syndrome. Discontinuation of carbamazepine and application of topical steroid resulted in clearance of the rash, normalization of liver function tests and improvement in eosinophilia. The photodistributed pattern in this case of carbamazepine-induced hypersensitivity syndrome is of interest.展开更多
The pathogenesis of metabolic-associated fatty liver disease(MAFLD)is complex and thought to be dependent on multiple parallel hits on a background of genetic susceptibility.The evidence suggests that MAFLD progressio...The pathogenesis of metabolic-associated fatty liver disease(MAFLD)is complex and thought to be dependent on multiple parallel hits on a background of genetic susceptibility.The evidence suggests that MAFLD progression is a dynamic two-way process relating to repetitive bouts of metabolic stress and inflammation interspersed with endogenous anti-inflammatory reparative responses.In MAFLD,excessive hepatic lipid accumulation causes the production of lipotoxins that induce mitochondrial dysfunction,endoplasmic reticular stress,and over production of reactive oxygen species(ROS).Models of MAFLD show marked disruption of mitochondrial function and reduced oxidative capacitance with impact on cellular processes including mitophagy,oxidative phosphorylation,and mitochondrial biogenesis.In excess,ROS modify insulin and innate immune signaling and alter the expression and activity of essential enzymes involved in lipid homeostasis.ROS can also cause direct damage to intracellular structures causing hepatocyte injury and death.In select cases,the use of anti-oxidants and ROS scavengers have been shown to diminish the proapoptopic effects of fatty acids.Given this link,endogenous anti-oxidant pathways have been a target of interest,with Nrf2 activation showing a reduction in oxidative stress and inflammation in models of MAFLD.Thyroid hormone receptorβ(THRβ)agonists and nuclear peroxisome proliferationactivated receptor(PPAR)family have also gained interest in reducing hepatic lipotoxicity and restoring hepatic function in models of MAFLD.Unfortunately,the true interplay between the clinical and molecular components of MAFLD progression remain only partly understood.Most recently,multiomics-based strategies are being adopted for hypothesis-free analysis of the molecular changes in MAFLD.Transcriptome profiling maps the unique genotype-phenotype associations in MAFLD and with various single-cell tran scriptome-based projects underway,there is hope of novel physiological insights to MAFLD progression and uncover therapeutic targets.展开更多
Headache is one of the commonest complaints that doctors need to address in clinical settings.The genetic mechanisms of different types of headache are not well understood while it has been suggested that self-reporte...Headache is one of the commonest complaints that doctors need to address in clinical settings.The genetic mechanisms of different types of headache are not well understood while it has been suggested that self-reported headache and self-reported migraine were genetically correlated.In this study,we performed a meta-analysis of genome-wide association studies(GWAS)on the self-reported headache phenotype from the UK Biobank and the self-reported migraine phenotype from the 23andMe using the Unified Score-based Association Test(metaUSAT)software for genetically correlated phenotypes(N=397,385).We identified 38 loci for headaches,of which 34 loci have been reported before and four loci were newly suggested.The LDL receptor related protein 1(LRP1)-Signal Transducer and Activator of Transcription 6(STAT6)-Short chain Dehydrogenase/Reductase family 9C member 7(SDR9C7)region in chromosome 12 was the most significantly associated locus with a leading p value of 1.24×10^(-62)of rs11172113.The One Cut homeobox 2(ONECUT2)gene locus in chromosome 18 was the strongest signal among the four new loci with a p value of 1.29×10^(-9)of rs673939.Our study demonstrated that the genetically correlated phenotypes of self-reported headache and self-reported migraine can be meta-analysed together in theory and in practice to boost study power to identify more variants for headaches.This study has paved way for a large GWAS meta-analysis involving cohorts of different while genetically correlated headache phenotypes.展开更多
