Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson's-like gut pathology.

Deposition of misfolded α-synuclein (αsyn) in the enteric nervous system (ENS) is found in multiple neurodegenerative diseases. It is hypothesized that ENS synucleinopathy contributes to both the pathogenesis and non-motor morbidity in Parkinson's Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we demonstrate that ENS-resident macrophages, which play a critical role in maintaining ENS homeostasis, initially respond to enteric neuronal αsyn pathology by upregulating machinery for complement-mediated engulfment. Pharmacologic depletion of ENS-macrophages or genetic deletion of C1q enhanced enteric neuropathology. Conversely, C1q deletion ameliorated gut dysfunction, indicating that complement partially mediates αsyn-induced gut dysfunction. Internalization of αsyn led to increased endo-lysosomal stress that resulted in macrophage exhaustion and temporally correlated with the progression of ENS pathology. These novel findings highlight the importance of enteric neuron-macrophage interactions in removing toxic protein aggregates that putatively shape the earliest stages of PD in the periphery.

Rectal cancer: prognostic indicators of long-term outcome in patients considered for surgery.

PURPOSE: Patients and clinicians seek an accurate prognosis after resectional surgery for rectal cancer. The aim of this study was to determine long-term outcomes after potentially curative surgery for rectal cancer with particular focus on factors associated with longer-term survival that are available to surgeons in the early post-operative setting. METHODS: We conducted a retrospective review of a prospectively gathered database of all primary rectal adenocarcinomas considered for surgery in the University Hospitals of Leicester National Health Service (NHS) Trust between 1998 and 2007. Survival was calculated using a Kaplan-Meier method. Factors thought to be associated with survival were subjected to univariate analysis followed by Cox proportion regression. RESULTS: One thousand and twelve patients with primary rectal adenocarcinoma diagnosed between 1998 and 2007 were identified. Eight hundred and fifty three patients did not have metastases at the time of presentation and 726 patients underwent major resectional surgery. Five-year survival was 66 %. Patients' age, Dukes' stage, UICC stage, nodal involvement and circumferential resection margin status were independently associated with long-term survival on multivariate analysis. CONCLUSION: This is one of the largest series of rectal cancers from a single NHS trust. We have demonstrated that age, Dukes' stage and CRM status are associated with long-term survival. These clinical factors are readily available to the surgeon at the time of first post-operative review and can provide a good clinical guide to prognosis.

Fresh frozen cadavers: an under-utilized resource in laparoscopic colorectal training in the United Kingdom.

AIM: To describe the use of fresh frozen cadavers in laparoscopic colorectal training. METHOD: The cadavers are washed and frozen to -20°C within a week of procurement before being thawed at room temperature prior to use. RESULTS: Fresh frozen cadavers provide perfect anatomy, normal tissue consistency and a realistic operative training experience. CONCLUSION: Fresh frozen cadavers have a number of clear advantages over other training models in laparoscopic colorectal surgery but are currently not widely used.

The prognostic value of circulating big endothelin-1 in patients undergoing potentially curative resection for colorectal cancer.

AIM: Elevated circulating endothelin-1 (ET-1) has been demonstrated in patients with colorectal cancer (CRC). The aim of this study was to examine the prognostic value of plasma big ET-1, the stable precursor of ET-1, in cancer-specific survival in patients having curative surgery for CRC. METHOD: Seventy-seven patients undergoing potentially curative surgery for CRC between January 2000 and January 2001 were studied. Clinicopathological data were obtained from a prospectively maintained database including long-term follow-up information (median follow up 84 months). The influence of plasma big ET-1 and clinicopathological variables upon over cancer-specific survival was determined by univariate and multivariable analysis. RESULTS: On univariate analysis, advanced Dukes' stage, tumour size and patient age were associated with shortened overall survival. Advanced Dukes' stage was the only factor associated with shortened survival on multivariable analysis. Plasma big ET-1 showed no association with either overall or cancer-specific survival following CRC resection. CONCLUSION: Plasma big ET-1 appears to have no prognostic value in primary CRC.

Predisposition to repeat breeding in UK cattle and success of artificial insemination alone or in combination with embryo transfer.

To investigate whether there was a subpopulation of repeat breeders (cows or heifers that returned to oestrus after three inseminations) that were less fertile after a fourth artificial insemination (AI) with or without additional embryo transfer, and to estimate the efficacy of AI plus embryo transfer to overcome repeat breeding problems, a two-part investigation was carried out. Part 1 involved 85 repeat breeders and 85 controls subjected to AI alone. In part 2, 128 repeat breeders received AI on day 0 plus an embryo transfer seven days later, while controls received embryo transfer alone on day 7. In repeat breeders, the interval between calving and pregnancy was 80 days longer than in the controls (P=0.01), irrespective of previous fertility treatment which had mainly focused on the ovaries. The incidence of dystocia was similar in repeat breeders and in controls, but repeat breeders had a higher previous incidence of moderate uterine infection compared with controls (P=0.04). In repeat breeder cows, pregnancy rates for AI alone were 30 per cent after the fourth AI (controls: 45 to 64 per cent after one to three inseminations) compared with 52.6 per cent after a fourth AI with embryo transfer (controls with embryo transfer alone: 49 per cent). Successful pregnancies after a fourth AI plus embryo transfer produced a 6.25 per cent incidence of twins.

