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Toxins May 2024A major pathogenic factor is the cholesterol-dependent cytolysin pneumolysin, binding membrane cholesterol and producing permanent lytic or transient pores. During...
A major pathogenic factor is the cholesterol-dependent cytolysin pneumolysin, binding membrane cholesterol and producing permanent lytic or transient pores. During brain infections, vascular damage with variable ischemia occurs. The role of ischemia on pneumolysin's pore-forming capacity remains unknown. In acute brain slice cultures and primary cultured glia, we studied acute toxin lysis (via propidium iodide staining and LDH release) and transient pore formation (by analyzing increases in the intracellular calcium). We analyzed normal peripheral tissue glucose conditions (80 mg%), normal brain glucose levels (20 mg%), and brain hypoglycemic conditions (3 mg%), in combinations either with normoxia (8% oxygen) or hypoxia (2% oxygen). At 80 mg% glucose, hypoxia enhanced cytolysis via pneumolysin. At 20 mg% glucose, hypoxia did not affect cell lysis, but impaired calcium restoration after non-lytic pore formation. Only at 3 mg% glucose, during normoxia, did pneumolysin produce stronger lysis. In hypoglycemic (3 mg% glucose) conditions, pneumolysin caused a milder calcium increase, but restoration was missing. Microglia bound more pneumolysin than astrocytes and demonstrated generally stronger calcium elevation. Thus, our work demonstrated that the toxin pore-forming capacity in cells continuously diminishes when oxygen is reduced, overlapping with a continuously reduced ability of cells to maintain homeostasis of the calcium influx once oxygen and glucose are reduced.
Topics: Streptolysins; Glucose; Animals; Bacterial Proteins; Oxygen; Cholesterol; Streptococcus pneumoniae; Brain; Calcium; Cells, Cultured; Neuroglia
PubMed: 38922127
DOI: 10.3390/toxins16060232 -
Annals of the Academy of Medicine,... Oct 2023Hypervolemia is a prevalent comorbidity of chronic kidney disease (CKD) patients. Thiazide diuretics (THZ) are the most common treatment for volume overload and...
INTRODUCTION
Hypervolemia is a prevalent comorbidity of chronic kidney disease (CKD) patients. Thiazide diuretics (THZ) are the most common treatment for volume overload and hypertension (HTN). This study examines the association between THZ usage and clinical outcomes among CKD patients in a nationwide cohort.
METHOD
The total number of patients in the study was 24,312. After matching with one non-user randomly selected from the CKD population, we identified 8501 patients in the THZ and the comparison cohorts. Cox proportional hazards regression analysis was conducted to estimate the associations of THZ on the incidence of all-cause mortality, end-stage renal disease (ESRD), congestive heart failure (CHF), acute myocardial infarction (AMI), peripheral arterial occlusive disease (PAOD), and stroke.
RESULTS
The all-cause mortality rate was significantly lower in THZ users than in non-users (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.60- 0.71). The THZ usage was associated with a lower incidence of ESRD, AMI, PAOD, and stroke (P<0.05). In subgroup analysis, some significant clinical outcomes were related with CKD stages 3 and 4 (P<0.05); however, there were no clinical associations in CKD stage 5. In further THZ subtype analysis, there were clinical associations with fewer deaths, ESRD, AMI, and PAOD accompanying chlorthalidone treatment. Moreover, the indapamide prescription was linked to lower mortality, ESRD, AMI, and PAOD prevalence. However, there were significantly greater incidences of ESRD, CHF, and AMI in the metolazone users.
CONCLUSION
THZ usage is associated with lower mortality and incidence of ESRD, AMI, PAOD, and stroke s in patients with CKD stages 3 and 4.