文摘AIM: To investigate the association between cholecystectomy and gastro-intestinal tract(GIT) cancers.METHODS: We conducted a systematic review according to the PRISMA guidelines. A MEDLINE search was performed with predefined search criteria for English Language articles on the association between cholecystectomy and GIT cancers. Additional articles were retrieved by manual search of references. All relevant articles were accessed in full text. Data onstudy type; cases; controls; country; effect estimate; adjustments for confounders and quality of publication were extracted. The quality of the publications were scored by adherence to the STROBE checklist. The data for each part of the GIT were presented in separate tables.RESULTS: Seventy-five studies and 5 meta-analyses satisfied the predefined criteria for inclusion and were included in this review. There were inconsistent reports and no strong evidence of an association between cholecystectomy and cancers of the oesophagus(Adenocarcinoma), pancreas, small bowel and rightsided colon cancers. In squamous cancer of the oesophagus, cancers of the stomach, liver, bile ducts, small bowel and left sided colon cancers, good quality studies suggested a lack of association with cholecystectomy. Equally, distal colon and rectal cancers were found not to be associated with cholecystectomy. Several mechanisms for carcinogenesis/promotion of carcinogensis have been proposed. These have focused on a role for bile salts in carcinogenesis with several potential mutagenic molecular events and gut metabolic hormones signaling cell proliferation or initiation of carcinogenesis.CONCLUSION: This is a comprehensive review of the association between GIT cancers and cholecystectomy. This review found no clear association between cholecystectomy and GIT cancers.
文摘Non-alcoholic fatty liver disease(NAFLD)is a widely prevalent hepatic disorder that covers wide spectrum of liver pathology.NAFLD is strongly associated with liver inflammation,metabolic hyperlipidaemia and insulin resistance.Frequently,NAFLD has been considered as the hepatic manifestation of metabolic syndrome.The pathophysiology of NAFLD has not been fully elucidated.Some patients can remain in the stage of simple steatosis,which generally is a benign condition;whereas others can develop liver inflammation and progress into non-alcoholic steatohepatitis,fibrosis,cirrhosis and hepatocellular carcinoma.The mechanism behind the progression is still not fully understood.Much ongoing proteomic researches have focused on discovering the unbiased circulating biochemical markers to allow early detection and treatment of NAFLD.Comprehensive genomic studies have also begun to provide new insights into the gene polymorphism to understand patientdisease variations.Therefore,NAFLD is considered a complex and mutifactorial disease phenotype resulting from environmental exposures acting on a susceptible polygenic background.This paper reviewed the current status of proteomic and genomic studies that have contributed to the understanding of NAFLD pathogenesis.For proteomics section,this review highlighted functional proteins that involved in:(1)transportation;(2)metabolic pathway;(3)acute phase reaction;(4)antiinflammatory;(5)extracellular matrix;and(6)immune system.In the genomic studies,this review will discuss genes which involved in:(1)lipolysis;(2)adipokines;and(3)cytokines production.
文摘The skin facilitates a number of key roles but its functioning can be impaired by disease. Atopic eczema is a chronic inflammatory disease where the skin barrier has become leaky, and inflammation occurs. It affects up to 20% of children and 3% of adults worldwide, manifesting as red itchy patches of skin with varying severity. This review aims to investigate the leaky skin barrier and immune mechanisms from the perspective of potential novel treatments. The complexity of atopic eczema as a disease is what makes it difficult to treat. Genome-wide association studies have highlighted possible genetic variations associated with atopic eczema, however in some cases, individuals develop the disease without these genetic risk factors. Loss of function mutations in the filaggrin gene are one of these associations and this is plausible due to its key role in barrier function. The Th2 immune response is the link with regards to the immune mechanisms as atopic inflammation often occurs through increased levels of interleukin(IL)-4 and IL-13. Eczematous inflammation also creates susceptibility to colonisation and damage by bacteria such as Staphylococcus aureus. Potential novel treatments are becoming ever more specific, offering the hope of fewer side effects and better disease control. The best new treatments highlighted in this review target the immune response with human beta defensin 2, phosphodiesterase-4 inhibitors and monoclonal antibodies all showing promise.
