A Transgenic Model for Conditional Induction and Rescue of Portal Hypertension Reveals a Role of VEGF-Mediated Regulation of Sinusoidal Fenestrations

Portal hypertension (PH) is a common complication and a leading cause of death in patients with chronic liver diseases. PH is underlined by structural and functional derangement of liver sinusoid vessels and its fenestrated endothelium. Because in most clinical settings PH is accompanied by parenchymal injury, it has been difficult to determine the precise role of microvascular perturbations in causing PH. Reasoning that Vascular Endothelial Growth Factor (VEGF) is required to maintain functional integrity of the hepatic microcirculation, we developed a transgenic mouse system for a liver-specific-, reversible VEGF inhibition. The system is based on conditional induction and de-induction of a VEGF decoy receptor that sequesters VEGF and preclude signaling. VEGF blockade results in sinusoidal endothelial cells (SECs) fenestrations closure and in accumulation and transformation of the normally quiescent hepatic stellate cells, i.e. provoking the two processes underlying sinusoidal capillarization. Importantly, sinusoidal capillarization was sufficient to cause PH and its typical sequela, ascites, splenomegaly and venous collateralization without inflicting parenchymal damage or fibrosis. Remarkably, these dramatic phenotypes were fully reversed within few days from lifting-off VEGF blockade and resultant re-opening of SECs' fenestrations. This study not only uncovered an indispensible role for VEGF in maintaining structure and function of mature SECs, but also highlights the vasculo-centric nature of PH pathogenesis. Unprecedented ability to rescue PH and its secondary manifestations via manipulating a single vascular factor may also be harnessed for examining the potential utility of de-capillarization treatment modalities

The Extended Learning Curve for Laparoscopic Fundoplication: A Cohort Analysis Of 400 Consecutive Cases

Many studies have looked at the learning curve associated with laparoscopic Nissen fundoplication (LNF) in a given institution. This study looks at the learning curve of a single surgeon with a large cohort of patients over a 10-year period. Prospective data were collected on 400 patients undergoing laparoscopic fundoplication for over 10 years. The patients were grouped consecutively into cohorts of 50 patients. The operating time, the length of postoperative hospital stay, the conversion rate to open operation, the postoperative dilatation rate, and the reoperation rate were analyzed. Results showed that the mean length of operative time decreased from 143 min in the first 50 patients to 86 min in the last 50 patients. The mean postoperative length of hospital stay decreased from 3.7 days initially to 1.2 days latterly. There was a 14% conversion to open operation rate in the first cohort compared with a 2% rate in the last cohort. Fourteen percent of patients required reoperation in the first cohort and 6% in the last cohort. Sixteen percent required postoperative dilatation in the first cohort. None of the last 150 patients required dilatation. In conclusion, laparoscopic fundoplication is a safe and effective operation for patients with gastroesophageal reflux disease. New techniques and better instrumentation were introduced in the early era of LNF. The learning curve, however, continues well beyond the first 20 patients

The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer

<p>Background: It is increasingly recognised that host-related factors may be important in determining cancer outcome. The aim was to examine the relationship between patient physiology, the systemic inflammatory response and survival after colorectal cancer resection.</p> <p>Methods: Patients undergoing potentially curative resection of colorectal cancer were identified from a prospectively maintained database. Patient physiology was assessed using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) criteria. The systemic inflammatory response was assessed using the modified Glasgow Prognostic Score (mGPS). Multivariate 5-year survival analysis was carried out with calculation of hazard ratios (HR).</p> <p>Results: A total of 320 patients were included. During follow-up (median 74 months), there were 136 deaths: 83 colorectal cancer related and 53 non-cancer related. Independent predictors of cancer-specific survival were age (HR: 1.46, P<0.01), Dukes stage (HR: 2.39, P<0.001), mGPS (HR: 1.78, P<0.001) and POSSUM physiology score (HR: 1.38, P=0.02). Predictors of overall survival were age (HR: 1.64, P<0.001), smoking (HR: 1.52, P=0.02), Dukes stage (HR: 1.64, P<0.001), mGPS (HR: 1.60, P<0.001) and POSSUM physiology score (HR: 1.27, P=0.03). A relationship between mGPS and POSSUM physiology score was also established (P<0.006).</p> <p>Conclusion: The POSSUM physiology score and the systemic inflammatory response are strongly associated and both are independent predictors of cancer specific and overall survival in patients undergoing potentially curative resection of colorectal cancer.</p&gt

