Preliminary evidence that low ankle-brachial index is associated with reduced bilateral hip extensor strength and functional mobility in peripheral arterial disease

ObjectivePeripheral arterial disease (PAD) has been associated with skeletal muscle pathology, including atrophy of the affected muscles. In addition, oxidative metabolism is impaired, muscle function is reduced, and gait and mobility are restricted. We hypothesized that greater severity of symptomatic PAD would be associated with lower levels of muscle mass, strength, and endurance, and that these musculoskeletal abnormalities in turn would impair functional performance and walking ability in patients with PAD.MethodsWe assessed 22 persons with intermittent claudication from PAD in this cross-sectional pilot study. Outcome assessments included initial claudication distance and absolute claudication distance via treadmill protocols and outcomes from the 6-minute walk (6MW). Secondary outcomes included one repetition maximum strength/endurance testing of hip extensors, hip abductors, quadriceps, hamstrings, plantar flexors, pectoral, and upper back muscle groups, as well as performance-based tests of function. Univariate and stepwise multiple regression models were constructed to evaluate relationships and are presented.ResultsTwenty-two participants (63.6% male; mean [standard deviation] age, 73.6 [8.2] years; range, 55-85 years) were studied. Mean (standard deviation) resting ankle-brachial index (ABI) was 0.54 ([0.13]; range, 0.28-0.82), and participants ranged from having mild claudication to rest pain. Lower resting ABI was significantly associated with reduced bilateral hip extensor strength (r = 0.54; P = .007) and reduced whole body strength (r = 0.32; P = .05). In addition, lower ABI was associated with a shorter distance to first stop during the 6MW (r = 0.38; P = .05) and poorer single leg balance (r = 0.44; P = .03). Reduced bilateral hip extensor strength was also significantly associated with functional outcomes, including reduced 6MW distance to first stop (r = 0.74; P = .001), reduced 6MW distance (r = 0.75; P < .001), and reduced total short physical performance battery score (worse function; r = 0.75; P = .003).ConclusionsOur results suggest the existence of a causal pathway from a reduction in ABI to muscle atrophy and weakness, to whole body disability represented by claudication outcomes and performance-based tests of functional mobility in an older cohort with symptomatic PAD. Longitudinal outcomes from this study and future trials are required to investigate the effects of an anabolic intervention targeting the muscles involved in mobility and activities of daily living and whether an increase in muscle strength will improve symptoms of claudication and lead to improvements in other functional outcomes in patients with PAD

Cyanoacrylate closure for peripheral veins: Consensus document of the Australasian College of Phlebology

Background: Cyanoacrylates are fast-acting adhesives used in procedural medicine including closure of superficial wounds, embolization of truncal vessels pre-operatively, vascular anomalies, visceral false aneurysms, endoleaks, gastrointestinal varices and gastrointestinal bleeding. More recently, catheter-directed cyanoacrylate adhesive closure was introduced as an alternative to endovenous thermal ablation (ETA) to occlude superficial veins of the lower limbs. Objectives: To formulate policies for the safe and effective delivery of cyanoacrylate adhesive closure procedures in Australasia, based on current experience and evidence. Methods: A panel of phlebologists including vascular surgeons, interventional radiologists, dermatologists and research scientists systematically reviewed the available data on cyanoacrylate products used in medicine and shared personal experience with the procedure. The reviewed material included bibliographic and biomedical data, material safety data sheets and data requested and received from manufacturers. Results and recommendations: Cyanoacrylate adhesive closure appears to be an effective treatment for saphenous reflux with occlusion rates at 36 months of 90–95%. We recommend a maximum dose of 10 mL of cyanoacrylate per treatment session. Serious complications are rare, but significant. Hypersensitivity to acrylates is reported in 2.4% of the population and is an important absolute contraindication to cyanoacrylate adhesive closure.1 Post-procedural inflammatory reactions, including hypersensitivity-type phlebitis, occur in 10–20% of patients.2 In the long term, cyanoacrylate adhesive closure results in foreign-body granuloma formation within 2–12 months of the procedure. We recommend against the use of cyanoacrylate adhesive closure in patients with uncontrolled inflammatory, autoimmune or granulomatous disorders (e.g. sarcoidosis). Caution should be exercised in patients with significant active systemic disease or infection and alternative therapies such as thermal ablation and foam sclerotherapy should be considered. Conclusions: Cyanoacrylate adhesive closure appears to be an effective endovenous procedure, with short-term closure rates comparable to ETA and therefore greater efficacy than traditional surgery for treating superficial veins of the lower limbs. Ongoing data collection is required to establish the long-term safety

Triage of patients with venous and lymphatic diseases during the COVID-19 pandemic – The Venous and Lymphatic Triage and Acuity Scale (VELTAS):: A consensus document of the International Union of Phlebology (UIP), Australasian College of Phlebology (ACP), American Vein and Lymphatic Society (AVLS), American Venous Forum (AVF), European College of Phlebology (ECoP), European Venous Forum (EVF), Interventional Radiology Society of Australasia (IRSA), Latin American Venous Forum, Pan-American Society of Phlebology and Lymphology and the Venous Association of India (VAI)