文摘There has long been a recognised association between non-alcoholic fatty liver disease(NAFLD)and the composite aspects of the metabolic syndrome.Part of this association highlighted the supposed co-existence of elevated uric acid levels in those with NAFLD.There is interest in exploitation of this as a putative diagnostic and prognostic biomarker in NAFLD.Given the increased economic and health burden associated with the NAFLD epidemic,improved methods of population-based,minimally-invasive methods and biomarkers are clearly highly sought and necessary.In this opinion review we review the proposed role of uric acid in the pathogenesis of NAFLD and its potential utilisation in the diagnosis and monitoring of the disease process.
文摘AIM: To the look at the current strength of evidence and the potential application of anti-oxidants in this setting.METHODS: Two electronic databases(Pub Med and Web of Knowledge) were searched to January 2013 to find studies addressing serum bilirubin levels in nonalcoholic fatty liver disease(NAFLD). The search used key word combinations in relation to NAFLD and serum bilirubin specific to human adults only. After screening selected studies were reviewed in depth by two independent reviewers. Data synthesis with further metaanalysis was planned but not possible due to the heterogeneity of the outcome measures in these studies.RESULTS: Out of 416 studies screened only seven studies were considered suitable for inclusion. All seven studies consistently reported an inverse association of bilirubin with NAFLD despite the heterogeneous sample of studies. Only two studies were prospective. No negative studies were found. CONCLUSION: Most studies suggest a correlationbetween high bilirubin levels of any type are inversely correlated with NAFLD. But to date most of these studies have been poorly designed to allow meaningful conclusions, except one cohort study. There is a need for a large prospective cohort study in multiple populations to test this hypothesis fully before mechanistic associations can be established and therapeutic options of the apparent anti-oxidant effect of bilirubin be explored in NAFLD. Furthermore these studies should include analysis of UGT1A1 gene to expound upon underlying cause of unconjugated hyperbilirubinaemia.
文摘Pancreatic neuroendocrine neoplasms are a rare and complex group of neoplastic lesions that develop from pancreatic islet cells.Their incidence has dramatically increased during the last two decades.Due to its complex nature and pathophysiological behaviour,surgical management continues to evolve.Surgery remains the cornerstone of treatment for most non-functional and functional pancreatic neuroendocrine tumours,while lymphadenectomy remains a controversial subject.Different techniques,such as pancreas-preserving and minimally invasive approaches,continue to evolve and offer the same overall outcomes as open surgery.This comprehensive review describes in detail the current and most up-todate classification and staging of pancreatic neuroendocrine tumours,explores the rationale for nonsurgical and surgical management,and focuses on surgical treatment and more specifically,on minimally invasive approaches.
文摘Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and is associated with significant morbidity and mortality. It is becoming increasingly evident diabetes is a significant risk factor for the development of AF. The reason for this link is not clearly understood, however it is clear that other co-morbid diseases associated with diabetes such as hypertension and obesity may be implicated or there may be direct arrthymogenic affects of glucose dysregulation on the myocardium. The development of AF in patients with diabetes may be an ominous sign given the increased risk of death from cardiovascular disease and we propose this is an under researched area where treatments may bring benefits over and above those patients without diabetes in terms of morbidity or death from cardiovascular disease.