Thirty years after Alma-Ata: a systematic review of the impact of community health workers delivering curative interventions against malaria, pneumonia and diarrhoea on child mortality and morbidity in sub-Saharan Africa

BACKGROUND: Over thirty years have passed since the Alma-Ata Declaration on primary health care in 1978. Many governments in the first decade following the declaration responded by developing national programmes of community health workers (CHWs), but evaluations of these often demonstrated poor outcomes. As many CHW programmes have responded to the HIV/AIDS pandemic, international interest in them has returned and their role in the response to other diseases should be examined carefully so that lessons can be applied to their new roles. Over half of the deaths in African children under five years of age are due to malaria, diarrhoea and pneumonia - a situation which could be addressed through the use of cheap and effective interventions delivered by CHWs. However, to date there is very little evidence from randomised controlled trials of the impacts of CHW programmes on child mortality in Africa. Evidence from non-randomised controlled studies has not previously been reviewed systematically. METHODS: We searched databases of published and unpublished studies for RCTs and non-randomised studies evaluating CHW programmes delivering curative treatments, with or without preventive components, for malaria, diarrhoea or pneumonia, in children in sub-Saharan Africa from 1987 to 2007. The impact of these programmes on morbidity or mortality in children under six years of age was reviewed. A descriptive analysis of interventional and contextual factors associated with these impacts was attempted. RESULTS: The review identified seven studies evaluating CHWs, delivering a range of interventions. Limited descriptive data on programmes, contexts or process outcomes for these CHW programmes were available. CHWs in national programmes achieved large mortality reductions of 63% and 36% respectively, when insecticide-treated nets and anti-malarial chemoprophylaxis were delivered, in addition to curative interventions. CONCLUSIONS: CHW programmes could potentially achieve large gains in child survival in sub-Saharan Africa if these programmes were implemented at scale. Large-scale rigorous studies, including RCTs, are urgently needed to provide policymakers with more evidence on the effects of CHWs delivering these interventions

Budd-Chiari Syndrome: Long term success via hepatic decompression using transjugular intrahepatic porto-systemic shunt

<p>Abstract</p> <p>Background</p> <p>Budd-Chiari syndrome (BCS) generally implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. Treatment depends on the underlying cause, the anatomic location, the extent of the thrombotic process and the functional capacity of the liver. It can be divided into medical treatment including anticoagulation and thrombolysis, radiological procedures such as angioplasty and transjugular intrahepatic porto-systemic shunt (TIPS) and surgical interventions including orthotopic liver transplantation (OLT). Controlled trials or reports on larger cohorts are limited due to rare disease frequency. The aim of this study was to report our single centre long term results of patients with BCS receiving one of three treatment options i.e. medication only, TIPS or OLT on an individually based decision of our local expert group.</p> <p>Methods</p> <p>20 patients with acute, subacute or chronic BCS were treated between 1988 and 2008. Clinical records were analysed with respect to underlying disease, therapeutic interventions, complications and overall outcome.</p> <p>Results</p> <p>16 women and 4 men with a mean age of 34 ± 12 years (range: 14-60 years) at time of diagnosis were included. Myeloproliferative disorders or a plasmatic coagulopathy were identified as underlying disease in 13 patients, in the other patients the cause of BCS remained unclear. 12 patients presented with an acute BCS, 8 with a subacute or chronic disease. 13 patients underwent TIPS, 4 patients OLT as initial therapy, 2 patients required only symptomatic therapy, and one patient died from liver failure before any specific treatment could be initiated. Eleven of 13 TIPS patients required 2.5 ± 2.4 revisions (range: 0-8). One patient died from his underlying hematologic disease. The residual 12 patients still have stable liver function not requiring OLT. All 4 patients who underwent OLT as initial treatment, required re-OLT due to thrombembolic complications of the graft. Survival in the TIPS group was 92.3% and in the OLT group 75% during a median follow-up of 4 and 11.5 years, respectively.</p> <p>Conclusion</p> <p>Our results confirm the role of TIPS in the management of patients with acute, subacute and chronic BCS. The limited number of patients with OLT does not allow to draw a meaningful conclusion. However, the underlying disease may generate major complications, a reason why OLT should be limited to patients who cannot be managed by TIPS.</p