The RAPID protocol enhances patient recovery after both laparoscopic and open colorectal resections.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs can accelerate recovery and shorten the hospital stay after colorectal resections. The RAPID (remove, ambulate, postoperative analgesia, introduce diet) protocol is a simplified ERAS program that consists of a simplified, user-friendly single-page pro forma schedule. This study aimed to evaluate the impact of the RAPID protocol on patients undergoing both laparoscopic and open colorectal resections in two specialized colorectal units. METHODS: A prospective, two-center study assessed 117 age-matched patients undergoing open or laparoscopic colorectal resection to compare the postoperative course for patients using the RAPID protocol with those treated in a traditional manner. RESULTS: Of the 117 patients studied, 70 underwent laparoscopic resection (55 with the RAPID protocol) and 47 underwent open resection (25 with the RAPID protocol). Patients undergoing laparoscopic resections with the RAPID protocol had a significantly shorter hospital stay (p = 0.01) and tolerance of a full diet (p = 0.002). Similarly, patients undergoing open resections with the RAPID protocol also have a significantly shorter hospital stay (p = 0.04). CONCLUSION: The RAPID protocol is a user-friendly, easy, and effective tool that facilitates earlier tolerance of diet and discharge from the hospital for patients undergoing laparoscopic or open colorectal resections.

A case of toxic megacolon in a patient with collagenous colitis.

Collagenous colitis is an uncommon inflammatory bowel disease, the aetiology of which is unknown. We report a case of toxic megacolon in a patient with collagenous colitis, a previously unreported complication.

Characterisation of Interleukin-8 and monocyte chemoattractant protein-1 expression within the abdominal aortic aneurysm and their association with mural inflammation.

OBJECTIVES: Abdominal aortic aneurysms (AAAs) are characterised by chronic transmural inflammation. This study investigated the expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) within the AAA, and their relationship with mural inflammation. METHODS: Biopsies were obtained from 25 AAAs, 15 abdominal aortas, and 10 atherosclerotic thoracic aortas. IL-8 and MCP-1 expression was measured in homogenised specimens by ELISA. Infiltrate composition and localised expression of IL-8 and MCP-1 were determined through immunohistochemistry. RESULTS: ELISA analysis demonstrated that IL-8 and MCP-1 were raised in the AAA compared to the controls [(IL-8, AAA vs. abdominal aorta: >28-fold, P<.001; AAA vs. thoracic aorta: >28-fold, P<.001) (MCP-1, AAA vs. abdominal aorta: 9-fold, P<.001; AAA vs. thoracic aorta: 19-fold, P<.001)]. Immunohistochemistry revealed that IL-8 was localised to the inflammatory infiltrate, which consisted predominantly of CD3(+) T- and CD20(+) B-lymphocytes. MCP-1 was predominantly expressed by CD68(+) macrophages. Increasing IL-8 expression was associated with an increase in mural inflammation, and an increase in CD3(+) T-lymphocytes of CD4(+) phenotype within the infiltrate population. CONCLUSION: Pathways involving IL-8 and MCP-1 may be involved in AAA pathogenesis. IL-8 may be directly involved in the chemotaxis of T(H)-lymphocytes into the AAA wall.

An algorithm for the management of bile leak following laparoscopic cholecystectomy.

INTRODUCTION: The management of bile leaks following laparoscopic cholecystectomy has evolved with increased experience of ERCP and laparoscopy. The purpose of this study was to determine the impact of a minimally invasive management protocol. PATIENTS AND METHODS: Twenty-four patients with a bile leak following laparoscopic cholecystectomy were recorded consecutively between 1993 and 2003. Between 1993-1998, 10 patients were managed on a case-by-case basis. Between 1998-2003, 14 patients were managed according to a minimally invasive protocol utilising ERC/biliary stenting and re-laparoscopy if indicated. RESULTS: Bile leaks presented as bile in a drain left in situ post laparoscopic cholecystectomy (8/10 versus 10/14) or biliary peritonitis (2/10 versus 4/14). Prior to 1998, neither ERC nor laparoscopy were utilised routinely. During this period, 4/10 patients recovered with conservative management and 6/10 (60%) underwent laparotomy. There was one postoperative death and median hospital stay post laparoscopic cholecystectomy was 10 days (range, 5-30 days). In the protocol era, ERC +/- stenting was performed in 11/14 (P = 0.01 versus pre-protocol) with the main indication being a persistent bile leak. Re-laparoscopy was necessary in 5/14 (P = 0.05 versus preprotocol). No laparotomies were performed (P < 0.01 versus pre-protocol) and there were no postoperative deaths. Median hospital stay was 11 days (range, 5-55 days). CONCLUSIONS: The introduction of a minimally invasive protocol utilising ERC and re-laparoscopy offers an effective modern algorithm for the management of bile leaks after laparoscopic cholecystectomy.