基金Supported by Wellcome Trust Intermediate Clinical Fellowship,No.086398/Z/08/Z
文摘Atopic dermatitis(AD) is a chronic inflammatory skin disorder which can precede asthma and allergic rhinitis in a disease trajectory known as the atopic march. The pathophysiology of AD includes cutaneous inflammation, disrupted epidermal barrier function, xerosis and propensity to secondary infections. AD had previously been thought to arise from the systemic atopic immune response and therapies are therefore directed towards ameliorating Th2-mediated inflammation. However in recent years the focus has shifted towards primary defects in the skin barrier as an initiating event in AD. Links between loss-of-function variants in the gene encoding filaggrin and disrupted activity of epidermal serine proteases and AD have been reported. Based on these observations, a mechanism has been described by which epidermal barrier dysfunction may lead to inflammation and allergic sensitization. Exogenous and endogenous stressors can further exacerbate inherited barrier abnormalities to promote disease activity. Pathways underlying progression of the atopic march remain unclear, but recent findings implicate thymic stromal lymphopoietin as a factor linking AD to subsequent airway inflammation in asthma. This new appreciation of the epidermis in the development of AD should lead to deployment of more specific strategies to restore barrier function in atopic patients and potentially halt the atopic march.
文摘Background: St John s wort (SJW) is widely used as a treatment for depression. A phototoxic reaction, due to its content of hypericin, can occur in animals and in cell culture, and has been reported in humans. Hypericin displays absorption within the ultraviolet (UV) A1 spectrum and there may therefore be a potential for phototoxicity if taken during high-dose UVA1 therapy. Objectives: To assess the phototoxicity risk of SJW ingestion. Methods: Eleven adult volunteers of skin types I and II were exposed to a geometric dose series of UVA1 irradiation from a high-output source (Dermalight Ultra 1; Dr H nle, Martinsreid, Germany; irradiance 70- 77 mW cm- 2) on the photoprotected lower back skin at eight 1.5-cm2 test areas. Irradiation was carried out at baseline and after 10 days of SJW extract 1020 mg (equivalent to 3000 μ g of hypericin) daily. Four, 8, 24 and 48 h after each exposure, the minimal erythema dose (MED) and the presence or absence of pigmentation were recorded visually and erythema was assessed objectively with an erythema meter. Results: The median MED and D0.025, an objective measure of MED, were lower at all time-points after SJW ingestion. The visual erythemal peak (lowest median MED), which was seen at 8 h postirradiation, was lower after SJW (median 14 J cm- 2, range 10- 56) than at baseline (median 20 J cm- 2, range 14- 56) (P = 0.047). Similarly, the median D0.025 at 8 h postirradiation was lower after SJW(median 22.0 J cm- 2, range 15.2- 53.9) than at baseline (median 33.7 J cm - 2, range 22.9- 136.0) (P = 0.014). The MED and D0.025 were also significantly different at the 48-h and 4-h time-points, respectively. Significance was not reached at the 24-h time-point. Median intensity of postirradiation erythema increased at all time-points after ingestion of SJW. Despite these differences, the maximum slope of the dose-response curve was not increased after SJW ingestion. Conclusions: These data suggest that SJW extract has the potential to lower the erythemal threshold to UVA1 irradiation in a significant proportion of individuals and highlight the importance of ascertaining a full drug history, including herbal remedies, before initiating UVA1 phototherapy.