Predictive Value of POSSUM and ACPGBI Scoring in Mortality and Morbidity of Colorectal Resection: A Case–Control Study

Contains fulltext : 97239.pdf (publisher's version ) (Open Access)BACKGROUND: Preoperative risk prediction to assess mortality and morbidity may be helpful to surgical decision making. The aim of this study was to compare mortality and morbidity of colorectal resections performed in a tertiary referral center with mortality and morbidity as predicted with physiological and operative score for enumeration of mortality and morbidity (POSSUM), Portsmouth POSSUM (P-POSSUM), and colorectal POSSUM (CR-POSSUM). The second aim of this study was to analyze the accuracy of different POSSUM scores in surgery performed for malignancy, inflammatory bowel diseases, and diverticulitis. POSSUM scoring was also evaluated in colorectal resection in acute vs. elective setting. In procedures performed for malignancy, the Association of Coloproctology of Great Britain and Ireland (ACPGBI) score was assessed in the same way for comparison. METHODS: POSSUM, P-POSSUM, and CR-POSSUM predictor equations for mortality were applied in a retrospective case-control study to 734 patients who had undergone colorectal resection. The total group was assessed first. Second, the predictive value of outcome after surgery was assessed for malignancy (n = 386), inflammatory bowel diseases (n = 113), diverticulitis (n = 91), and other indications, e.g., trauma, endometriosis, volvulus, or ischemia (n = 144). Third, all subgroups were assessed in relation to the setting in which surgery was performed: acute or elective. In patients with malignancy, the ACPGBI score was calculated as well. In all groups, receiver operating characteristic (ROC) curves were constructed. RESULTS: POSSUM, P-POSSUM, and CR-POSSUM have a significant predictive value for outcome after colorectal surgery. Within the total population as well as in all four subgroups, there is no difference in the area under the curve between the POSSUM, P-POSSUM, and CR-POSSUM scores. In the subgroup analysis, smallest areas under the ROC curve are seen in operations performed for malignancy, which is significantly worse than for diverticulitis and in operations performed for other indications. For elective procedures, P-POSSUM and CR-POSSUM predict outcome significantly worse in patients operated for carcinoma than in patients with diverticulitis. In acute surgical interventions, CR-POSSUM predicts mortality better in diverticulitis than in patients operated for other indications. The ACPGBI score has a larger area under the curve than any of the POSSUM scores. Morbidity as predicted by POSSUM is most accurate in procedures for diverticulitis and worst when the indication is malignancy. CONCLUSION: The POSSUM scores predict outcome significantly better than can be expected by chance alone. Regarding the indication for surgery, each POSSUM score predicts outcome in patients operated for diverticulitis or other indications more accurately than for malignancy. The ACPGBI score is found to be superior to the various POSSUM scores in patients who have (elective) resection of colorectal malignancy

Antiphospholipid syndrome; its implication in cardiovascular diseases: a review

Antiphospholipid syndrome (APLS) is a rare syndrome mainly characterized by several hyper-coagulable complications and therefore, implicated in the operated cardiac surgery patient. APLS comprises clinical features such as arterial or venous thromboses, valve disease, coronary artery disease, intracardiac thrombus formation, pulmonary hypertension and dilated cardiomyopathy. The most commonly affected valve is the mitral, followed by the aortic and tricuspid valve. For APLS diagnosis essential is the detection of so-called antiphospholipid antibodies (aPL) as anticardiolipin antibodies (aCL) or lupus anticoagulant (LA). Minor alterations in the anticoagulation, infection, and surgical stress may trigger widespread thrombosis. The incidence of thrombosis is highest during the following perioperative periods: preoperatively during the withdrawal of warfarin, postoperatively during the period of hypercoagulability despite warfarin or heparin therapy, or postoperatively before adequate anticoagulation achievement. Cardiac valvular pathology includes irregular thickening of the valve leaflets due to deposition of immune complexes that may lead to vegetations and valve dysfunction; a significant risk factor for stroke. Patients with APLS are at increased risk for thrombosis and adequate anticoagulation is of vital importance during cardiopulmonary bypass (CPB). A successful outcome requires multidisciplinary management in order to prevent thrombotic or bleeding complications and to manage perioperative anticoagulation. More work and reporting on anticoagulation management and adjuvant therapy in patients with APLS during extracorporeal circulation are necessary