Surface entrenched ß-sitosterol niosomes for enhanced cardioprotective activity against isoproterenol induced cardiotoxicity in rats.

Cardiotoxicity (CT) is a severe condition that negatively impacts heart function. ß-sitosterol (BS) is a group of phytosterols and known for various pharmacological benefits, such as managing diabetes, cardiac protection, and neuroprotection. This study aims to develop niosomes (NS) containing BS, utilizing cholesterol as the lipid and Tween 80 as the stabilizer. The research focuses on designing and evaluating both conventional BS-NS and hyaluronic acid (HA) modified NS (BS-HA-NS) to enhance the specificity and efficacy of BS within cardiac tissue. The resulting niosomal formulation was spherical, with a size of about 158.51 ± 0.57 nm, an entrapment efficiency of 93.56 ± 1.48 %, and a drug loading of 8.07 ± 1.62 %. To evaluate cytotoxicity on H9c2 heart cells, the MTT assay was used. The cellular uptake of BS-NS and BS-HA-NS was confirmed by confocal microscopy on H9c2 cardiac cells. Administering BS-NS and BS-HA-NS intravenously at a dose of 10 mg/kg showed the ability to significantly decrease the levels of cardiac troponin-I (cTn-I), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and lipid peroxidation (MDA). Tissue histopathology indicated a substantial potential for repairing cardiac tissue after treatment with BS-NS and BS-HA-NS and strong cardioprotection against ISO induced myocardial tissue damages. Thus, enhancing BS's therapeutic effectiveness through niosome surface modification holds promise for mitigating cardiac damage resulting from CT.

Transcutaneous vagus nerve stimulation ameliorates cardiac abnormalities in chronically stressed rats.

Chronically stressed patients often have low vagal tone and increased levels of proinflammatory cytokines, which increase their risk for developing cardiac dysfunction. Transcutaneous vagus nerve stimulation (taVNS) is a way to activate the parasympathetic system, which has the ability to reduce inflammation and antagonize excessive sympathetic responses. However, the effectiveness of taVNS in treating cardiac dysfunction caused by chronic unpredictable stress (CUS) has not been studied. To investigate this, we first validated a rat model of CUS, in which the rats were exposed to random stressors daily for 8 weeks. Post CUS, the rats were treated with taVNS (1.0 ms, 6 V, 6 Hz, for 40 min × 2 weeks, alternatively) and their cardiac function and cholinergic flow were evaluated. Furthermore, serum cardiac troponin I (cTnI), cardiac caspase-3, inducible nitric oxide synthase (iNOS), and transforming growth factor (TGF)-ß1 expression in rats were also assessed. The chronically stressed rats showed depressed behavior with increased levels of serum corticosterone and proinflammatory cytokines. Electrocardiogram (ECG) and heart rate variability (HRV) studies revealed elevated heart rate, diminished vagal tone, and altered sinus rhythm in CUS rats. Furthermore, the CUS rats demonstrated cardiac hypertrophy and fibrosis with increased caspase-3, iNOS, and TGF-ß expression in their myocardium and increased levels of serum cTnI. Interestingly, alternate taVNS therapy for 2 weeks, post CUS, helped alleviate these cardiac abnormalities. These suggest that taVNS could be a useful adjunctive and non-pharmacological approach for managing CUS induced cardiac dysfunction.

Chronic stress predisposes to the aggravation of inflammation in autoimmune diseases with focus on rheumatoid arthritis and psoriasis.

The global incidence of autoimmune diseases is on the rise, and many healthcare professionals believe that chronic stress plays a prominent role in both the aggravation and remission of these conditions. It is believed that prolonged exposure to stress is associated with neuroimmune axis malfunction, which eventually dysregulates multiple immunological factors as well as deregulates autoimmune responses that play a central role in various autoimmune diseases, including rheumatoid arthritis and psoriasis. Herein, we performed validation of an 8-week long rat model of chronic unpredictable stress (CUS) which consisted of exposing groups of rats to random stressors daily for 8 weeks. Additionally, we developed a novel rat model combining 8-week long random stressor-induced CUS with CIA-triggered arthritis and IMQ-triggered psoriasis and have successfully used both these models to assess the role of chronic stress in the aggravation of arthritis and psoriasis, respectively. Notably, the 8-week CUS protocol extensively aggravated and prolonged both arthritis and psoriasis condition in the rat model by upregulating the release of different pro-inflammatory cytokines, dysregulation of immune cell responses and oxidative stress system, which were all related to severe inflammation. Further, CUS aggravated macroscopic features and the increase in destruction of joint tissue and epidermal thickness induced by CIA and IMQ, respectively, in rats. In conclusion, this study suggests that exposure to an 8-week long CUS paradigm aggravates the distinctive characteristics of rheumatoid arthritis and psoriasis in rats via amplifying the inflammatory circuits and immune cell responses linked to these autoimmune diseases.

