[TRANSLATIONAL MEDICINE - THE FRONTLINE OF MEDICAL RESEARCH].

INTRODUCTION: In this journal we collected original papers and review papers in translational medicine. Translational medicine is a bio-medical field of research that translates findings discovered in the laboratory to clinical life, for example: diagnostic methods, new cutting-edge medications, high-tech tools, and novel public health policy. This research combines different fields in science using new advanced technologies to improve medical care and wellbeing. The most significant impact was accomplished by the National Institutes of Health (NIH) twenty years ago, when a National Center for Translational Research was built. One of the achievements was the opening of a genetic research center that focused on RNA, circular RNAs and interference RNA. This research discovered the importance of these RNA particles in neurological and metabolic diseases, which were found to be applicable for treatment of these diseases. In this journal, original papers and reviews will express the diversity and the capabilities of this research field that has inspired so many physicians and researchers.

RV size may predict death in unstable patients with PE.

BACKGROUND: Pulmonary emboli (PE) is a life threatening condition that discovered in many patients only "post mortem". Sub massive and massive PE that led to hemodynamic collapse characterized by right ventricular (RV) dysfunction, leading to a higher risk of death. OBJECTIVES: To assess the ability to predict in hospital death of patients with acute PE, using a non-gated computed tomography pulmonary angiography (CTPA), based on the dimensions of the right ventricle. METHODS: A retrospective study that analyzed CTPA images of patients admitted with acute PE during the years 2012-2017. The cohort study included 300 patients with documented acute PE, among them 255 hospitalized in medical (non-intensive care unit) wards, 45 were hospitalized in an intensive care unit (ICU). RESULTS: Among the 45 patients admitted to the ICU 8% died. Larger RV diameters predicted mortality (OR = 10.14, 95% CI [1.09-93.86]) as well as lower systolic and diastolic blood pressure measurements (p = 0.001 and 0.01). Among the 255 patients admitted to the Internal Medicine Ward 7% died. Older age (p = 0.028), sepsis and cancer (both p < 0.001), high WBCs count (p < 0.001), and renal failure (p < 0.001) predicted death. Lower blood pressure (systolic and diastolic) (p < 0.001, 0.008), older age (p < 0.007), sepsis (p < 0.001), cancer (p = 0.006), higher WBCs count (p < 0.001), and impaired renal function (p < 0.001) predicted death in patients admitted with acute PE. CONCLUSIONS: Clinical parameters and hematological parameters could predict death of patients admitted with acute PE. RV diameter, measured by the non-ECG gated CTPA, had an additive predictive value for patients who admitted to the ICU.

Improvement in Endothelial Function in Men Taking Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction.

BACKGROUND: The purpose of this research was to explore the mechanistic protective cardiovascular effects of phosphodiesterase-5 inhibitors (PDE5-Is) in males with erectile dysfunction. Erectile dysfunction and endothelial dysfunction both precede clinical atherosclerosis. Studies have shown that treatment for erectile dysfunction with PDE5-Is decreased death, heart failure, myocardial infarction, and revascularization in males with erectile dysfunction who had previous myocardial infarction, and cardiovascular events. METHODS: This was a pilot study that recruited 5 men with erectile dysfunction without cardiovascular disease. Endothelial function (flow-mediated percent change of the diameter of the brachial artery), erectile dysfunction grade, high-sensitivity C-reactive protein, and body mass index were measured before and 3 months after starting treatment with tadalafil, 5 mg daily. Pearson's analysis was performed to study a correlation between the change in erectile dysfunction and the change in endothelial function. RESULTS: A significant correlation was found between changes in flow-mediated percent change of the diameter of the brachial artery and changes in erectile dysfunction following the administration of tadalafil (P = .010; Pearson correlation coefficient = 0.959). No change was observed in C-reactive protein or weight. CONCLUSIONS: Erectile dysfunction and endothelial dysfunction are risk factors for cardiovascular disease. Our study showed that PDE5-Is improved endothelial function and erectile dysfunction (with a significant correlation). Improving endothelial function could be the mechanism that leads to a reduction in cardiovascular events and death in men with erectile dysfunction treated with PDE5-Is.