文摘Background:High-dose ultraviolet (UV) A1 therapy (doses in the order of 130 J cm-2) is effective for atopic dermatitis and scleroderma. UVA1 has been shown to induce a dose-dependent increase in p53 expression in keratinocytes. Objectives:To examine the effect of UVA1 on the activation of p53 by phosphorylation, which has not yet been studied. Methods:Five adult volunteers were exposed to dose series of UVA1 (10-100 J cm-2) and, for comparison, narrowband UVB (TL-01) (25-550 mJ cm-2) and solar-simulated radiation (SSR) (5.6-30 J cm-2)on photoprotected buttock skin and the minimal erythema dose (MED) for each was determined at 24 h. Separate sites on the buttock were subsequently irradiated with a 3-MED dose of UVA1, TL-01 and SSR. At 24 h, punch biopsies (4 mm) were taken from each irradiated site and from an adjacent unirradiated control site, and immunohistochemical staining for p53 (Do-1), activation of p53 (assessed by phosphorylation at serine 12 and serine 392) and p21 was performed. Cell staining was expressed as the mean number of cells stained per three high-power fields (HPFs) and as a percentage of 1000 cells. Sunburn cells (SBCs)were also counted per HPF. Results UVA1 produced negligible numbers of SBCs, relatively little p53 (Do-1) staining (mean±.SD cell count per HPF 16±10),no p53 activation and very little evidence of p21 expression (mean±SD cell count per HPF 5.3±7), in contrast to TL-01 (mean±SD cell count per HPF of 11.83±2.1 SBCs, 146.3±38 for Do-1, 26.6±15 for serine 15, 14.9±12 for serine 392 and 77.9±30 for p21) or SSR irradiation (mean±SD cell count per HPF of 3.5±1.2 SBCs, 147.5±62 for Do-1, 54±50 for serine 15, 38.9±18 for serine 392 and 56.7±30 for p21). Conclusions:These data indicate that there are fundamental differences in the effects of UVA1 on p53 and its activation pathways compared with TL-01 and SSR, and may in part explain the differential effects of these phototherapies.
文摘Background: Accumulation of molecular alterations, including mutations in Kirsten-ras (K-ras), p53, and adenomatous polyposis coli (APC), contribute to colorectal carcinogenesis. Our group has previously characterised a panel of sporadic colorectal adenocarcinomas for mutations in these three genes and has shown that p53 and K-ras mutations rarely occur in the same colorectal tumour. This suggests that mutations in these genes are on separate pathways to colorectal cancer development and may influence patient prognosis independently. Aims: To correlate the presence or absence of mutations in K-ras, p53, and APC with survival in a cohort of colorectal cancer patients. Patients: A series of 107 inpatients treated surgically for colorectal cancer in Tayside, Scotland between November 1997 and December 1999. Methods: Colorectal tumours were characterised for mutations in K-ras, p53, and APC. Kaplan-Meier survival curves were constructed using overall survival and disease specific survival as the primary end points. Patient survival was analysed using the log rank test and Cox proportional hazards model. Results: Patients with K-ras mutations had significantly poorer overall survival than patients without K-ras mutations (p = 0.0098). Multivariate analysis correcting for Dukes’ stage, age, and sex confirmed this (hazard ratio 2.9 (95% confidence interval 1.4-6.2); p = 0.0040). K-ras mutations were also significantly associated with poorer disease specific survival. The presence of APC and p53 mutations did not affect survival in this cohort of patients (p = 0.9034 and p = 0.8290, respectively). Conclusions: Our data indicate that the presence of K-ras mutations predicts poor patient prognosis in colorectal cancer, independently of tumour stage.
文摘Objective: To determine the time course and dose-response characteristics of UV-A1 erythema in the Tayside region of Scotland. Design: Adult volunteers (skin types I and II [n=13]- and III and IV [n=11])were exposed to geometric dose series of UV-A1 irradiation from a high-output source on photoprotected lower back and inner forearm skin. Setting: Photobiology unit in a university hospital. MainOutcomeMeasures: The minimal erythema dose (MED) was recorded visually and erythema was assessed objectively by erythema meter at 4, 8, 24, and 48 hours after exposure. Results: Peak erythema (lowest visual MED) was seen at 8 hours on the back and arm in 11 subjects with skin types I and II and on the back at 8 hours in 9 subjects and on the arm at 4 hours in 10 subjects with skin types III and IV. The lowest median (range) MED was 20 J/cm2 (14- 56 J/cm2) on the back and 42 J/cm2 (20 to >80 J/cm2) on the arm at 8 hours for subjects with skin types I and II and 28 J/cm2 (20- 112 J/cm2) at 8 hours on the back and 56 J/cm2 (28- 80 J/cm2) at 4 hours on the arm for subjects with skin types III and IV. The D0.025, an objective measure that corresponds approximately to the visual MED, demonstrated a broad peak from 8 to 24 hours. Conclusions: Our local population is more erythemally sensitive to UV-A1 radiation than reports suggest. Daily dose regimens may risk cumulative erythema. Lower starting doses should be used in this population. The wide range of MEDs highlights the need for MED testing.