Salbutamol ameliorates skeletal muscle wasting and inflammatory markers in streptozotocin (STZ)-induced diabetic rats.

Diabetes accelerates muscle atrophy, leading to the deterioration of skeletal muscles. This study aimed to assess the potential of the ß2-adrenoceptor agonist, salbutamol (SLB), to alleviate muscle atrophy in streptozotocin (STZ)-induced diabetic rats. Male Sprague Dawley rats were randomized into four groups (n=6): control, SLB, STZ (55 mg/kg, single i.p.), and STZ + SLB (6 mg/kg, orally for 4 weeks). After the final SLB dose, animals underwent tests to evaluate muscle strength and coordination, including forelimb grip strength, wire-hanging, actophotometer, rotarod, and footprint assessments. Rats were then sacrificed, and serum and gastrocnemius (GN) muscles were collected for further analysis. Serum evaluations included proinflammatory markers (tumor necrosis factor α, interleukin-1ß, interleukin-6), muscle markers (creatine kinase, myostatin), testosterone, and lipidemic markers. Muscle oxidative stress (malonaldehyde, protein carbonyl), antioxidants (glutathione, catalase, superoxide dismutase), and histology were also performed. Additionally, 1H nuclear magnetic resonance serum profiling was conducted. SLB notably enhanced muscle grip strength, coordination, and antioxidant levels, while reduced proinflammatory markers and oxidative stress in STZ-induced diabetic rats. Reduced serum muscle biomarkers, increased testosterone, restored lipidemic levels, and improved muscle cellular architecture indicated SLB's positive effect on muscle condition in diabetic rats. Metabolomics profiling revealed that the STZ group significantly increased the phenylalanine-to-tyrosine ratio (PTR), lactate-to-pyruvate ratio (LPR), acetate, succinate, isobutyrate, and histidine. SLB administration restored these perturbed serum metabolites in the STZ-induced diabetic group. In conclusion, salbutamol significantly protected against skeletal muscle wasting in STZ-induced diabetic rats.

Salbutamol Attenuates Diabetic Skeletal Muscle Atrophy by Reducing Oxidative Stress, Myostatin/GDF-8, and Pro-Inflammatory Cytokines in Rats.

Type 2 diabetes is a metabolic disorder that leads to accelerated skeletal muscle atrophy. In this study, we aimed to evaluate the effect of salbutamol (SLB) on skeletal muscle atrophy in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic rats. Male Sprague Dawley rats were divided into four groups (n = 6): control, SLB, HFD/STZ, and HFD/STZ + SLB (6 mg/kg orally for four weeks). After the last dose of SLB, rats were assessed for muscle grip strength and muscle coordination (wire-hanging, rotarod, footprint, and actophotometer tests). Body composition was analyzed in live rats. After that, animals were sacrificed, and serum and gastrocnemius (GN) muscles were collected. Endpoints include myofibrillar protein content, muscle oxidative stress and antioxidants, serum pro-inflammatory cytokines (interleukin-1ß, interleukin-2, and interleukin-6), serum muscle markers (myostatin, creatine kinase, and testosterone), histopathology, and muscle 1H NMR metabolomics. Findings showed that SLB treatment significantly improved muscle strength and muscle coordination, as well as increased lean muscle mass in diabetic rats. Increased pro-inflammatory cytokines and muscle markers (myostatin, creatine kinase) indicate muscle deterioration in diabetic rats, while SLB intervention restored the same. Also, Feret's diameter and cross-sectional area of GN muscle were increased by SLB treatment, indicating the amelioration in diabetic rat muscle. Results of muscle metabolomics exhibit that SLB treatment resulted in the restoration of perturbed metabolites, including histidine-to-tyrosine, phenylalanine-to-tyrosine, and glutamate-to-glutamine ratios and succinate, sarcosine, and 3-hydroxybutyrate (3HB) in diabetic rats. These metabolites showed a pertinent role in muscle inflammation and oxidative stress in diabetic rats. In conclusion, findings showed that salbutamol could be explored as an intervention in diabetic-associated skeletal muscle atrophy.

