Metabolic profile and post-operative outcomes in contemporary patients with peripheral arterial disease and critical limb ischaemia

Background: Peripheral arterial disease (PAD) is an established occlusive disease of the peripheral arteries and is not uncommon in the elderly. Atherosclerosis accounts for 90% of the pathology. Only 15% of affected individuals become symptomatic. Most symptomatic individuals present with intermittent claudication (IC). Only a small proportion (1%) of affected individuals present with critical limb ischaemia (CLI). Revascularization aimed at limb salvage, and recovery of ambulation and independent living is the ultimate therapeutic option for the advanced form of PAD (CLI). Traditionally, the success of revascularization for CLI has been defined by graft patency rates and limb salvage rates. Functional outcomes such as ischaemic wound healing and recovery of ambulatory function for independent living have been the focus in more recent publications. However, these assessments do not consider the patients' pre-operative metabolic profile as a predictor of postoperative outcomes. Purpose: The purpose of this study was to determine, in a prospective manner, the influence of preoperative metabolic profile on post-operative outcomes in contemporary patients with peripheral arterial disease presenting with critical limb ischaemia at a tertiary hospital in South Africa. Methods: All consecutive patients, ≥ 18 years, with CLI admitted to the vascular unit at Groote Schuur Hospital over a two-year period (1st January, 2015 to 31st December, 2016) with reconstructable disease were recruited for the study. Written informed consent was obtained from all participants. Revascularization entailed either open surgical revascularization, endovascular interventions or both (hybrid procedures). Data was analyzed according to the clinical level of disease and the type of surgical intervention. Post-operative outcome measures were determined. Primary endpoints (functional and technical outcomes) • Ambulatory recovery at six months and one year • Complete ischaemic wound healing at six months and one year • Limb salvage rate at six months and one year • Primary graft patency rate at six months and one year Secondary endpoint • The influence of pre-operative metabolic profile on the post-operative outcomes The association between pre-operative metabolic profile and post-operative outcomes was determined by Pearson Chi-square statistical test and logistic regression model. Results: A total of 73 consecutive patients were recruited for this study with a mean age of 58 ± 9 years (Range: 30 - 75 years). Seventeen patients (23.3%) had rest pain and 56 (76.7%) had tissue loss [Minor tissue loss was 47 (64.4%) and major tissue loss was 9 (12.3%)]. Current smokers and previous smokers constituted 86% of the sample population with a male to female ratio of approximately 1:1. Our study population was generally overweight based on the BMI. There was high prevalence of abdominal obesity and high body fat for both males and females. Recovery of ambulatory status was 69% and 67% at six months and one year follow-up respectively. The rate of ischaemic wound healing at six months and one year was 48.2% and 75.0% respectively. Surgical site sepsis was the most common local wound complication. Limb salvage rate was 78% and 79% at six months and one year respectively. Overall primary graft patency at six months was 69.0% but reduced to 60.0% at one year. Major amputation rate at one year was 21%. Most of the postoperative wound-related complications occurred among patients with diabetes. More diabetic patients had major amputations compared to non-diabetic patients (57.9% vs 42.1%). One year amputation-free survival (AFS) was 69.9%. There were no statistically significant associations between metabolic profile of patients and post-operative clinical outcomes. Conclusion: Demographics, co-morbidities, and procedural details of our study population, reflected a relatively younger population with CLI. The profile of this contemporary vascular surgery patients is that of overweight, high abdominal obesity, and high prevalence of smoking among both gender. The technical and functional outcomes observed in this study are consistent with available western literature. Diabetes was associated with prolonged ischaemic wound healing, higher risk of major amputation and local wound complications. A statistically significant association was not found between patients' metabolic profile and post-operative outcome but this could be due to the small sample size and short follow up period

A PCA3 gene-based transcriptional amplification system targeting primary prostate cancer.

