Biomarkers in diabetic nephropathy: Present and future

Diabetic nephropathy(DN) is the leading cause of end stage renal disease in the Western world. Microalbuminuria(MA) is the earliest and most commonly used clinical index of DN and is independently associated with cardiovascular risk in diabetic patients. Although MA remains an essential tool for risk stratification and monitoring disease progression in DN, a number of factors have called into question its predictive power. Originally thought to be predictive of future overt DN in 80% of patients, we now know that only around 30% of microalbuminuric patients progress to overt nephropathy after 10 years of follow up. In addition, advanced structural alterations in the glomerular basement membrane may already have occurred by the time MA is clinically detectable.Evidence in recent years suggests that a significant proportion of patients with MA can revert to normoalbuminuria and the concept of nonalbuminuric DN is well-documented, reflecting the fact that patients with diabetes can demonstrate a reduction in glomerular filtration rate without progressing from normo-to MA. There is an unmet clinical need to identify biomarkers with potential for earlier diagnosis and risk stratification in DN and recent developments inthis field will be the focus of this review article.

Enhanced recovery programme in colorectal surgery:Does one size fit all?

Enhanced recovery after surgery(ERAS) employs a multimodal perioperative care pathway with the aim of attenuating the stress response to surgery and accelerating recovery.It has been difficult to determine the relative importance of some of the individual components of these pathways such as epidural analgesia and laparoscopic colorectal surgery.Some argue that only a rigid adherence to the published ERAS protocol can achieve the proposed benefits of fast-track surgery.In this article,we explore some of the areas where the evidence base may be changing and ask whether a more flexible and individualised approach should be considered.

Endoscopic ultrasound-guided elastography in the nodal staging of oesophageal cancer

AIM： To assess quantitative endoscopic ultrasound （EUS）- guided elastography in the nodal staging of oesophago- gastric cancers.METHODS： This was a single tertiary centre study as- sessing 50 patients with established oesophago-gastric cancer undergoing EUS-guided fine needle aspiration biopsy （FNAB） of lymph nodes between July 2007 and July 2009. EUS-guided elastography of lymph nodes was performed before EUS-FNAB. Standard EUS charac- teristics were also described. Cytological determination of whether a lymph node was malignant or benign was used as the gold standard for this study. Comparisons of elastography and standard EUS characteristics were made between the cytologically benign and malignant nodes. The main outcome measure was the accuracy of elastography in differentiating between benign and malignant lymph nodes in oesophageal cancers.

Update on risk scoring systems for patients with upper gastrointestinal haemorrhage

Upper gastrointestinal haemorrhage (UGIH) remains a common medical emergency worldwide. It is increasingly recognised that early risk assessment is an important part of management, which helps direct appropriate patient care and the timing of endoscopy. Several risk scores have been developed, most of which include endoscopic findings, although a minority do not. These scores were developed to identify various end-points including mortality, rebleeding or clinical intervention in the form of transfusion, endoscopic therapy or surgery. Recent studies have reported accurate identification of a very low risk group on presentation, using scores which require simple clinical or laboratory parameters only. This group may not require admission, but could be managed with early out-patient endoscopy. This article aims to describe the existing pre- and post-endoscopy risk scores for UGIH and assess the published data comparing them in the prediction of outcome. Recent data assessing their use in clinical practice, in particular the early identification of low-risk patients, are also discussed.

欧洲肿瘤内科协会对非上皮性卵巢癌的诊断、治疗和随访所制定的临床实践指南

非上皮性卵巢癌是一类少见的卵巢癌,因此,其诊断较难建立。然而,通过仔细观察各种肿瘤的标记物[尤其是人绒毛膜促性腺激素β亚单位（β-hCG）、α-甲胎蛋白（α-AFP）和乳酸脱氢酶（LDH）]、临床体征（如妊娠期体征,

Radiofrequency ablation for early oesophageal squamous neoplasia:Outcomes form United Kingdom registry

AIM:To report outcomes on patients undergoing radiofrequency ablation(RFA)for early oesophageal squamous neoplasia from a National Registry.METHODS:A Prospective cohort study from 8 tertiary referral centres in the United Kingdom.Patients with squamous high grade dysplasia(HGD)and early squamous cell carcinoma(ESCC)confined to the mucosa were treated.Visible lesions were removed by endoscopic mucosal resection(EMR)before RFA.Following initial RFA treatment,patients were followed up 3monthly.Residual flat dysplasia was treated with RFA until complete reversal dysplasia(CR-D)was achieved or progression to invasive Squamous cell cancer defined as infiltration into the submucosa layer or beyond.The main outcome measures were CR-D at 12 mo from start of treatment,long term durability,progression to cancer and adverse events.RESULTS:Twenty patients with squamous HGD/ESCC completed treatment protocol.Five patients(25%)had EMR before starting RFA treatment.CR-D was 50%at12 mo with a median of 1 RFA treatment,mean 1.5(range 1-3).Two further patients achieved CR-D with repeat RFA after this time.Eighty per cent with CR-D remain dysplasia free at latest biopsy,with median follow up 24 mo(IQR 17-54).Six of 20 patients(30%)progressed to invasive cancer at 1 year.Four patients(20%)required endoscopic dilatations for symptomatic structuring after treatment.Two of these patients have required serial dilatations thereafter for symptomatic dysphagia with a median of 4 dilatations per patient.The other 2 patients required only a single dilatation to achieve an adequate symptomatic response.One patient developed cancer during follow up after end of treatment protocol.CONCLUSION:The role of RFA in these patients re-mains unclear.In our series 50%patients responded at12 mo.These figures are lower than limited published data.