Butein ameliorates chronic stress induced atherosclerosis via targeting anti-inflammatory, anti-fibrotic and BDNF pathways.

Chronic stress is a major risk factor for various diseases, including cardiovascular diseases (CVDs). Chronic stress enhances the release of pro-inflammatory cytokines like IL-1ß, IL-6, and TNF-α, making individuals susceptible to atherosclerosis which is dominant cause for CVDs. In present study, we validated a mouse model of chronic unpredictable stress (CUS), and assessed the characteristic features of atherosclerosis in thoracic aortas of CUS mice. The CUS procedure consisted of exposing groups of mice to random stressors daily for 10-weeks. The stress response was verified by presence of depressive-like behaviors and increased serum corticosterone in mice which was determined by battery of behavioural tests (SPT, EPMT, NSFT) and ELISA, respectively. Atherosclerosis parameters in CUS mice were evaluated by lipid indices estimation followed by histological assessment of plaque deposition and fibrosis in thoracic aorta. Further, we assessed the efficacy of a polyphenol, i.e. Butein in conferring protection against chronic stress-induced atherosclerosis and the possible mechanism of action. Butein (20 mg/kg x 28 days, alternatively, i.p.) was administered to CUS mice after 6-weeks of CUS exposure till the end of the protocol. Butein treatment decreased peripheral IL-1ß and enhanced peripheral as well as central BDNF levels. Histological assessment revealed decreased macrophage expression and reduced fibrosis in thoracic aorta of Butein treated mice. Further, treatment with Butein lowered lipid indices in CUS mice. Our findings thus, suggest that 10-weeks of CUS induce characteristic features of atherosclerosis in mice and Butein can offer protection in CUS-induced atherosclerosis through multiple mechanisms including anti-inflammatory, antifibrotic and anti-adipogenic actions.

A Pilot Study to Assess the Clinical Onset of IV Heparin in Interventional Cardiology and Cardiac Surgery.

OBJECTIVES: To determine the onset of heparin anticoagulation, using 2 different measures of activated clotting times (ACT), thromboelastography (TEG; R-time), and anti-Xa levels, after administering low- (100 U/kg) and high- (300 U/kg) dose intravenous (IV) heparin to patients undergoing transcatheter aortic valve replacement (TAVR) and cardiac surgery, respectively. DESIGN: Prospective study. SETTING: Single academic institution. PARTICIPANTS: Patients with normal baseline coagulation presenting for TAVR or cardiac valve surgery. INTERVENTIONS: Coagulation studies were performed at baseline, 30 seconds, 90 seconds, and 180 seconds after IV heparin administration. The tests included iSTAT (iACT) and Hemochron ACT (hACT), TEG R-Time, and anti-Xa levels. At the authors' institution, anti-Xa is the preferred measure of heparin anticoagulation when time permits. ACT, a rapid point- of-care test, is used to assess intraprocedural anticoagulation. MEASUREMENTS AND MAIN RESULTS: After both low- and high-dose heparin, there are peak increases in ACT and anti-Xa at 30 seconds, followed by a decline at 90 seconds and plateau at 180 seconds. The TEG R-time remained elevated (>80 minutes) throughout. For TAVR cases, all anti-Xa was >1.5 IU/mL, and was associated with an iACT >180 seconds and an hACT >200 seconds. For cardiac valve surgery cases, all anti-Xa was >2.4 and associated with an iACT >420 seconds and and hACT >340 seconds. Compared with hACT, iACTs were significantly lower at all time points after low-dose heparin, but not after high-dose heparin. CONCLUSIONS: In this pilot study, heparin anticoagulation was detected as early as 30 seconds after IV administration, based on ACT, anti-Xa levels, and TEG R-time.

Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity.

