Preconditioning of surgical pedicle flaps with DNA plasmid expressing hypoxia-inducible factor-1α (HIF-1α) promotes tissue viability.

Ischemic necrosis of surgical flaps after reconstruction is a major clinical problem. Hypoxia-inducible factor-1α (HIF-1α) is considered the master regulator of the adaptive response to hypoxia. Among its many properties, it regulates the expression of genes encoding angiogenic growth factors, which have a short half-life in vivo. To achieve a continuous application of the therapeutic, we utilized DNA plasmid delivery. Transcription of the DNA plasmid confirmed by qRT-PCR showed significantly increased mRNA for HIF-1α in the transfected tissue compared to saline control tissue. Rats were preconditioned by injecting with either HIF-1α DNA plasmid or saline intradermally in the designated flap region on each flank. Seven days after preconditioning, each rat had two isolated pedicle flaps raised with a sterile silicone sheet implanted between the skin flap and muscle layer. The flaps preconditioned with HIF-1α DNA plasmid had significantly less necrotic area. Angiogenesis measured by CD31 staining showed a significant increase in the number of vessels per high powered field in the HIF-1α group (p < 0.05). Our findings offer a potential therapeutic strategy for significantly promoting the viability of surgical pedicle flaps by ischemic preconditioning with HIF-1α DNA plasmid.

Arrhythmia-Induced Cardiomyopathy: JACC State-of-the-Art Review.

Arrhythmias frequently accompany heart failure and left ventricular dysfunction. Tachycardias, atrial fibrillation, and premature ventricular contractions can induce a reversible form of dilated cardiomyopathy (CM) known as arrhythmia-induced CM (AiCM). The intriguing question is why certain individuals are more susceptible to AiCM, despite similar arrhythmia burdens. The primary challenge is determining the extent of arrhythmias' contribution to left ventricular systolic dysfunction. AiCM should be considered in patients with a mean heart rate of >100 beats/min, atrial fibrillation, or a PVC burden of >10%. Confirmation of AiCM occurs when CM reverses upon eliminating the responsible arrhythmia. Therapy choice depends on the specific arrhythmia, patient comorbidities, and preferences. After left ventricular function is restored, ongoing follow-up is essential if an abnormal myocardial substrate persists. Accurate diagnosis and treatment of AiCM have the potential to enhance patients' quality of life, improve clinical outcomes, and reduce hospital admissions and overall health care costs.

Left ventricular remodeling in premature ventricular contraction-induced cardiomyopathy: Effect of coupling intervals and atrioventricular dissociation.

Background: Left ventricular dyssynchrony (LVD) and postextrasystolic potentiation (PESP) associated with premature ventricular contractions (PVCs) may play a role in the development of premature ventricular contraction-induced cardiomyopathy (PVC-CM). Long-coupled (LC) PVCs have a greater LVD than short-coupled (SC) PVCs, whereas SC-PVCs have a stronger PESP than LC-PVCs. Objective: The purpose of this study was to compare SC-PVCs and LC-PVCs to evaluate the roles of LVD, PESP, and atrioventricular dissociation (AVD) in the development of PVC-CM. Methods: Thirty-six canines underwent pacemaker implantation to induce bigeminal right ventricular apical epicardial PVCs (50% burden) for 12 weeks. Telemetry assessed PVC burden and AVD. Animals were grouped as SC-PVC (coupling interval [CI] 200-220ms), LC-PVC (CI 330 ms), or sham (control). Echocardiographic changes, AVD, and hemodynamics were monitored for 12 weeks. Results: PVC burden was similar between SC-PVC and LC-PVC groups but was statistically higher in the SC-PVC group (50% vs 47.5%; P = .028). After 12 weeks, left ventricular ejection fraction (LVEF) significantly decreased in both SC-PVC and LC-PVC groups (47.1% ± 1.4% and 45.5% ± 2%, respectively) compared to sham group (61% ± 1.6%; P <.001). Overall AVD was similar between SC-PVC and LC-PVC groups, and there was no significant correlation between AVD and reduction in LVEF at 12 weeks (r = 0.09, P = .5; and r = 0.06, P = .8, respectively). Additionally, both SC-PVC and LC-PVC groups experienced substantial declines in max and min dP/dt after 12 weeks compared to baseline. Conclusion: Neither PVC CI nor AVD played an independent role in the development or severity of PVC-CM. LVD and PESP make equal relative contributions to the development of PVC-CM.