The coronavirus disease 2019 (COVID-19) global pandemic has resulted in diversion of healthcare resources to the management of patients infected with SARS-CoV-2 virus. Elective interventions and surgical procedures in most countries have been postponed and operating room resources have been diverted to manage the pandemic. The Venous and Lymphatic Triage and Acuity Scale was developed to provide an international standard to rationalise and harmonise the management of patients with venous and lymphatic disorders or vascular anomalies. Triage urgency was determined based on clinical assessment of urgency with which a patient would require medical treatment or surgical intervention. Clinical conditions were classified into six categories of: (1) venous thromboembolism (VTE), (2) chronic venous disease, (3) vascular anomalies, (4) venous trauma, (5) venous compression and (6) lymphatic disease. Triage urgency was categorised into four groups and individual conditions were allocated to each class of triage. These included (1) medical emergencies (requiring immediate attendance), example massive pulmonary embolism; (2) urgent (to be seen as soon as possible), example deep vein thrombosis; (3) semiurgent (to be attended to within 30-90 days), example highly symptomatic chronic venous disease, and (4) discretionary/nonurgent- (to be seen within 6-12 months), example chronic lymphoedema. Venous and Lymphatic Triage and Acuity Scale aims to standardise the triage of patients with venous and lymphatic disease or vascular anomalies by providing an international consensus-based classification of clinical categories and triage urgency. The scale may be used during pandemics such as the current COVID-19 crisis but may also be used as a general framework to classify urgency of the listed conditions

Gene Therapy with p14/tBID Induces Selective and Synergistic Apoptosis in Mutant Ras and Mutant p53 Cancer Cells In Vitro and In Vivo

Any gene therapy for cancer will be predicated upon its selectivity against cancer cells and non-toxicity to normal cells. Therefore, safeguards are needed to prevent its activation in normal cells. We designed a minimal p14ARF promoter with upstream Ap1 and E2F enhancer elements and a downstream MDR1 inhibitory element, TATA box, and a transcription initiation site (hereafter p14ARFmin). The modified p14ARFmin promoter was linked to bicistronic P14 and truncated BID (tBID) genes, which led to synergistic apoptosis via the intrinsic and extrinsic pathways of apoptosis when expressed. The promoter was designed to be preferentially activated by mutant Ras and completely inhibited by wild-type p53 so that only cells with both mutant Ras and mutant p53 would activate the construct. In comparison to most p53 gene therapies, this construct has selective advantages: (1) p53-based gene therapies with a constitutive CMV promoter cannot differentiate between normal cells and cancer cells, and can be toxic to normal cells; (2) our construct does not induce p21WAF/CIPI in contrast to other p53-based gene therapies, which can induce cell cycle arrest leading to increased chemotherapy resistance; (3) the modified construct (p14ARFmin-p14-tBID) demonstrates bidirectional control of its promoter, which is completely repressed by wild-type p53 and activated only in cells with both RAS and P53 mutations; and (4) a novel combination of genes (p14 and tBID) can synergistically induce potent intrinsic and extrinsic apoptosis in cancer cells

C-Terminal p53 Palindromic Tetrapeptide Restores Full Apoptotic Function to Mutant p53 Cancer Cells In Vitro and In Vivo

We previously demonstrated that a synthetic monomer peptide derived from the C-terminus of p53 (aa 361–382) induced preferential apoptosis in mutant p53 malignant cells, but not normal cells. The major problem with the peptide was its short half-life (half-life His) with purified peptide at 7 µM and 15 µM produced 52% and 75%, cell death, respectively. Comparatively, the monomeric p53 C-terminal peptide-Ant (aa 361–382, termed p53p-Ant), at 15 µM and 30 µM induced 15% and 24% cell death, respectively. Compared to the p53p-Ant, the exogenous 4R-pal-p53p-Ant was over five-fold more potent for inducing apoptosis at an equimolar concentration (15 µM). Endogenous 4R-Pal-p53p expression (without Ant), induced by Dox, resulted in 43% cell death in an engineered MB468 breast cancer stable cell line, while endogenous p53 C-terminal monomeric peptide expression produced no cell death due to rapid peptide degradation. The mechanism of apoptosis from 4R-Pal-p53p involved the extrinsic and intrinsic pathways (FAS, caspase-8, Bax, PUMA) for apoptosis, as well as increasing reactive oxygen species (ROS). All three death pathways were induced from transcriptional/translational activation of pro-apoptotic genes. Additionally, mRNA of p53 target genes (Bax and Fas) increased 14-fold and 18-fold, respectively, implying that the 4R-Pal-p53p restored full apoptotic potential to mutant p53. Monomeric p53p only increased Fas expression without a transcriptional or translational increase in Fas, and other genes and human marrow stem cell studies revealed no toxicity to normal stem cells for granulocytes, erythrocytes, monocytes, and macrophages (CFU-GEMM). Additionally, the peptide specifically targeted pre-malignant and malignant cells with mutant p53 and was not toxic to normal cells with basal levels of WT p53