Role of toll-like receptor 4 in skeletal muscle damage in chronic limb-threatening ischemia.

Objective: Toll-like receptors (TLRs) are key pattern recognition receptors in the innate immune system. In particular, the TLR4-mediated immune response has been implicated in ischemia-induced tissue injury. Mounting evidence supports a detrimental role of the innate immune system in the pathophysiology of skeletal muscle damage in patients with chronic limb-threatening ischemia (CLTI), in whom patient-oriented functional outcomes are poor. The overall aim of this study was to investigate the potential role of TLR4 in skeletal muscle dysfunction and damage in CLTI. Methods: The role of TLR4 in ischemic muscle was investigated by (1) studying TLR4 expression and distribution in human gastrocnemius muscle biopsies, (2) evaluating the functional consequences of TLR4 inhibition in myotubes derived from human muscle biopsies, and (3) assessing the therapeutic potential of modulating TLR4 signaling in ischemic muscle in a mouse hindlimb ischemia model. Results: TLR4 was found to be expressed in human muscle biopsies, with significant upregulation in samples from patients with CLTI. In vitro studies using cultured human myotubes demonstrated upregulation of TLR4 in ischemia, with activation of the downstream signaling pathway. Inhibition of TLR4 before ischemia was associated with reduced ischemia-induced apoptosis. Upregulation of TLR4 also occurred in ischemia in vivo and TLR4 inhibition was associated with decreased inflammatory cell infiltration and diminished apoptosis in the ischemic limb. Conclusions: TLR4 is upregulated and activated in ischemic skeletal muscle in patients with CLTI. Modulating TLR4 signaling in vitro and in vivo was associated with attenuation of ischemia-induced skeletal muscle damage. This strategy could be explored further for potential clinical application.

Primary angiosarcoma of aorta: A systematic review.

PURPOSE: To elucidate the epidemiology, anatomical, presentation, classification, pathology, investigative modalities, management and prognosis of primary angiosarcoma of the aorta. MATERIAL AND METHODS: A systematic review of literature from the database inception to January 2021 in PubMed and Embase, CINAHL and Cochrane Library in accordance to PRISMA was conducted. Retrieval and extraction was performed by two independent reviewers. The hierarchy of the evidence was assessed through the National Institute for Health and Care Excellence Checklist. Data were subjected to pooled prevalence analysis, Kaplan-Meier survival and test of probability using log-rank analysis. This review is registered with International Prospective Register of Systematic Reviews: RD42021231314. RESULTS: 82 studies with n = 123 cases met the inclusion criterion. Abdominal (45%) aorta was the commonest anatomical site with female predominance in ascending aorta (4:1) and aortic arch (2:1). The longest survival was in the ascending aorta and the shortest in the abdominal aorta [540 (interquartile range [IQR], 7-1560 days vs. 180 (IQR, 1-5730 days)], respectively. The overall median survival was 210 days (IQR, 1-5730 days) or 7 months. Lack of metastasis (47%) was a marker of longer survival (p < 0.03) irrespective of other attributes. CONCLUSION: The pathophysiology appears to be a trend of increasing fatigue, fever and weight loss associated with segmental dysfunction of the aorta projecting occlusive or destructive phenotypes. Computed tomography angiography features of volume-occupying, bulky, polypoid (intraluminal), protrusive vegetation, hyper vascular without atherosclerotic lesions are extremely suggestive of PA of the aorta at 5th and 6th decades of life.

Toll-like receptors 2 and 6 mediate apoptosis and inflammation in ischemic skeletal myotubes.

Critical limb ischemia (CLI) is associated with skeletal muscle damage. However, the pathophysiology of the muscle damage is poorly understood. Toll-like receptors (TLR) have been attributed to play a role in ischemia-induced tissue damage but their role in skeletal muscle damage in CLI is unknown. TLR2 and TLR6 expression was found to be upregulated in skeletal muscle of patients with CLI. In vitro, ischemia led to upregulation of TLR2 and TLR6 by myotubes, and activation of the downstream TLR signaling pathway. Ischemia-induced activation of the TLR signaling pathway led to secretion of the pro-inflammatory cytokine interleukin-6 and muscle apoptosis, which were abrogated by neutralising TLR2 and TLR6 antibodies. Our study demonstrates that TLR2 and TLR6 are upregulated in ischemic muscle and play a role in ischemia-induced muscle damage. Thus, manipulating the TLR pathway locally may be of potential therapeutic benefit.

Sentinel lymph node biopsy before mastectomy and immediate breast reconstruction does not significantly delay surgery in early breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) before mastectomy and immediate breast reconstruction (IBR) may help to avoid the negative cosmetic effects of radiotherapy on reconstructed breasts in lymph node-positive patients. Concerns have been raised regarding possible delays whilst awaiting the SLNB result prior to definitive surgery, which needs to be performed within 31 days of cancer diagnosis. The aim was to investigate whether initial SLNB delays mastectomy and IBR. METHODS: All patients who had IBR between January 2005 and 2007 were reviewed retrospectively. Before October 2005 axillary staging was performed simultaneously with mastectomy and IBR (Group I). After October 2005, SLNB was performed as an initial procedure and patients with positive SLNB were only offered a temporary tissue expander to be replaced by autogenous reconstruction after completing the cancer treatment (Group II). Date of diagnosis and waiting times were recorded and the two groups were compared. Different reasons for delays in treatment were studied. RESULTS: One hundred and thirty-nine IBR (123 patients) were included in the statistical analysis (67 IBR in Group I and 72 IBR in Group II). Seventy-one patients (57.7%) had no delay (mean waiting time of 23 days). Fifty-two patients (42.3%) had delay longer than 31 days (mean waiting time of 66 days). Group I patients had a mean waiting time (standard deviation) of 38.8 (38) days and Group II patients 42.7 (24) days (p = 0.51). CONCLUSIONS: In this group of patients, SLNB before mastectomy and IBR does not significantly delay definitive breast cancer surgery.

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.

The effect of intravenous administration of dexamethasone on postoperative pain, nausea, and vomiting after intrathecal injection of meperidine.

BACKGROUND: Different drugs have been used to enhance postoperative neuraxial opioid analgesia and reduce adverse effects. METHODS: We randomized 60 patients into 2 groups to receive either 2 mL saline or 0.1 mg/kg dexamethasone IV before the administration of intrathecal anesthesia (15 mg and meperidine 15 mg). After surgery, patients were asked to score their pain at 6, 12, 18, and 24 h. The presence of postoperative nausea and vomiting (PONV), pruritus and respiratory depression were recorded. RESULTS: The total dose of diclofenac (P < 0.05), visual analog scale pain score at 6-h intervals (P < 0.001), and the incidence of PONV (P < 0.05) were significantly lower in the dexamethasone group. CONCLUSIONS: Administration of IV dexamethasone prior to intrathecal meperidine injection enhances analgesia and reduces PONV.