Topics: Humans; Renal Insufficiency, Chronic; Male; Female; Aged; Sodium Chloride Symporter Inhibitors; Middle Aged; Heart Failure; Kidney Failure, Chronic; Myocardial Infarction; Stroke; Peripheral Arterial Disease; Incidence; Proportional Hazards Models; Hypertension; Cardiovascular Diseases; Singapore
PubMed: 38920202
DOI: 10.47102/annals-acadmedsg.202359 -
Annals of Vascular Diseases Jun 2024We examined the relationship between plasma eicosapentaenoic acid (EPA) level and long-term all-cause death (ACD) and cardiovascular or limb events in patients with...
We examined the relationship between plasma eicosapentaenoic acid (EPA) level and long-term all-cause death (ACD) and cardiovascular or limb events in patients with peripheral arterial disease (PAD). We performed a prospective cohort study on 637 PAD patients. The endpoints were ACD, major adverse cardiovascular events (MACEs), and lower extremity arterial events (LEAEs). The incidences of ACD, MACEs, and LEAEs had correlation with EPA levels (p <0.05). Plasma EPA level had significant positive correlations with high-density lipoprotein cholesterol, triglyceride, and estimated glomerular filtration rate (eGFR), and negative correlation with C-reactive protein (CRP). In Cox stepwise multivariate analysis, lower EPA (hazard ratio [HR]: 0.996, 95% confidence interval [CI]: 0.993-1.000, p = 0.034), ankle brachial pressure index (ABI), body mass index, serum albumin, eGFR, age, CRP, D-dimer, critical limb ischemia, diabetes, cerebrovascular disease (CVD), and statin were related to ACD (p <0.05); lower EPA (HR: 0.997, 95% CI: 0.994-1.000, p = 0.038), ABI, serum albumin, eGFR, age, diabetes, coronary heart disease, CVD, and statin were related to MACEs (p <0.05); and lower EPA (HR: 0.988, 95% CI: 0.982-0.993, p <0.001), ABI, and low-density lipoprotein cholesterol were related to LEAEs (p <0.05). Low plasma EPA level was a significant risk factor for ACD, MACEs, and LEAEs in patients with PAD.
PubMed: 38919321
DOI: 10.3400/avd.oa.23-00079 -
Current Diabetes Reviews Jun 2024The term "Diabetic neuropathy" refers to a collection of clinical and subclinical symptoms caused by problems with the peripheral nervous system. Diabetes, which affects...
The term "Diabetic neuropathy" refers to a collection of clinical and subclinical symptoms caused by problems with the peripheral nervous system. Diabetes, which affects approximately 381 million people worldwide, is the source of dysfunction due to the emergence of microvascular complications. It is anticipated that in the next ten years, Diabetic neuropathy will manifest in about 50% of patients who are currently diagnosed with diabetes. Clinical diagnosis can be established by getting a thorough patient history and exploring the symptoms to rule out alternative causes. Although distal symmetrical polyneuropathy, or just, is the most common and well-researched variant of the disorder, this review will concentrate on it. The multifactorial pathogenesis is linked to various inflammatory, vascular, metabolic, and neurodegenerative illnesses. The three fundamental molecular alterations that lead to the development of diabetic neuropathic pain are oxidative stress, endothelial dysfunction, and chronic inflammation. These three elements are crucial in the development of polyneuropathy because their combination might result in direct axonal damage and nerve ischemia. The purpose of this article was to provide a narrative review of diabetic neuropathy. We provide an overview of the most recent data on biomarkers, the pathogenesis of the illness, the most recent epidemiology of diabetic neuropathy, and the existing screening and diagnosis outcome measures used in both clinical and research contexts.
PubMed: 38919000
DOI: 10.2174/0115733998295741240606104106 -
The Journal of Surgical Research Jun 2024The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial results suggest that in patients with chronic...
INTRODUCTION
The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial results suggest that in patients with chronic limb-threatening ischemia (CLTI) and adequate single-segment great saphenous vein (SSGSV) by preoperative duplex ultrasonography, a surgical-first treatment strategy is superior to an endovascular-first strategy. However, the utilization of vein mapping prior to endovascular-first revascularization for CLTI in actual clinical practice is not known.