BACKGROUND: The close interaction and interdependence of astrocytes and neurons allows for the possibility that astrocyte dysfunction contributes to and amplifies neurodegenerative pathology. Molecular pathways that trigger reactive astrocytes may represent important targets to preserve normal homeostatic maintenance and modify disease progression. METHODS: Semaphorin 4D (SEMA4D) expression in the context of disease-associated neuropathology was assessed in postmortem brain sections of patients with Huntington's (HD) and Alzheimer's disease (AD), as well as in mouse models of HD (zQ175) and AD (CVN; APPSwDI/NOS2-/-) by immunohistochemistry. Effects of SEMA4D antibody blockade were assessed in purified astrocyte cultures and in the CVN mouse AD model. CVN mice were treated weekly from 26 to 38 weeks of age; thereafter mice underwent cognitive assessment and brains were collected for histopathology. RESULTS: We report here that SEMA4D is upregulated in neurons during progression of neurodegenerative diseases and is a trigger of reactive astrocytes. Evidence of reactive astrocytes in close proximity to neurons expressing SEMA4D is detected in brain sections of patients and mouse models of HD and AD. We further report that SEMA4D-blockade prevents characteristic loss of GABAergic synapses and restores spatial memory and learning in CVN mice, a disease model that appears to reproduce many features of AD-like pathology including neuroinflammation. In vitro mechanistic studies demonstrate that astrocytes express cognate receptors for SEMA4D and that ligand binding triggers morphological variations, and changes in expression of key membrane receptors and enzymes characteristic of reactive astrocytes. These changes include reductions in EAAT-2 glutamate transporter and glutamine synthetase, key enzymes in neurotransmitter recycling, as well as reduced GLUT-1 glucose and MCT-4 lactate transporters, that allow astrocytes to couple energy metabolism with synaptic activity. Antibody blockade of SEMA4D prevented these changes and reversed functional deficits in glucose uptake. CONCLUSIONS: Collectively, these results suggest that SEMA4D blockade may ameliorate disease pathology by preserving normal astrocyte function and reducing the negative consequences of reactive astrogliosis.

Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial.

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington's disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

Genetic architecture of motor neuron diseases.

Motor neuron diseases (MNDs) are rare and frequently fatal neurological disorders in which motor neurons within the brainstem and spinal cord regions slowly die. MNDs are primarily caused by genetic mutations, and > 100 different mutant genes in humans have been discovered thus far. Given the fact that many more MND-related genes have yet to be discovered, the growing body of genetic evidence has offered new insights into the diverse cellular and molecular mechanisms involved in the aetiology and pathogenesis of MNDs. This search may aid in the selection of potential candidate genes for future investigation and, eventually, may open the door to novel interventions to slow down disease progression. In this review paper, we have summarized detailed existing research findings of different MNDs, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal bulbar muscle atrophy (SBMA) and hereditary spastic paraplegia (HSP) in relation to their complex genetic architecture.

Interleukin-6 expression and its modulation by diacerein in a rat model of chronic stress induced cardiac dysfunction.

People with chronic stress have higher levels of pro-inflammatory cytokines, which enhance their susceptibility to cardiovascular diseases. Diacerein has ability to modulate pro-inflammatory cytokines such as IL-1ß and IL-6; however, its efficacy in chronic stress associated cardiovascular diseases is not yet assessed. In this study, we standardized a rat model of chronic unpredictable stress (CUS) demonstrating cardiovascular dysfunctions and further assessed the effect of IL-6 modulator, diacerein, on cardiovascular functions in CUS exposed rats. The CUS procedure consisted of exposing male albino Wistar rats to random stressors, everyday for 8 weeks. The binding affinity of diacerein with IL-6 was ascertained using Docking tools viz AutoDock and SwissDock. Moreover, diacerein was administered (50 mg/kg/day x 20 days P.O) post CUS exposure to rats and the serum IL-6 levels and heart functions of CUS rats were determined by ELISA and ECG-HRV analysis, respectively. 8 weeks of CUS exposure resulted in two-fold increase in serum corticosterone and IL-6 levels in rats. The ECG and HRV analysis of CUS rats showed altered sinus rhythm, elevated heart rate, systolic blood pressure and sympathetic tone. Molecular docking studies revealed diacerein high binding affinity towards IL-6 receptor. The post-treatment of diacerein in CUS rats prevented these cardiovascular dysfunctions. Our findings thus suggests that IL-6 may have a prominent role in chronic stress induced cardiovascular dysfunctions and diacerein, could be used as a preventive measure for such conditions.

Anti-Semaphorin 4D Rescues Motor, Cognitive, and Respiratory Phenotypes in a Rett Syndrome Mouse Model.