HOTAIR-Loaded Mesenchymal Stem/Stromal Cell Extracellular Vesicles Enhance Angiogenesis and Wound Healing.

Chronic wounds remain a substantial source of morbidity worldwide. An emergent approach that may be well-suited to induce the complex, multicellular processes such as angiogenesis that are required for wound repair is the use of extracellular vesicles (EVs). EVs contain a wide variety of proteins and nucleic acids that enable multifactorial signaling. Here, the capability of EVs is leveraged to be engineered via producer cell modification to investigate the therapeutic potential of EVs from mesenchymal stem/stromal cells (MSCs) transfected to overexpress long non-coding RNA HOX transcript antisense RNA (HOTAIR). HOTAIR is previously shown by the authors' group to be critical in mediating angiogenic effects of endothelial cell EVs, and MSCs are chosen as EV producer cells for this study due to their widely reported intrinsic angiogenic properties. The results indicate that MSCs overexpressing HOTAIR (HOTAIR-MSCs) produce EVs with increased HOTAIR content that promote angiogenesis and wound healing in diabetic (db/db) mice. Further, endothelial cells exposed to HOTAIR-MSC EVs exhibit increased HOTAIR content correlated with upregulation of the angiogenic protein vascular endothelial growth factor. Thus, this study supports EV-mediated HOTAIR delivery as a strategy for further exploration toward healing of chronic wounds.

Comparison on frequencies of pericardial effusion and tamponade following open heart surgery in patients with or without low negative pressure suction on chest tube.

INTRODUCTION: Pericardial effusion and tamponade are accounted as the two most important complications following open-heart surgeries which are known to increase mortality and morbidity rates. Putting a low negative pressure suction on the chest tube of patients might be a useful way for better drainage and also reducing the occurrence of pericardial effusion and tamponade. In the present study, we aimed to compare the prevalence of pericardial effusion and tamponade in patients undergoing open-heart surgeries with and without low negative pressure suction on the chest tube. METHODS: This clinical trial was performed in 2018-2019 in Tehran, Iran. 100 patients who were candidates for open-heart surgery were entered. After surgeries, patients were divided into two groups: group 1 had a low negative pressure suction on their chest tube and group 2 had no suction. Patients were then observed for clinical and imaging characteristics of pleural effusion and tamponade. Data were gathered and analyzed using SPSS software. RESULTS: In the present study, we indicated that the prevalence of pericardial effusion is significantly lower in patients with low negative pressure on their chest tube (P=0.04). No significant differences were observed between two groups regarding to: frequency of tamponade and post-operative ejection fraction (P> 0.05). CONCLUSION: The usage of a low negative pressure suction on the chest tube following open cardiac surgeries is associated with a lower prevalence of pericardial effusion. We suggest that such systems could be commonly used in cardiac surgeries or surgeries of the thorax.

Tuberculosis-associated HLH in a patient with chronic kidney disease on haemodialysis.

Haemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder that is accompanied by a high mortality rate when the underlying aetiology is miliary tuberculosis. We report a case of tuberculosis (TB)-associated HLH in a haemodialysis patient, from a TB-endemic region, who missed two sessions of dialysis before developing the primary symptoms of HLH. The patient presented with non-specific findings including pancytopenia, coagulopathy and transaminitis. Computer-tomography imaging and microbiology from bronchoalveolar lavage evidenced miliary tuberculosis. Further testing revealed the TB-associated-HLH characteristic pattern of thrombocytosis, leukopenia, transaminitis, hyperferritinemia and elevated fibrinogen. The patient initially demonstrated improvement after initiation of anti-TB therapy. However, soon thereafter began to paradoxically deteriorate and then expire from apparent tuberculosis-immune reconstitution inflammatory syndrome. This case highlights the importance of early diagnosis and treatment, and consequently of the utility of diagnostic systems such as the HScore in cases of high clinical suspicion.

Effects of fingolimod treatments on alanine transaminase and aspartate transaminase levels in patients with multiple sclerosis.