Endovascular abdominal aortic aneurysm repair.

The operative mortality following conventional abdominal aortic aneurysm (AAA) repair has not fallen significantly over the past two decades. Since its inception in 1991, endovascular aneurysm repair (EVAR) has provided an alternative to open AAA repair and perhaps an opportunity to improve operative mortality. Two recent large randomised trials have demonstrated the short and medium term benefit of EVAR over open AAA repair, although data on the long term efficacy of the technique are still lacking. This review aimed at providing an overview of EVAR and a discussion of the potential benefits and current limitations of the technique.

Patients with abdominal aortic aneurysm: are we missing the opportunity for cardiovascular risk reduction?

INTRODUCTION: Antiplatelet agents, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statin drugs), angiotensin converting enzyme (ACE) inhibitors, and beta-adrenergic receptor blockers (beta-blockers) reduce cardiovascular risk and mortality in patients with specific manifestations of cardiovascular disease and risk factors. Occlusive arterial disease, in particular, coronary heart disease, is prevalent in patients with abdominal aortic aneurysm (AAA) and results in reduced life expectancy. The purpose of this study was to investigate the prevalence of cardiovascular disease and risk factors in patients with AAA. In particular, numbers of patients in whom pharmacologic therapy is indicated and numbers of patients who are receiving adequate treatment were determined. METHODS: This was a prospective study of 313 patients with AAA in Leicestershire over the 15 months between September 2002 and December 2003. RESULTS: Data that enabled determination of an indication for antiplatelet agents and statin drugs were available for 262 patients (84%), and for a beta-blocker and ACE inhibitor for 313 patients (100%). An antiplatelet agent was indicated in 242 of 262 patients (92%), a statin drug was indicated in 196 of 262 patients (75%), a beta-blocker was indicated in 107 of 313 patients (34%), and an ACE inhibitor was indicated in 178 of 313 patients (57%). In patients with an indication, 146 of 242 patients (60%) were using an antiplatelet agent, 81 of 196 (41%) were using a statin drug, 41 of 313 (38%) were using a beta-blocker, and 69 of 313 (39%) were using an ACE inhibitor. CONCLUSION: Cardiovascular disease, for which there is evidence for the survival benefit of pharmacologic risk reduction, is prevalent in patients with AAA. The data show that current treatment of cardiovascular risk is suboptimal and could be improved, with an expected reduction in cardiovascular morbidity and mortality.

Feasibility of preoperative computer tomography in patients with ruptured abdominal aortic aneurysm: a time-to-death study in patients without operation.

INTRODUCTION: Despite advances in surgery, anaesthesia, and critical care, mortality from ruptured abdominal aortic aneurysms (AAAs) has not decreased over the last 20 years. Endovascular aneurysm repair (EVAR) of ruptured AAAs is an alternative to open repair, which may improve outcome. However, a computed tomography (CT) scan is usually required to assess the anatomic suitability of the aneurysm for EVAR. This may result in delay in transferring patients to the operating room. We evaluated all patients admitted to hospital with a ruptured AAA who died without undergoing surgery, to determine time to death after AAA rupture and thus the potential time available for obtaining a CT scan. METHODS: A retrospective case note review was conducted of 56 patients admitted to a single center with ruptured AAAs who did not undergo surgery because of advanced age or associated comorbidity over 8 years from 1995 to 2003. Statistical analysis was performed with the Fisher exact test. RESULTS: The 56 patients (33 men, 59%; 23 women, 41%) had a median age of 85 years (range, 71-98 years). Reasons for no operation being performed were shock (9%), cardiac arrest (11%), quality of life (29%), malignancy (7%), cardiac disease (15%), respiratory disease (16%) and age (14%). Median systolic blood pressure at admission was 110 mm Hg, heart rate was 88 beats per minute, and hemoglobin concentration was 10.5 g/dL. Patients were not aggressively resuscitated once a decision was made to not perform surgery. Death within 2 hours of hospital admission occurred in 7 (12.5%) patients, and 49 (87.5%) patients died more than 2 hours after admission. Median interval between onset of symptoms and admission to hospital was 2 hours 30 minutes (range, 44 minutes-36 hours), and the median interval between admission and death was 10 hours 45 minutes (range, 1 hour 1 minute-143 hours 55 minutes). The median total time to death from onset of symptoms was 16 hours 38 minutes (range, 2 hours 6 minutes-146 hours 50 minutes). CONCLUSION: Most (87.5%) patients admitted to hospital with a ruptured AAA died after more than 2 hours. These data show that most patients with a ruptured AAA who reach the hospital alive are sufficiently stable to undergo CT and consideration of EVAR.