Upper gastrointestinal bleeding in Scotland 2000-2010: Improved outcomes but a significant weekend effect

AIM: To assess numbers and case fatality of patients with upper gastrointestinal bleeding(UGIB),effects of deprivation and whether weekend presentation affected outcomes.METHODS: Data was obtained from Information Services Division(ISD) Scotland and National Records of Scotland(NRS) death records for a ten year period between 2000-2001 and 2009-2010. We obtained data from the ISD Scottish Morbidity Records(SMR01) database which holds data on inpatient and daycase hospital discharges from non-obstetric and nonpsychiatric hospitals in Scotland. The mortality data was obtained from NRS and linked with the ISD SMR01 database to obtain 30-d case fatality. We used 23 ICD-10(International Classification of diseases) codes which identify UGIB to interrogate database. We analysed these data for trends in number of hospital admissions with UGIB,30-d mortality over time and assessed effects of social deprivation. We compared weekend and weekday admissions for differences in 30-d mortality and length of hospital stay. We determined comorbidities for each admission to establish if comorbidities contributed to patient outcome. RESULTS: A total of 60643 Scottish residents were admitted with UGIH during January,2000 and October,2009. There was no significant change in annual number of admissions over time,but there was a statistically significant reduction in 30-d case fatality from 10.3% to 8.8%(P < 0.001) over these 10 years. Number of admissions with UGIB was higher for the patients from most deprived category(P < 0.05),although case fatality was higher for the patients from the least deprived category(P < 0.05). There was no statistically significant change in this trend between 2000/01-2009/10. Patients admitted with UGIB at weekends had higher 30-d case fatality compared with those admitted on weekdays(P < 0.001). Thirty day mortality remained significantly higher for patients admitted with UGIB at weekends after adjusting for comorbidities. Length of hospital stay was also higher overall for patients admitted at the weekend when compared to weekdays,although only reached statistical significance for the last year of study 2009/10(P < 0.0005). CONCLUSION: Despite reduction in mortality for UGIB in Scotland during 2000-2010,weekend admissions show a consistently higher mortality and greater lengths of stay compared with weekdays.

Mediastinal node staging by positron emission tomographycomputed tomography and selective endoscopic ultrasound with fine needle aspiration for patients with upper gastrointestinal cancer:Results from a regional centre

AIM To investigate the impact of endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA) and positron emission tomography-computed tomography(PET-CT) in the nodal staging of upper gastrointestinal(GI) cancer in a tertiary referral centre.METHODS We performed a retrospective review of prospectively recorded data held on all patients with a diagnosis of upper GI cancer made between January 2009 and December 2015. Only those patients who had both a PET-CT and EUS with FNA sampling of a mediastinal node distant from the primary tumour were included. Using a positive EUS-FNA result as the gold standard for lymph node involvement, the sensitivity, specificity, positive and negative predictive values(PPV and NPV) and accuracy of PET-CT in the staging of mediastinal lymph nodes were calculated. The impact on therapeutic strategy of adding EUS-FNA to PET-CT was assessed.RESULTS One hundred and twenty one patients were included. Sixty nine patients had a diagnosis of oesophageal adenocarcinoma(Thirty one of whom were junctional), forty eight had oesophageal squamous cell carcinoma and four had gastric adenocarcinoma. The FNA results were inadequate in eleven cases and the PET-CT findings were indeterminate in two cases, therefore thirteen patients(10.7%) were excluded from further analysis. There was concordance between PET-CT and EUS-FNA findings in seventy one of the remaining one hundred and eight patients(65.7%). The sensitivity, specificity, PPV and NPV values of PET-CT were 92.5%, 50%, 52.1% and 91.9% respectively. There was discordance between PET-CT and EUS-FNA findings in thirty seven out of one hundred and eight patients(34.3%). MDT discussion led to a radical treatment pathway in twenty seven of these cases, after the final tumour stage was altered as a direct consequence of the EUS-FNA findings. Of these patients, fourteen(51.9%) experienced clinical remission of a median of nine months(range three to forty two months). CONCLUSION EUS-FNA leads to altered staging of upper GI cancer, resulting in more patients receiving radical treatment that would have been the case using PET-CT staging alone.

