Daryll M. Baker

Upper Limb Deep Vein Thrombosis: A Literature Review to Streamline the Protocol for Management

Objective: The objective of this article is to provide up-to-date information about aetiology, pathogenesis, diagnostic modalities and treatment of upper limb deep vein thrombosis (ULDVT). Methods: Generic terms including ULDVT, axillary-subclavian DVT, and complications of central venous catheters were searched on electronic database. We analysed original studies, review articles and evaluation studies published over the last 25 years. Results: Forty-seven studies on ULDVT encompassing 2,557 patients were evaluated. The incidence of ULDVT was quoted 1–4% of the total DVT. Primary ULDVT (20% of the total) was due to activity-related venous trauma. Secondary ULDVT (80% of the total) was due to central venous catheters and malignancy. Duplex ultrasound (sensitivity 78–100% and specificity 82–100%), contrast venography (gold standard) and magnetic resonance venography were the diagnostic tools used. Pulmonary embolism (2–35%) and post-thrombotic syndrome (7–46%) were the main sequelae. Anticoagulation was the universal intervention, giving 79% symptom relief (13.2% rethrombosis rate). Thrombolysis and/or percutaneous thrombectomy were used in 38% of cases for the management of ULDVT, giving 83% symptom relief (90% recanalization rate and 9% rethrombosis rate). Surgical decompression, venous angioplasty and superior vena cava filters were the main adjunctive interventions. Conclusion: ULDVT, although rare, is associated with considerable morbidity and mortality (29–40%) due to potential risks of pulmonary embolism, post-thrombotic syndrome and loss of vascular access. Simple anticoagulation is suitable for the majority of patients. Thrombolysis/thrombectomy is often successful but less frequently used. Surgical decompression, venous angioplasty and superior vena cava filters have some role in recurrent cases. An optimal management protocol can be established using a multimodality approach.

The innate immune system, toll-like receptors and dermal wound healing: A review

Wound healing is a complex physiological process comprised of discrete but inter-related and overlapping stages, requiring exact timing and regulation to successfully progress, yet occurs spontaneously in response to injury. It is characterised by four phases, coagulation, inflammation, proliferation and remodelling. Each phase is predominated by particular cell types, cytokines and chemokines. The innate immune system represents the first line of defence against invading microorganisms. It is entirely encoded with the genome, and comprised of a cellular response with specificity provided by pattern recognition receptors (PRRs) such as toll-like receptors (TLRs). TLRs are activated by exogenous microbial pathogen associated molecular patterns (PAMPs), initiating an immune response through the production of pro-inflammatory cytokines and further specialist immune cell recruitment. TLRs are also activated by endogenous molecular patterns termed damage associated molecular patterns (DAMPs). These ligands, usually shielded from the immune system, act as alarm signals alerting the immune system to damage and facilitate the normal wound healing process. TLRs are expressed by cells essential to wound healing such as keratinocytes and fibroblasts, however the specific role of TLRs in this process remains controversial. This article reviews the current knowledge on the potential role of TLRs in dermal wound healing where inflammation arising from pathogenic activation of these receptors appears to play a role in chronic ulceration associated with diabetes, scar hypertrophy and skin fibrosis.

Toll-Like Receptors in Ischaemia and Its Potential Role in the Pathophysiology of Muscle Damage in Critical Limb Ischaemia

Toll-like receptors (TLRs) are key receptors of the innate immune system which are expressed on immune and nonimmune cells. They are activated by both pathogen-associated molecular patterns and endogenous ligands. Activation of TLRs culminates in the release of proinflammatory cytokines, chemokines, and apoptosis. Ischaemia and ischaemia/reperfusion (I/R) injury are associated with significant inflammation and tissue damage. There is emerging evidence to suggest that TLRs are involved in mediating ischaemia-induced damage in several organs. Critical limb ischaemia (CLI) is the most severe form of peripheral arterial disease (PAD) and is associated with skeletal muscle damage and tissue loss; however its pathophysiology is poorly understood. This paper will underline the evidence implicating TLRs in the pathophysiology of cerebral, renal, hepatic, myocardial, and skeletal muscle ischaemia and I/R injury and discuss preliminary data that alludes to the potential role of TLRs in the pathophysiology of skeletal muscle damage in CLI.