INTRODUCTION: Multiple Sclerosis (MS) is a chronic neurological disorder with no known cause or cure. Fingolimod (FTY720) is an oral medication recently approved for the treatment of MS as well as other diseases with autoimmune aspects. However, the drug is not without side effects. The severity and prevalence of these side effects are not completely understood. One of the most common causes for the patient cessation of fingolimod is an increase in liver enzymes, indicating possible inflammation or damage to liver cells. Alanine transaminase (ALT) and aspartate transaminase (AST) are the most common liver enzymes used as indicators of hepatic health. OBJECTIVES: This three-month prospective cohort study selected patients who were diagnosed with relapsing-remitting MS (RRMS) and who were not taking fingolimod oral treatment. ALT and AST levels were determined for these patients at baseline and then after three months of taking FTY720 to determine if these liver enzymes were changed. METHODS: 36 RRMS patients completed this study, which lasted three months. They were started on 0.5 oral FTY720 after approval from a physician and completion of an AST/ALT blood test. Baseline levels were determined and then taken again three months later. Statistical analysis of these values was performed using P<0.05 as a significance threshold. RESULTS: In this sample of patients, only ALT levels were significantly increased after fingolimod treatment in the general cohort (P=0.00). The general cohort showed an insignificant increase in AST levels. In male and female populations separately, AST was not significantly increased. ALT was only significantly increased in men (P=0.00) and insignificantly increased in women. CONCLUSION: This study further confirms our concerns about fingolimod's possible effects on the liver. While these numbers do support the claim that the drug does on average increase ALT in patient populations, it is important to note that most of these patients have no real hepatic side effects. In addition, previous studies have cited a return to normal ALT and AST levels after cessation of fingolimod, suggesting its effects are temporary and not severely damaged in the usual patient.

Alcohol and multiple sclerosis: an immune system-based review.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS). Although the exact etiology of multiple sclerosis is unknown, researchers suggest that genetic, environmental, and microbial factors play a central role in causing multiple sclerosis. Pathology of multiple sclerosis is based on inflammation as T cells enter the brain via disruptions in the blood-brain barrier, recognizing myelin as foreign antigen; and as a result, the T cells attack myelin and start the inflammatory processes, enhancing inflammatory cytokines and antibodies. Since previous studies show ethanol can suppress the immune system such as innate, humoral, and cellular immunity and increases the production of anti-inflammatory cytokines, we hypothesized maybe ethanol also have ameliorating effects on multiple sclerosis symptoms. Although alcohol induces apoptosis in oligodendrocytes and neurons, causing demyelination and affects CNS directly, in this study we will investigate ethanol's effects on some aspects of the immune system in multiple sclerosis.

How is the association between urinary prostate cancer antigen 3 (PCA3) levels and Gleason scores in patients suspicious of prostate cancer?

INTRODUCTION: Prostate cancer is one of the most common cancers in men which is mostly slow growing and responses well to treatments if early diagnosed. Urinary prostate cancer antigen 3 (PCA3) assay is a new method with effective results in diagnosing prostate cancer. The aim of this present study was evaluate the correlation between urinary PCA3 and Gleason scores in patients who are suspicious of prostate cancer and undergo tissue biopsies. METHODS: This is a cross-sectional study which was performed in 2017-2018. The patients included this study complain of prostate problems and were selected from Nour hospital, Ali-Asghar hospital and Ordibehesht clinic in Tehran, Iran. Urinary PCA3 levels were checked in all patients and then they went under prostate biopsies. Amounts of PCA3 and Gleason scores were collected and analyzed using SPSS software. FINDINGS: We evaluated a total number of 80 patients. 40 patients had prostate cancer and 40 had no cancer. We indicated that no significant relation was reported between Gleason scores and urinary PCA3 levels. Levels of urinary PCA3 were higher in patients with prostate cancer than in patients with no cancer (P=0.007). DISCUSSION: Generally, urinary PCA3 test is indicated as a non-invasive method to improve the specificity of prostate cancer diagnosis and its potential predictive value was studied in numerous clinical researches, but here we found higher PCA3 levels in patients with prostate cancer than in patients with and other prostate problems. We conclude that PCA3 functions as a diagnostic test and its changes in prostate cancer need to be further studied in different populations and races.