The changing face of femoral artery false aneurysms.

OBJECTIVES: To review the aetiology and method of treatment of all femoral artery false aneurysms from a single centre during the last 9 years. DESIGN: Retrospective case-note study. METHODS: All patients with a diagnosis of false aneurysm were identified from the hospital data-base between January 1995 and September 2003. A manual search of the case-notes was performed, and data collected on the location, cause and method of repair of the false aneurysm. For all patients with a diagnosis of femoral artery false aneurysm, the patients' medical and drug history and admission time attributable to the false aneurysm were recorded. RESULTS: One hundred and seven patients were identified. Seventy-nine had false aneurysms of the femoral artery. The majority (40.5%) were caused by coronary angiography, the second commonest cause being breakdown of previous graft anastomosis (29.1%). Over time, the method of treatment became increasingly radiological (most commonly ultrasound-guided thrombin injection), resulting in a significantly reduced hospital admission time (P=0.018). CONCLUSIONS: The incidence of femoral artery false aneurysms appears to be increasing. This is largely a result of an increase in the number of cardiac interventional and diagnostic procedures performed. The introduction of ultrasound-guided thrombin-injection has reduced the inpatient stay of patients with femoral false aneurysms.

Transanal endoscopic microsurgery--lessons from a single UK centre series.

OBJECTIVES: Transanal endoscopic microsurgery (TEM), a minimally invasive technique has been employed in the excision of benign and selected malignant rectal tumours since 1983. We present a single surgeon's series of 102 procedures. PATIENTS AND METHODS: A retrospective case note review of 102 procedures performed over a 6-year period between 1996 and 2001. RESULTS: One hundred and two TEM procedures were performed on 100 patients. 68 for adenomas, 19 potentially curative excisions for carcinoma, 13 palliative procedures for advanced carcinoma and 2 for solitary rectal ulcer syndrome (SRUS). Four adenomas recurred and were successfully treated by various procedures. None went on to develop malignancy, or a further recurrence. Of the cancers, six T1 and 10 T2 were excised with curative intent. Three T3 cancers were excised before endorectal ultrasound was available in the unit and went on to have definitive procedures. One T1 and two T2 carcinomas were not completely histologically excised. These patients were offered definitive procedure and there have been no recurrences. 11 patients underwent palliative TEM procedures, 2 went on to have a recurrence of symptoms. Both underwent a successful second TEM procedure. CONCLUSIONS: Although longer term follow up is still required, TEM appears to be an effective method of excising benign tumours and T1 carcinomas of the rectum. The role of TEM in the treatment of T2 carcinomas is, as yet, unclear and needs further evaluation although the results of our series and others are encouraging.

Severe disease in adult dairy cattle in three UK dairy herds associated with BVD virus infection.

During 1993 outbreaks of diarrhoea in adult dairy cows in three geographically unrelated herds were found to be caused by bovine viral diarrhoea virus (BVDV). The affected animals showed signs of acute watery diarrhoea, agalactia and pyrexia (39.4 to 42 degrees C). Ulceration of the buccal mucosa, a mucoid nasal discharge and stiffness were inconsistent signs. The disease spread rapidly in each case. The diagnosis was confirmed by the isolation of non-cytopathic BVDV from blood and tissues and by the demonstration of significantly rising titres to BVDV by an ELISA. The highest morbidity recorded was 40 per cent with one herd experiencing a 10 per cent mortality. There was no increased incidence of abortion in any of the herds, either at the time of or subsequent to the outbreaks of diarrhoea. In one herd the purchase of a persistently viraemic heifer 14 days before the outbreak was thought to be the source of infection, but in the other two herds the source was not established.

Separation of Mycobacterium leprae from contamination with armadillo-liver-derived "pigment" particles.

Mycobacterium leprae isolated from armadillo liver by the widely used IMMLEP protocol is sometimes contaminated with a particulate "pigment." This paper describes a simple, efficient, and rapid method for purifying large quantities of contaminated bacteria, which may readily be used as an additional step added at the end of the protocol when necessary. The process involves a discontinuous Percoll gradient and generates an essentially pure fraction containing greater than 90% of the original bacteria, and a fraction of "pigment" slightly contaminated with bacteria. Use of the system should release large additional numbers of pure M. leprae suitable for use in human vaccine trials.