Increased angiogenic response but deficient arteriolization and abnormal microvessel ultrastructure in critical leg ischaemia

Ischaemia is known to induce angiogenesis, but the effects of critical leg ischaemia (CLI) on angiogenesis remain unclear. The aim of this study was to examine the physiological angiogenic response in CLI by investigating the extent of neovascularization, characterizing microvessel subtypes and determining the microvessel ultrastructure.

Therapeutic role of toll-like receptor modification in cardiovascular dysfunction

Toll-like receptors (TLR) are key pattern recognition receptors in the innate immune system. The TLR-mediated immune response against pathogens is usually protective however inappropriate TLR activation may lead to excessive tissue damage. It is well recognised that TLRs respond to a variety of endogenous as well as exogenous ligands. By responding to endogenous ligands that are exposed during cellular damage, TLRs have been implicated in a range of pathological conditions associated with cardiovascular dysfunction. Increasing knowledge on the mechanisms involved in TLR signalling has encouraged the exploration of therapeutic pharmacological modulation of TLR activation in conditions such as atherosclerosis, ischaemic heart disease, heart failure and ischaemic reperfusion injury. The aim of this review is to explore the translational potentials of TLR modification in cardiovascular dysfunction, where these agents have been studied.

Stem cells of the lower limb: Their role and potential in management of critical limb ischemia

Peripheral arterial occlusive disease (PAOD) contributes to decreased exercise tolerance, poor balance, impaired proprioception, muscle atrophy and weakness, with advanced cases resulting in critical limb ischemia (CLI) where the viability of the limb is threatened. Patients with a diagnosis of CLI have a poor life expectancy due to concomitant cardio and cerebrovascular diseases. The current treatment options to avoid major amputation by re-establishing a blood supply to the limb generally have poor outcomes. Human skeletal muscle contains both multipotent stem cells and progenitor cells and thus has a capacity for regeneration. Phase I and II studies involving transplantation of bone marrow-derived progenitor cells into CLI limbs show positive effects on wound healing and angiogenesis; the increase in quiescent satellite cell numbers observed in CLI muscle may also provide a sufficient in vivo source of resident stem cells. These indigenous cells have been shown to be capable of forming multiple mesodermal cell lineages aiding the repair and regeneration of chronically ischemic muscle. They may also serve as a repository for autologous transplantation. The behavior and responses of the stem cell population in CLI is poorly understood and this review tries to elucidate the potential of these cells and their future role in the management of CLI.

Nitric oxide manipulation: a therapeutic target for peripheral arterial disease?

Peripheral Arterial Disease (PAD) is a cause of significant morbidity and mortality in the Western world. Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present. However, a significant number of patients still require major amputation. There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD. This paper reviews experimental work implicating the ADMA-DDAH-NO pathway in PAD, focussing on both the vascular dysfunction and effects within the ischaemic muscle, and examines the potential of manipulating this pathway as a novel adjunct therapy in PAD.

Purinoceptor expression on keratinocytes reflects their function on the epidermis during chronic venous insufficiency.