Targeting specifically primary prostate cancer (PCa) cells for immune therapy, gene therapy or molecular imaging is of high importance. The PCA3 long non-coding RNA is a unique PCa biomarker and oncogene that has been widely studied. This gene has been mainly exploited as an accurate diagnostic urine biomarker for PCa detection. In this study, the PCA3 promoter was introduced into a new transcriptional amplification system named the 3-Step Transcriptional Amplification System (PCA3-3STA) and cloned into type 5 adenovirus. PCA3-3STA activity was highly specific for PCa cells, ranging between 98.7- and 108.0-fold higher than that for benign primary prostate epithelial or non-PCa cells, respectively. In human PCa xenografts, PCA3-3STA displayed robust bioluminescent signals at levels that are sufficient to translate to positron emission tomography (PET)-based reporter imaging. Remarkably, when freshly isolated benign or cancerous prostate biopsies were infected with PCA3-3STA, the optical signal produced from primary PCa biopsies was significantly higher than from benign prostate biopsies (4.4-fold, p < 0.0001). PCA3-3STA therefore represents a PCa-specific expression system with the potential to target, with high accuracy, primary or metastatic PCa epithelial cells for imaging, vaccines, or gene therapy

A Drosophila Mutant with a Temperature-Sensitive Block in Nerve Conduction

A mutant, napts (no action potential, temperature-sensitive), is described in which axonal conduction fails at high temperature. Synaptic transmission at the larval neuromuscular junction is unimpaired. Larvae and adults are rapidly paralyzed at restrictive temperatures; they recover rapidly when the temperature is decreased. The mutant gene is recessive and is located on the second chromosome at map position 56

Management of severe Raynaud’s Phenomenon secondary to autoimmune vasculopathy in a young woman

Raynaud’s phenomenon as a cause of acute limb ischaemia in the warmer climates of Sub-Saharan Africa region is uncommon because it is usually thought of as a disease common in cold weather. The prevalence of connective tissue diseases among Black Africans is increasing, and these conditions are associated with secondary Raynaud’s phenomenon and ischaemic digital lesions. We present the case of a 36-year old female with dermatomyositis/systemic sclerosis overlap and secondary Raynaud’s phenomenon who presented with acute limb ischemia (wet gangrene of all digits) in a Tertiary Hospital in Ghana. Young patients presenting with acute limb ischaemia should also be screened for an underlying connective tissue disease. In patients with connective tissue disease, the onset of digital vasculopathy can be rapid and progressive, hence treatment must be prompt and comprehensive to enable better clinical outcomes

Role of Auxilin and Heat Shock Protein 70kDa in Clathrin Uncoating

An interaction between auxilin and heat shock protein 70kDa (Hsc70) was initially discovered in 1995. There exists a large amount of data supporting the basis for their interaction in vitro and their function in clathrin uncoating in vivo. This review examines the key experiments in elucidating this interaction and introduces a third protein that may connect constriction or fission with hsc70/auxilin mediated clathrin uncoating.

Predictors of post-operative outcomes in patients with peripheral arterial disease and critical limb ischaemia: a systematic review and meta-analysis

Background: A very small proportion (1%) of patients with peripheral artery disease (PAD) present with critical limb threatening ischaemia (CLTI) with poor prognosis. The present review showcased several pre-operative predictors and key post-operative outcomes. Identification of any modifiable predictors may impact positively on surgical outcomes.Design: PubMed/Medline, Google scholar and Cochrane databases were searched using terms such as “peripheral arterial disease” AND “critical limb ischemia,” “post-operative outcome,” AND “predictors of post-operative outcomes”. Search was for relevant English-language articles published between January 1997 and December 2007 Selected articles were screened first by title and abstract, and selection of full articles was based on relevance using our inclusion and exclusion criteria and quality ratings performed with the MINORS score.Results: The included studies were published between 1997 and 2007. Only six (6) articles out of a total of 2,114 were deemed suitable for analysis. Ambulatory recovery was >70% at six months, 86.7% and 70.0% at one year and five years respectively. Rate of local wound complications was between 12% and 24%. Reported limb salvage rates were >90% at six months, >70% at one year and 70.0-90.0% at five years. Primary graft patency rate at one year ranged from 63% and 76.6%. Gangrene, diabetes and impaired pre-operative ambulatory function are associated with more wound complications, low limb salvage, reduced graft patency and poor functional outcome.Conclusion: Pre-operative ambulatory status was the most important predictor of post-operative ambulatory recovery. Diabetes mellitus was an important risk factor for prolonged wound healing, local wound complications and major amputation