Rett syndrome is a neurodevelopmental disorder caused by mutations of the methyl-CpG binding protein 2 gene. Abnormal physiological functions of glial cells contribute to pathogenesis of Rett syndrome. Semaphorin 4D (SEMA4D) regulates processes central to neuroinflammation and neurodegeneration including cytoskeletal structures required for process extension, communication, and migration of glial cells. Blocking SEMA4D-induced gliosis may preserve normal glial and neuronal function and rescue neurological dysfunction in Rett syndrome. We evaluated the pre-clinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody in the Rett syndrome Mecp2T158A transgenic mouse model and investigated the contribution of glial cells as a proposed mechanism of action in treated mice and in primary glial cultures isolated from Mecp2T158A/y mutant mice. SEMA4D is upregulated in neurons while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1-positive cells are upregulated in Mecp2T158A/y mice. Anti-SEMA4D treatment ameliorates Rett syndrome-specific symptoms and improves behavioural functions in both pre-symptomatic and symptomatic cohorts of hemizygous Mecp2T158A/y male mice. Anti-SEMA4D also reduces astrocyte and microglia activation in vivo. In vitro experiments demonstrate an abnormal cytoskeletal structure in mutant astrocytes in the presence of SEMA4D, while anti-SEMA4D antibody treatment blocks SEMA4D-Plexin B1 signaling and mitigates these abnormalities. These results suggest that anti-SEMA4D immunotherapy may be an effective treatment option to alleviate symptoms and improve cognitive and motor function in Rett syndrome.

Moderate, intermittent voluntary exercise in a model of Gulf War Illness improves cognitive and mood function with alleviation of activated microglia and astrocytes, and enhanced neurogenesis in the hippocampus.

Persistent cognitive and mood impairments in Gulf War Illness (GWI) are associated with chronic neuroinflammation, typified by hypertrophied astrocytes, activated microglia, and increased proinflammatory mediators in the brain. Using a rat model, we investigated whether a simple lifestyle change such as moderate voluntary physical exercise would improve cognitive and mood function in GWI. Because veterans with GWI exhibit fatigue and post-exertional malaise, we employed an intermittent voluntary running exercise (RE) regimen, which prevented exercise-induced stress. The GWI rats were provided access to running wheels three days per week for 13 weeks, commencing ten weeks after the exposure to GWI-related chemicals and stress (GWI-RE group). Groups of age-matched sedentary GWI rats (GWI-SED group) and naïve rats were maintained parallelly. Interrogation of rats with behavioral tests after the 13-week RE regimen revealed improved hippocampus-dependent object location memory and pattern separation function and reduced anxiety-like behavior in the GWI-RE group compared to the GWI-SED group. Moreover, 13 weeks of RE in GWI rats significantly reversed activated microglia with short and less ramified processes into non-inflammatory/antiinflammatory microglia with highly ramified processes and reduced the hypertrophy of astrocytes. Moreover, the production of new neurons in the hippocampus was enhanced when examined eight weeks after the commencement of RE. Notably, increased neurogenesis continued even after the cessation of RE. Collectively, the results suggest that even a moderate, intermittent physical exercise has the promise to improve brain function in veterans with GWI in association with suppression of neuroinflammation and enhancement of hippocampal neurogenesis.

A Phase Ib/II Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer.

PURPOSE: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition. PATIENTS AND METHODS: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity. RESULTS: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria. CONCLUSIONS: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.

Clinical safety and efficacy of World's thinnest (50 µm), very long (>40 mm) Everolimus Eluting Stent (SES) among real world patients.