METHODS
Data from a multicenter clinical data warehouse (2008-2019) were linked to Medicare claims data for patients undergoing endovascular-first treatment of infra-inguinal CLTI. Only patients who would have otherwise been eligible for enrollment in BEST-CLI were included. Adequate SSGSV was defined as healthy vein >3.0 mm in diameter from the groin through the knee. Logistic regression was used to estimate associations between preprocedure characteristics and vein mapping. Survival methods were used to estimate the risk of major adverse limb events and death.
RESULTS
A total of 142 candidates for either surgical or endovascular treatment underwent endovascular-first management of CLTI. Ultrasound assessment for SSGSV was not performed in 76% of patients prior to endovascular-first revascularization. Of those who underwent preprocedure vein mapping, 44% had adequate SSGSV for bypass. Within one year postprocedure, 12.0% (95% confidence interval 7.4-18.0%) of patients underwent open surgical bypass and 54.7% (95% confidence interval 45.3-62.4%) experienced a major adverse limb event or death.
CONCLUSIONS
In a real-world cohort of BEST-CLI-eligible patients undergoing endovascular-first intervention for infra-inguinal CLTI, three-quarters of patients had no preprocedure ultrasound assessment of great saphenous vein conduit. Practice patterns for vein conduit assessment in the real-world warrant reconsideration in the context of BEST-CLI trial results.
PubMed: 38917575
DOI: 10.1016/j.jss.2024.05.011 -
Herz Jun 2024Peripheral arterial occlusive disease (PAOD) is a frequent manifestation of atherosclerosis with a high risk of cardiovascular events (myocardial infarction, stroke,...
Peripheral arterial occlusive disease (PAOD) is a frequent manifestation of atherosclerosis with a high risk of cardiovascular events (myocardial infarction, stroke, amputation, cardiovascular death). A distinction is made between the stable form of intermittent claudication and chronic limb-threatening ischemia (CLTI, pain at rest, wounds). The most frequent risk factors are diabetes mellitus and smoking. As the disease is often asymptomatic early diagnostic necessary. Measurement of the ankle-brachial index (ABI) is suitable for screening. Consistent treatment of cardiovascular risk factors and antithrombotic medication are important. At the stage of intermittent claudication, exercise training should be performed. In CLTI early endovascular or surgical revascularization must be performed to avoid amputation of the extremity.
PubMed: 38916707
DOI: 10.1007/s00059-024-05252-3 -
Journal of Vascular Surgery Jun 2024Lower extremity acute limb ischemia (LE-ALI) is associated with high morbidity and mortality rates, and a burden on patient quality of life (QoL). There is limited...
OBJECTIVE
Lower extremity acute limb ischemia (LE-ALI) is associated with high morbidity and mortality rates, and a burden on patient quality of life (QoL). There is limited medium- to long-term evidence on mechanical aspiration thrombectomy (MT) in patients with LE-ALI. The STRIDE study was designed to assess safety and efficacy of MT using the Indigo Aspiration System in patients with LE-ALI. Thirty-day primary and secondary endpoints and additional outcomes were previously published. Here, we report 365-day secondary endpoints and QoL data from STRIDE.
METHODS
STRIDE was a multicenter, prospective, single-arm, observational cohort study that enrolled 119 patients across 16 sites in the United States and Europe. Patients were treated first-line with MT using the Indigo Aspiration System (Penumbra, Inc). The study completed follow-up in October 2023. Secondary endpoints at 365 days included target limb salvage and mortality. Additionally, the VascuQoL-6 questionnaire, developed for evaluating patient-centered QoL outcomes for peripheral arterial disease, was assessed at baseline and follow-up through 365 days.