Patient factors influencing the prescribing of lipid lowering drugs for primary prevention of cardiovascular disease in UK general practice: a national retrospective cohort study

BACKGROUND: Guidelines indicate eligibility for lipid lowering drugs, but it is not known to what extent GPs' follow guidelines in routine clinical practice or whether additional clinical factors systematically influence their prescribing decisions. METHODS: A retrospective cohort analysis was undertaken using electronic primary care records from 421 UK general practices. At baseline (May 2008) patients were aged 30 to 74 years, free from cardiovascular disease and not taking lipid lowering drugs. The outcome was prescription of a lipid lowering drug within the next two years. The proportions of eligible and ineligible patients prescribed lipid lowering drugs were reported and multivariable logistic regression models were used to investigate associations between age, sex, cardiovascular risk factors and prescribing. RESULTS: Of 365,718 patients with complete data, 13.8% (50,558) were prescribed lipid lowering drugs: 28.5% (21,101/74,137) of those eligible and 10.1% (29,457/291,581) of those ineligible. Only 41.7% (21,101/50,558) of those prescribed lipid lowering drugs were eligible. In multivariable analysis prescribing was most strongly associated with increasing age (OR for age ≥65 years 4.21; 95% CI 4.05–4.39); diabetes (OR 4.49; 95% CI 4.35–4.64); total cholesterol level ≥7 mmol/L (OR 2.20; 95% CI 2.12–2.29); and ≥4 blood pressure measurements in the past year (OR 4.24; 95% CI 4.06–4.42). The predictors were similar in eligible and ineligible patients. CONCLUSIONS: Most lipid lowering drugs for primary prevention are prescribed to ineligible patients. There is underuse of lipid lowering drugs in eligible patients

Endoglin Is Essential for the Maintenance of Self-Renewal and Chemoresistance in Renal Cancer Stem Cells.

Renal cell carcinoma (RCC) is a deadly malignancy due to its tendency to metastasize and resistance to chemotherapy. Stem-like tumor cells often confer these aggressive behaviors. We discovered an endoglin (CD105)-expressing subpopulation in human RCC xenografts and patient samples with a greater capability to form spheres in vitro and tumors in mice at low dilutions than parental cells. Knockdown of CD105 by short hairpin RNA and CRISPR/cas9 reduced stemness markers and sphere-formation ability while accelerating senescence in vitro. Importantly, downregulation of CD105 significantly decreased the tumorigenicity and gemcitabine resistance. This loss of stem-like properties can be rescued by CDA, MYC, or NANOG, and CDA might act as a demethylase maintaining MYC and NANOG. In this study, we showed that Endoglin (CD105) expression not only demarcates a cancer stem cell subpopulation but also confers self-renewal ability and contributes to chemoresistance in RCC

The function and evolution of the restriction factor viperin in primates was not driven by lentiviruses

Abstract Background Viperin, also known as RSAD2, is an interferon-inducible protein that potently restricts a broad range of different viruses such as influenza, hepatitis C virus, human cytomegalovirus and West Nile virus. Viperin is thought to affect virus budding by modification of the lipid environment within the cell. Since HIV-1 and other retroviruses depend on lipid domains of the host cell for budding and infectivity, we investigated the possibility that Viperin also restricts human immunodeficiency virus and other retroviruses. Results Like other host restriction factors that have a broad antiviral range, we find that viperin has also been evolving under positive selection in primates. The pattern of positive selection is indicative of Viperin's escape from multiple viral antagonists over the course of primate evolution. Furthermore, we find that Viperin is interferon-induced in HIV primary target cells. We show that exogenous expression of Viperin restricts the LAI strain of HIV-1 at the stage of virus release from the cell. Nonetheless, the effect of Viperin restriction is highly strain-specific and does not affect most HIV-1 strains or other retroviruses tested. Moreover, knockdown of endogenous Viperin in a lymphocytic cell line did not significantly affect the spreading infection of HIV-1. Conclusion Despite positive selection having acted on Viperin throughout primate evolution, our findings indicate that Viperin is not a major restriction factor against HIV-1 and other retroviruses. Therefore, other viral lineages are likely responsible for the evolutionary signatures of positive selection in viperin among primates.</p