Nodular regenerative hyperplasia related portal hypertension in a patient with hypogammaglobulinaemia

Nodular regenerative hyperplasia (NRH) of liver is a relatively rare liver disorder, but a frequent cause of noncirrhotic portal hypertension. We present a lady with common variable immune deficiency who presented with upper gastrointestinal bleeding and deranged liver function tests but preserved synthetic function. Upper gastrointestinal endoscope showed bleeding gastric varices and non-bleeding oesophageal varices. Although her oesophageal varices were eradicated by repeated endoscopic band ligation, the gastric varices failed to resolve after repeated endoscopic histocryl injection and she eventually needed transjugular intrahepatic portosystemic shunt placement. Liver biopsy showed NRH. We review the association of hypogammaglobinaemia and NRH and discuss the appropriate management of portal hypertension in NRH.

Targeting inflammation in pancreatic cancer: Clinical translation

Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma.

Catastrophic gastrointestinal complication of systemic immunosuppression

We present a case of acute upper gastrointestinal haemorrhage in a patient with systemic vasculitis immunosuppressed on cyclophosphamide and prednisolone.The patient presented with a diffuse haemorrhagic oesophagitis and a non-specific duodenitis.Biopsies taken from the oesophagus and duodenum demonstrated infection with herpes simplex virus(HSV)and cytomegalovirus(CMV)respectively.Viral infection of the upper gastrointestinal tract is a recognised complication of immunosuppression and HSV is one of the most common pathogens.CMV on the other hand most commonly causes a colitis or less commonly oesophagitis.CMV enteritis is rare as is the synchronous infection with two viral agents in an immunocompromised patient having being described in a few case series only.Viral infection of the gastrointestinal tract in immunocompromised patients should be treated with systemic anti-viral medication and consideration to withdrawal of the immunosuppressive therapy if possible and appropriate.The authors highlight the need for a high suspicion of viral infection in immunosuppressed patients presenting with upper gastrointestinal bleeding.

Drug therapy for heart failure in older patients —what do they want？

Chronic heart failure （CHF） is predominantly seen in older patients, and therefore real life medicine often requires the extrapolation of findings from trials conducted in much younger populations. Prescribing patterns and potential benefits in the elderly are heavily influenced by polypharmacy and co-morbid pathologies. Increasing longevity may become less relevant in the frail elderly, whereas improving quality of life （QoL） often becomes priority; the onus being on improving wellbeing, maintaining independence for longer, and delaying institution- alisation. Specific studies evaluating elderly patients with CHF are lacking and little is known regarding the tolerability and side-effect profile of evidence based drug therapies in this population. There has been recent interest on the impact of heart rate in patients with symptomatic CHF. Ivabradine, with selective heart rate lowering capabilities, is of benefit in patients with CHF and left ventricular systolic dysfunction in sinus rhythm, resulting in reduction of heart failure hospitalisation and cardiovascular death. This manuscript will focus on CHF and the older patient and will discuss the impact of heart rate, drug therapies and tolerability. It will also highlight the tmmet need for specific studies that focus on patient-centred study end points rather than mortality targets that characterise most therapeutic trials. An on-going study evalu- ating the impact of ivabradine on QoL that presents a unique opportunity to evaluate the tolerability and impact of an established therapy on a wide range of real life, older patients with CHF will be discussed.

Observation or resection of pancreatic intraductal papillary mucinous neoplasm:An ongoing tug of war

An increasing number of patients are being referred to pancreatic centres around the world due to often incidentally discovered cystic neoplasms of the pancreas.The evaluation and management of pancreatic cystic neoplasms is a controversial topic and with existing guidelines based on a lack of strong evidence there is discordance between centres and guidelines with regard to when to offer surgery and when to favour surveillance.The frequency,duration and modality of surveillance is also controversial as this is resource-consuming and must be balanced against the perceived benefits and risks involved.While there is consensus that the risk of malignancy should be balanced against the lifeexpectancy and comorbidities,the indications for surgery and surveillance strategies vary among the guidelines.Thus,the tug of war between surveillance or resection continues.Here we discuss the recommendations from guidelines with further accumulating data and emerging reports on intraductal papillary mucinous neoplasm in the literature.