RESULTS
Seventy-three percent of patients (87/119) were available for 365-day follow-up. Mean age of these patients was 65.0 ± 13.3 years, and 44.8% were female. Baseline ischemic severity was classified as Rutherford I in 12.6%, Rutherford IIa in 51.7%, and Rutherford IIb in 35.6%. In general, baseline and disease characteristics (demographics, medical history, comorbidities, target thrombus) of these patients are similar to the enrolled cohort of 119 patients. The secondary endpoints at 365 days for target limb salvage was 88.5% (77/87) and mortality rate was 12.0% (12/100). VascuQoL-6 improved across all domains, with a median total score improvement from 12.0 (interquartile range, 9.0-15.0) at baseline to 19.0 (interquartile range, 16.0-22.0) at 365 days.
CONCLUSIONS
These 365-day results from STRIDE demonstrate that first-line MT with the Indigo Aspiration System for LE-ALI portray continued high target limb salvage rates and improved patient-reported QoL. These findings indicate Indigo as a safe and effective therapeutic option for LE-ALI.
PubMed: 38914349
DOI: 10.1016/j.jvs.2024.05.043 -
Current Vascular Pharmacology Jun 2024Restenosis (RS) poses a significant concern, leading to recurrent ischemia and the potential for amputation following intraluminal angioplasty in the treatment of...
BACKGROUND
Restenosis (RS) poses a significant concern, leading to recurrent ischemia and the potential for amputation following intraluminal angioplasty in the treatment of Peripheral Artery Disease (PAD). Through microRNA microarray analysis, the study detected a significant downregulation of miR-199a-5p within arterial smooth muscle cells (ASMCs) associated with RS.
OBJECTIVE
This research aims to explore the possible function and the underlying mechanisms of miR-199a-5p in the context of RS.
METHODS
Primary ASMCs were extracted from the femoral arteries of both healthy individuals and patients with PAD or RS. The expression levels of miR-199a-5p were assessed using both qRT-PCR and in situ hybridization techniques. To examine the impacts of miR-199a-5p, a series of experiments were performed, including flow cytometry, TUNEL assay, EdU assay, CCK8 assay, Transwell assay, and wound closure assay. A rat carotid balloon injury model was employed to elucidate the mechanism through which miR-199a-5p mitigated neointimal hyperplasia.
RESULTS
MiR-199a-5p exhibited downregulation in RS patients and was predominantly expressed within ASMCs. Elevated the expression of miR-199a-5p resulted in an inhibitory effect of proliferation and migration in ASMCs. Immunohistochemistry and a dual-luciferase reporter assay uncovered that RS exhibited elevated expression levels of both HIF-1α and E2F3, and they were identified as target genes regulated by miR-199a-5p. The co-transfection of lentiviruses carrying HIF-1α and E2F3 alongside miR-199a-5p further elucidated their role in the cellular responses mediated by miR-199a-5p. In vivo, the delivery of miR-199a-5p via lentivirus led to the mitigation of neointimal formation following angioplasty, achieved by targeting HIF-1α and E2F3.
CONCLUSION
MiR-199a-5p exhibits promise as a prospective therapeutic target for RS since it alleviates the condition by inhibiting the proliferation and migration of ASMCs via its regulation of HIF-1α and E2F3.
PubMed: 38910413
DOI: 10.2174/0115701611280634240616062413 -
Journal of Vascular Surgery Jun 2024Controversy exists regarding the value and limitations of different sites of service for peripheral artery disease (PAD) treatment. We aimed to examine practice patterns...
OBJECTIVE
Controversy exists regarding the value and limitations of different sites of service for peripheral artery disease (PAD) treatment. We aimed to examine practice patterns associated with peripheral vascular interventions (PVI) performed in the office-based laboratory (OBL) vs. outpatient hospital site of service using a nationally representative database.
METHODS
Using 100% Medicare fee-for-service claims data, we identified all patients undergoing PVI for claudication or chronic limb-threatening ischemia (CLTI) between 01/2017 and 12/2022. We evaluated the associations of patient and procedure characteristics with site of service using multivariable hierarchical logistic regression. We used multinomial regression models to estimate the relative risk ratios (RRR) of site of service and intervention type (angioplasty, stent, atherectomy) and intervention level (iliac, femoropopliteal, tibial) after adjusting for baseline patient characteristics and clustering by physician.