文摘Objectives: To determine whether the improved clinical status after newborn screening (NBS) for cystic fibrosis (CF) segregates with increased therapeutic intervention compared with presentation by clinical diagnosis (CD). Study design: In 2002, two populations (1 to 9 years of age) who presented (excluding meconium ileus) by NBS ≤ 3 months of age or by CD were compared in an observational, cross-sectional design. NBS and CD populations (184 and 950 patients, respectively) were divided into 3-year age groups (1 to 3, 4 to 6, and 7 to 9 years)-. Therapies of duration >3 months were compared together with Pseudomonas aeruginosa infection status. Results: NBS patients≤ 6 years of age received significantly fewer and less demanding therapies not explained by age, genotype, geography, or social deprivation. In 7-to 9-year-olds, significantly fewer NBS patients received intravenous antibiotics. NBS patients without P aeruginosa infection received significantly fewer therapies, but no differences were found between intermittently or chronically infected NBS and CD populations. Comparable results were found in Δ F508/Δ F508 subpopulations. Conclusions: CF populations diagnosed by NBS are associated with reduced treatment compared with age and genotype-matched CD control subjects.
文摘Objectives: To determine whether early identification of babies with cystic fibrosis (CF) improves outcome in the current environment of new improved treatments, considering the criticism that there may be only marginal benefit gained by CF newborn screening (NBS). Study design: We tested whether CF NBS in the setting of modern CF center care still afforded benefit using the UK CF Database (UKCFD; www.cystic-fi-brosis.org.uk) to compare clinical outcomes in infants who underwent NBS and control subjects who were clinically diagnosed (CD). With Mann-Whitney rank tests, 184 patients who underwent NBS aged 1 to 9 years in 2002 (excluding meconium ileus) were compared with matched patients who were CD in 3-year age groups (950 control subjects). Results: Patients as old as 6 years who underwent NBS had significantly greater median height z-scores, less severe Northern chest radiography scores, better Shwachman-Kulczycki scores, and lower rates of chronic Pseudomonas aeruginosa infection. No difference was found for weight z-score or % predicted forced expiratory value in 1 second or forced volume capacity. Nutritional benefit was demonstrated in patients who underwent NBS and were homozygous for the Δ F508 mutation. Conclusions: NBS segregates with better outcomes in patients as old as 6 years compared with age and gene-matched control subjects who are CD. This cross-sec-tional study shows that infants who undergo screening derive nutritional benefit in improved median height and reduced morbidity.
文摘Background: Dead Sea (DS) salt solution soaks are used in combination with narrowband ultraviolet B (NB- UVB) to treat psoriasis in many centres, particularly in continental Europe. No previously published controlled study has assessed DS salt + NB- UVB balneophototherapy. Objectives: To compareDS salt balneophototherapy with NB- UVB monotherapy for chronic plaque psoriasis. Methods: Sixty patients with chronic plaque psoriasis participated in this paired, controlled study, with pretreatment DS salt soaks randomly allocated to each participant’ s right or left study limb. Psoriasis severity was assessed with a Scaling, Erythema and Induration score by a blinded observer. Assessments were weekly during the therapy course, and thereafter 8- weekly until relapse or for up to 1 year after clearance. Results: The mean area under the psoriasis severity- time curves during treatment was not detectably lower with DS salt balneophototherapy than with NB- UVB monotherapy (P=0.099). The psoriasis severity score fell slightly more from beginning to end of courses with DS salt balneophototherapy than with NB- UVB monotherapy (P=0.019). There was no detectable difference in times to relapse. Conclusions: In this population the addition of pretreatment DS salt soaks to NB- UVB did not result in a clinically important improvement in clearance of psoriasis.