Utility of faecal calprotectin analysis in adult inflammatory bowel disease

The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are chronic relapsing, remitting disorders. Diagnosis, along with assessment of disease activity and prognosis present challenges to managing clinicians. Faecal biomarkers, such as faecal calprotectin, are a non-invasive method which can be used to aid these decisions. Calprotectin is a calcium and zinc binding protein found in the cytosol of human neutrophils and macrophages. It is released extracellularly in times of cell stress or damage and can be detected within faeces and thus can be used as a sensitive marker of intestinal inflammation. Faecal calprotectin has been shown to be useful in the diagnosis of IBD, correlates with mucosal disease activity and can help to predict response to treatment or relapse. With growing evidence supporting its use, over the last decade this faecal biomarker has significantly changed the way IBD is managed.

Ivabradine tolerability in heart failure

The Systolic Heart failure treatment with the I( inhibitor ivabradine Trial (SHIFT, n = 6505) evaluated patients with symptomatic chronic heart failure (CHF), in sinus rhythm with resting heart rate ≥70 beats/min and left ventricular ejection fraction (LVEF)≤ 35%, average age 60 ± 11 years[1].

Update on gastric varices

Although less common than oesophageal variceal haemorrhage, gastric variceal bleeding remains a serious complication of portal hypertension, with a high associated mortality. In this review we provide an update on the aetiology, classification and management of gastric varices, including acute bleeding, prevention of rebleeding and primary prophylaxis. We describe the optimum management strategies for gastric varices including drug, endoscopic and radiological therapies, focusing on recent published evidence.

Femoro Patella Vialla patellofemoral arthroplasty: An independent assessment of outcomes at minimum 2-year follow-up

AIM: To determine outcomes using the Femoro-Patella Vialla(FPV) arthroplasty and if there is an ideal patient for this implant. METHODS: A total of 41 FPV patellofemoral joint replacements were performed in 31 patients(22 females, 9 males, mean age 65 years). Mean followup was 3.2 years(minimum 2 years). Radiographs were reviewed preoperatively and postoperatively. We assessed whether gender, age, previous surgery, patella atla or trochlear dysplasia influenced patient satisfaction or patient functional outcome.RESULTS: The median Oxford Knee Score was 40 and the median Melbourne Patellofemoral Score was 21 postoperatively. Seventy-six percent of patients were satisfied, 10% unsure and 14% dissatisfied postoperatively. There was no radiological progression of tibiofemoral joint arthritis, using the Ahlback grading,in any patient. One patient, who was diagnosed with rheumatoid arthritis postoperatively, underwent revision to total knee replacement. There were no intraoperative lateral releases and no implant failures. Gender, age, the presence of trochlear dysplasia, patella alta or bilateral surgery did not influence patient outcome. Previous surgery did not correlate with outcome. CONCLUSION: In contrast to the current literature, the FPV shows promising early results. However, we cannot identify a subgroup of patients with superior outcomes.

TRANSFORMING-GROWTH FACTOR-PI PREFERENTIALLY INHIBITS THE INDUCTION OF CYTOTOXICITY IN HUMAN T CELLS STIMULATED VIA CD28

Generally, TGF-βs are held to down- regulate the growth of immune cells and to inhibit the development of certain differentiated functions, such as the induction of LAK activity by IL-2. In the present study, the effects of TGF-β1 on the proliferation and cytotoxicity of human PBMC activated by anti-CD3 or and-CD3 plus anti-CD28 was investigated. The results demonstrated that TGF- β1 clearly inhibits the induction of cytotoxic ability in human PBMC stimulated via CD3 or CD3 and CD28 ( P<0. 01) , without significantly altering the proliferative response to these stimuli, at the tested doses of TGF-β1. Co-stimulation with IL-2 was hardly altered, suggesting that TGF-β1 action is affected by the nature of the costimulatory signals.

吗啡和苯巴比妥用于治疗新生儿戒断综合征的随机对照试验

研究背景:在过去10年间,Glasgow地区新生儿戒断综合征(NAS)的发病率增加了10倍。女王皇家妇产科医院特殊监护婴儿病房(SCBU)收治的患儿中,有17%即为该病。目的:对比阿片类替代物(硫酸吗啡)疗法和现行的标准疗法(苯巴比妥)对于NAS的疗效。初级研究终点是药物治疗的疗程。

营养不良和皮肤

Malnutrition states are relatively uncommon in the UK but we have seen two recent cases which have heightened our awareness of both dermatological manifestations of malnutrition and of nutritional sequelae of a dermatological problem. Case 1 is a patient with anorexia nervosa presenting with features of pellagra. This condition is due to deficiency of niacin and responds rapidly to replacement therapy. Classical presentation is an erythematous rash on photoexposed sites, often related to heat or friction. There are three reported cases of pellagra occurring in patients with anorexia nervosa. Case 2 is an adult atopic with sensitizations to multiple foodstuffs. A self-imposed restriction diet caused multiple nutritional deficiencies. Restriction diets in adult atopies are not particularly common in the UK, but there is some evidence to suggest that they may cause significant nutritional deficiency. A nutrition screen may be indicated more frequently than is currently recognized.