RESULTS
Of 848,526 PVI, 485,942 (57.3%) were performed in an OBL. OBL use increased significantly over time from 48.3% in 2017 to 65.5% in 2022 (P<0.001). Patients treated in OBLs were more likely to be Black (aOR 1.14, 95%CI 1.11-1.18) or other non-white race (aOR 1.13, 95%CI 1.08-1.18), have fewer comorbidities, and receive treatment for claudication vs. CLTI (aOR 1.30, 95%CI 1.26-1.33) compared to patients treated in outpatient hospital settings. Physicians with majority practice (>50% procedures) in an OBL were more likely to practice in urban settings (aOR 21.58, 95%CI 9.31-50.02), specialize in radiology (aOR 18.15, 95%CI 8.92- 36.92), and have high-volume PVI practices (aOR 2.15, 95%CI 2.10-2.29). The median time from diagnosis to treatment was shorter in OBLs, particularly for patients with CLTI (29 vs. 39 days, P<0.001). The OBL setting was the strongest predictor of patients receiving an atherectomy alone (aRRR 6.67, 95%CI 6.59-6.76) or atherectomy+stent (aRRR 10.84, 95%CI 10.64-11.05), and these findings were consistent in subgroup analyses stratified by PVI indication. OBL setting was also associated with higher risk of tibial interventions for both claudication (aRRR 3.18, 95%CI 3.11-3.25) and CLTI (aRRR 1.89, 95%CI 1.86-1.92). Average reimbursement (including procedure and facility fees) was slightly higher for OBLs compared to the hospital ($8,742/case vs. $8,459/case; P<0.001). However, in a simulated cohort resetting the OBL's intervention type distribution to that of the hospital, OBLs were associated with a hypothetical cost savings of $221,219,803 overall and $2,602 per case.
CONCLUSION
The OBL site of service was associated with greater access to care for non-white patients and shorter time from diagnosis to treatment, but more frequently performed high-cost interventions compared to the outpatient hospital setting. The benefit to patients from improved access to PAD care in OBL settings must be balanced with the potential limitations of receiving differential care.
PubMed: 38908807
DOI: 10.1016/j.jvs.2024.06.006 -
Cell Death Discovery Jun 2024Peripheral vascular disease (PVD) is an emerging public health burden with a high rate of disability and mortality. Gasdermin D (GSDMD) has been reported to exert...
Peripheral vascular disease (PVD) is an emerging public health burden with a high rate of disability and mortality. Gasdermin D (GSDMD) has been reported to exert pyroptosis and play a critical role in the pathophysiology of many cardiovascular diseases. We ought to determine the role of GSDMD in the regulation of perfusion recovery after hindlimb ischemia (HLI). Our study revealed that GSDMD-mediated pyroptosis occurred in HLI. GSDMD deletion aggravated perfusion recovery and angiogenesis in vitro and in vivo. However, how GSDMD regulates angiogenesis after ischemic injury remains unclear. We then found that GSDMD-mediated pyroptosis exerted the angiogenic capacity in macrophages rather than endothelial cells after HLI. GSDMD deletion led to a lower level of CCL11 in mice serum. GSDMD knockdown in macrophages downregulated the expression and decreased the releasing level of CCL11. Furthermore, recombinant CCL11 improved endothelial functions and angiogenesis, which was attenuated by CCL11 antibody. Taken together, these results demonstrate that GSDMD promotes angiogenesis by releasing CCL11, thereby improving blood flow perfusion recovery after hindlimb ischemic injury. Therefore, CCL11 may be a novel target for prevention and treatment of vascular ischemic diseases.
PubMed: 38906863
DOI: 10.1038/s41420-023-01764-9