Purines are extracellular nucleotides that have long-term effects on keratinocyte proliferation, differentiation and death through P2Y1, P2Y2, P2X5 and P2X7 receptors. This study examined changes in expression of these P2 receptors on lower leg epidermal keratinocytes in control and chronic venous insufficiency (CVI) states. Lower limb skin biopsies from CVI (CEAP classification 4a and 4b) and control skin were immunostained for the above P2 receptor subtypes and epidermal area was calculated. Our results with CVI show an increase in P2Y1 and P2Y2 receptor expression in basal and spinosal layers of the epidermis and an increase of P2X5 receptors mainly in the spinosal layer and extending further into the stratum granulosum. In contrast, P2X7 receptors were reduced in the stratum corneum in CVI. In conclusion, a thinner epidermis was found in CVI, which might be the result of the changes in expression of P2Y and P2X receptors on keratinocytes: that is, increased proliferation via P2Y1 and P2Y2 receptors and reduced P2X7 receptor-mediated cell death opposed by a dominant decrease in cell numbers as a result of increased P2X5 receptor-mediated differentiation (which is in effect antiproliferative). Thus, increased keratinocyte P2X5 receptor activity may, in part, be accountable for epidermal thinning in CVI.

Treatment of Primary Hyperhidrosis with Oral Anticholinergic Medications: A Systematic Review

Primary hyperhidrosis is a condition characterized by excessive sweating. Patients are treated off‐license with oral anticholinergic medications and report adverse events associated with systemic anticholinergic interactions. This review assesses clinical evidence of efficacy, impact on quality of life and adverse events associated with oral anticholinergic therapy for primary hyperhidrosis. PRISMA guidelines were implemented to complete a systematic review (PROSPERO:CRD42016036326). MEDLINE, EMBASE and PubMed were searched from 1946 to 2015. Inclusion criteria included observational and experimental studies, anticholinergic medication use in primary hyperhidrosis, oral therapy and clear diagnostic and outcome measures. Twenty‐three articles relevant to the inclusion criteria were analysed. Oxybutynin therapy improved symptoms in an average of 76.2% (range 60–97%) patients and improved QOL in 75.6% (range 57.6–100%) of patients. Methantheline bromide therapy was associated with a 41% reduction in axillary sweating, 16.4% reduction in palmar sweating, 25% decrease in HDSS score and 40.9% increase in DLQI score. Outcome measures of glycopyrrolate therapy were too variable to collate. Dry mouth was reported in 73.4% (range 43.3–100%) of participants taking oxybutynin 10 mg/day, 38.6% (range 27.8–63.2%) of patients taking glycopyrrolate and 68.8% of patients taking methantheline bromide. Nine studies reported that patients stopped therapy due to adverse events. In eight of these studies, a mean of 10.9% of total participants ceased treatment due to dry mouth. Evidence of oral anticholinergic therapy for hyperhidrosis is limited. However, its use is associated with improvement in quality of life and clinical symptoms but at the cost of considerable adverse events.

Development of an in vitro model of myotube ischemia

Critical limb ischemia causes severe damage to the skeletal muscle. This study develops a reproducible model of myotube ischemia by simulating, in vitro, the critical parameters that occur in skeletal muscle ischemia. Monolayers of C2C12 myoblasts were differentiated into mature myotubes and exposed to nutrition depletion, hypoxia and hypercapnia for variable time periods. A range of culture media and gas mixture combinations were used to obtain an optimum ischemic environment. Nuclear staining, cleaved caspase-3 and lactate dehydrogenase (LDH) release assay were used to assess apoptosis and myotube survival. HIF-1α concentration of cell lysates, pH of conditioned media as well as partial pressures of oxygen (PO2) and carbon dioxide (PCO2) in the media were used to confirm ischemic simulation. Culturing myotubes in depleted media, in a gas mixture containing 20% CO2+80% N2 for 6–12 h increased the PCO2 and decreased the pH and PO2 of culture media. This attempts to mimic the in vivo ischemic state of skeletal muscle. These conditions were used to study the potential tissue-protective effects of erythropoietin (EPO) in C2C12 myotubes exposed to ischemia. EPO (60 ng/ml) suppressed LDH release, decreased cleaved caspase-3 and reduced the number of apoptotic nuclei, suggesting significantly decreased ischemia-induced apoptosis in myotubes (P<0.01) and a potential role in tissue protection. Additional therapeutic agents designed for tissue protection can also be evaluated using this model.