文摘A 76-year-old man was commenced on carbamazepine for partial seizures. This was followed by the development of a rash in an apparently photodistributed pattern, fever, lymphadenopathy, eosinophilia, abnormal liver function tests and atypical lymphocytosis fulfilling the criteria for drug-induced hypersensitivity syndrome. Discontinuation of carbamazepine and application of topical steroid resulted in clearance of the rash, normalization of liver function tests and improvement in eosinophilia. The photodistributed pattern in this case of carbamazepine-induced hypersensitivity syndrome is of interest.
文摘The pathogenesis of metabolic-associated fatty liver disease(MAFLD)is complex and thought to be dependent on multiple parallel hits on a background of genetic susceptibility.The evidence suggests that MAFLD progression is a dynamic two-way process relating to repetitive bouts of metabolic stress and inflammation interspersed with endogenous anti-inflammatory reparative responses.In MAFLD,excessive hepatic lipid accumulation causes the production of lipotoxins that induce mitochondrial dysfunction,endoplasmic reticular stress,and over production of reactive oxygen species(ROS).Models of MAFLD show marked disruption of mitochondrial function and reduced oxidative capacitance with impact on cellular processes including mitophagy,oxidative phosphorylation,and mitochondrial biogenesis.In excess,ROS modify insulin and innate immune signaling and alter the expression and activity of essential enzymes involved in lipid homeostasis.ROS can also cause direct damage to intracellular structures causing hepatocyte injury and death.In select cases,the use of anti-oxidants and ROS scavengers have been shown to diminish the proapoptopic effects of fatty acids.Given this link,endogenous anti-oxidant pathways have been a target of interest,with Nrf2 activation showing a reduction in oxidative stress and inflammation in models of MAFLD.Thyroid hormone receptorβ(THRβ)agonists and nuclear peroxisome proliferationactivated receptor(PPAR)family have also gained interest in reducing hepatic lipotoxicity and restoring hepatic function in models of MAFLD.Unfortunately,the true interplay between the clinical and molecular components of MAFLD progression remain only partly understood.Most recently,multiomics-based strategies are being adopted for hypothesis-free analysis of the molecular changes in MAFLD.Transcriptome profiling maps the unique genotype-phenotype associations in MAFLD and with various single-cell tran scriptome-based projects underway,there is hope of novel physiological insights to MAFLD progression and uncover therapeutic targets.
基金Funding This study was mainly funded by the Wellcome Trust Strategic Award“Stratifying Resilience and Depression Longitudinally”(STRADL)with Reference Number 104036/Z/14/Z.
文摘Headache is one of the commonest complaints that doctors need to address in clinical settings.The genetic mechanisms of different types of headache are not well understood while it has been suggested that self-reported headache and self-reported migraine were genetically correlated.In this study,we performed a meta-analysis of genome-wide association studies(GWAS)on the self-reported headache phenotype from the UK Biobank and the self-reported migraine phenotype from the 23andMe using the Unified Score-based Association Test(metaUSAT)software for genetically correlated phenotypes(N=397,385).We identified 38 loci for headaches,of which 34 loci have been reported before and four loci were newly suggested.The LDL receptor related protein 1(LRP1)-Signal Transducer and Activator of Transcription 6(STAT6)-Short chain Dehydrogenase/Reductase family 9C member 7(SDR9C7)region in chromosome 12 was the most significantly associated locus with a leading p value of 1.24×10^(-62)of rs11172113.The One Cut homeobox 2(ONECUT2)gene locus in chromosome 18 was the strongest signal among the four new loci with a p value of 1.29×10^(-9)of rs673939.Our study demonstrated that the genetically correlated phenotypes of self-reported headache and self-reported migraine can be meta-analysed together in theory and in practice to boost study power to identify more variants for headaches.This study has paved way for a large GWAS meta-analysis involving cohorts of different while genetically correlated headache phenotypes.