BACKGROUND: Safety and efficacy of newer-generation and World's thinnest everolimus eluting stent (Evermine 50) in patients with very long and multiple lesions. METHOD: Total of 711 patients received >40 mm long, World's thinnest (50 µm) Evermine 50 Everolimus eluting stent (Meril Life Sciences Pvt. Ltd., India) for various indications at LPS Institute of Cardiology, GSVM Medical College, Kanpur, UP, India between August 2017 and December 2018. Primary outcome as Device-oriented composite outcome (DOCO)- composite of cardiovascular death, target vessel myocardial infarction, and target lesion revascularization, secondary end points including peri-procedural device failure (failure of stent delivery, change of stent, edge dissection, stent fracture), target vessel failure (TVF), Global Cardiovascular End Points (GCEP)- composite of all-cause death, any MI, and any revascularization, and stent thrombosis (ST) were evaluated at 1-year follow-up. RESULT: Mean age was 52.7±15.9 years and majority (78.6%) were male. Indications for implantation were STEMI (n=284; 46.2%), NSTEMI (n=201; 32.8%), UA (n=78; 12.6%), and CCS (n=52; 8.4%). Total of 989 lesions were treated among 711 patients. Median length of stent per lesion was 54±14 mm. DOCO occurred in 47 (6.6%) which was contributed by target vessel MI and TLR in 23 (3.2%) and 15 (2.1%) patients respectively. GCEP was observed in 117 (16.4%) at 12-month follow-up mainly attributed by any revascularization 60 (8.4%). Stent failure was seen in 36 (5.1%) patients mainly as result of failure of assigned stent delivery (n=18; 2.5%), and edge dissection (n=15; 2.1%). Definite and probable ST were observed in 8 (1.1%) and 6 (0.8%) patients respectively. CONCLUSION: Evermine 50 Everolimus eluting stent is safe and effective to treat unduly long and multiple lesions.

Percutaneous coronary intervention provided better long term results than optimal medical therapy alone in patients with chronic total occlusion: A meta-analysis.

AIMS: Studies comparing the outcome of percutaneous coronary intervention (PCI) along with optimal medical therapy (OMT) versus OMT alone in treatment of chronic total occlusion (CTO) are limited by observational design, variable follow-up period, diverse clinical outcomes, high drop-out and cross-over rates. This study aims to conduct a meta-analysis of published data of observational as well as randomized studies comparing long term outcomes of PCI+OMT versus OMT alone. METHODS AND RESULTS: PubMed, Embase and Cochrane databases were systematically reviewed. 15 studies meeting criteria were included in the meta-analysis. The New-castle Ottawa scale was used to appraise the overall quality of the studies. Random-effects model with inverse variance method was undertaken. Major adverse cardiovascular events (MACE) which comprises of cardiac death, myocardial infarction, stroke, and un-planned revascularization were significantly lower in the PCI+OMT group (RR:0.76; 95% CI:0.61 to 0.95; P=<0.00001; I2 = 85%). All-cause mortality and cardiac death were significantly lower in the PCI+OMT group (P=<0.00001 in both). Myocardial infarction and stroke rates were lower in the PCI+OMT group, however they did not reach statistical significance (P = 0.24, P = 0.15 respectively). Unplanned revascularizations (of any vessel) were also similar in both the groups (P = 0.78, I2 = 88%). CONCLUSION: PCI of CTO is rewarded with better long term outcome, in terms of MACE, all-cause mortality and cardiac death with similar rates of un-planned revascularization.

Alcohol induces programmed death receptor-1 and programmed death-ligand-1 differentially in neuroimmune cells.

Engagement of programmed death-1 (PD-1) receptor by its ligands (PD-L1/PD-L2) in activated immune cells is known to be involved in inflammatory neurological disease via a co-inhibitory signal pathway. Interaction of PD-1/PD-L1 is believed to occur only in activated neuroimmune cells because there are undetectable levels of PD-1/PD-L1 in normal physiological conditions. Here, we evaluated whether activation of neuroimmune cells such as human macrophage, brain endothelial cells (hBECs), astrocytes, microglia, and neurons by non-toxic concentrations of ethanol (EtOH) exposure can alter PD-1/PD-L1 expression. Thus, the present study is limited to the screening of PD-1/PD-L1 alterations in neuroimmune cells following ethanol exposure. We found that exposure of human macrophage or microglia to EtOH in primary culture immediately increased the levels of PD-L1 and gradually up-regulated PD-1 levels (beginning at 1-2 h). Similarly, ethanol exposure was able to induce PD-1/PD-L1 levels in hBECs and neuronal culture in a delayed process (occurring at 24 h). Astrocyte culture was the only cell type that showed endogenous levels of PD-1/PD-L1 that was decreased by EtOH exposure time-dependently. We concluded that ethanol (alcohol) mediated the induction of PD-1/PD-L1 differentially in neuroimmune cells. Taken together, our findings suggest that up-regulation of PD-1/PD-L1 by chronic alcohol use may dampen the innate immune response of neuroimmune cells, thereby contributing to neuroinflammation and neurodegeneration.