The Effect of Metformin on Vitamin B12 Deficiency and Stroke.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a known risk factor for cardiovascular disease and stroke. Metformin is an old, relatively safe, first line therapy for T2DM; however, it has been associated with stroke. OBJECTIVES: To study the effects of metformin use and vitamin B12 deficiency on stroke rate among patients with T2DM. METHODS: We conducted a prospective study of patients admitted with ischemic stroke within 12 months (starting March 2020). We studied the clinical impact of metformin on vitamin B12 deficiency and stroke evolution. Student's t-test and ANOVA were used to compare the groups of patients and to determine whether there was any direct or indirect effect of metformin use on vitamin B12 deficiency and stroke. RESULTS: In total, 80 patients were admitted with ischemic stroke. Clinical status and biochemical data were collected and compared with healthy volunteers. There were 39 diabetic patients, 16 took metformin for at least 1 year. Among those who took metformin for at least 1 year, 9 had vitamin B12 level < 240 pg/ml (56.2%); 23 diabetic patients did not get metformin and only 4 had vitamin B12 level < 240 pg/ml (17.4%) (P = 0.014). CONCLUSIONS: T2DM is a significant risk factor to the development of ischemic stroke. We found an association between metformin use and vitamin B12 deficiency and an association between vitamin B12 deficiency and stroke risk in patients with T2DM. Diabetic patients who are taking metformin should monitor their vitamin B12 level.

On the anti-correlation between COVID-19 infection rate and natural UV light in the UK.

While it is well established that the rate of COVID-19 infections can be suppressed by social distancing, environmental effects may also affect it. We consider the hypothesis that natural Ultra-Violet (UV) light is reducing COVID-19 infections by enhancing human immunity through increasing levels of Vitamin-D and Nitric Oxide or by suppressing the virus itself. We focus on the United Kingdom (UK), by examining daily COVID-19 infections (F) and UV Index (UVI) data from 23 March 2020 to 10 March 2021. We find an intriguing empirical anti-correlation between log10(F) and log10(UVI) with a correlation coefficient of -0.934 from 11 May 2020 (when the first UK lockdown ended) to 10 March 2021. The anti-correlation may reflect causation with other factors which are correlated with the UVI. We advocate that UVI should be added as a parameter in modelling the pattern of COVID-19 infections and deaths. We started quantifying such correlations in other countries and regions.

Effect of Telemedicine Dietary Intervention for Endothelial Function in Patients with Type 2 Diabetes Mellitus on Mediterranean Diet.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have a high rate of cardiovascular disease (CVD). The Mediterranean diet is preferred for CVD prevention. Endothelial dysfunction is demonstrated early in T2DM. OBJECTIVES: To study the effects of dietary intervention of T2DM patients without known CVD on endothelial function and vascular inflammation. METHODS: A prospective study enrolled 22 patients with T2DM. Patients were divided randomly into two groups: an intervention group with 12 patients (55 ± 7 years old, 6 women) and a control group with 10 patients (59 ± 10 years old, 5 women). Clinical evaluation included body mass index (BMI) and endothelial function measured by the flow mediated percent change (FMD%). Fasting blood was drawn on entry to the study and 3 months later, measuring C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), total cholesterol, triglycerides, and glycosylated hemoglobin (HbA1C%). The intervention was based on weekly telephone calls by a clinical dietitian for 3 months. RESULTS: In the intervention group CRP and ICAM-1 were reduced (from 4.2 ± 3.3 mg/dl to 0.4 ± 0.5 mg/dl, P = 0.01 and from 258.6 ± 98.3 ng/ml to 171.6 ± 47.7 ng/ml, P = 0.004). Endothelial function (FMD%) was improved (from 0.5 ± 8.0% to 9.5 ± 11.5%, P = 0.014). No change was observed in BMI, HbA1C%, total cholesterol, and triglycerides levels in either group. CONCLUSIONS: Patients with T2DM on the Mediterranean diet who received a weekly telephone call for 3 months improved their endothelial function with reduction of markers of inflammation.

Platelets and Breast Cancer.

BACKGROUND: An association was shown between thrombocytosis and future development of several cancers. OBJECTIVES: To investigate whether pre-treatment platelet counts correlated with clinical outcomes of patients with breast cancer. METHODS: This retrospective study included 22 patients who had been diagnosed with stage I breast cancer and were 66.8 ± 13.2 years of age. Of these, 22 with stage II were 61.6 ± 12.3 years old and 9 with stage III and IV were 64.4 ± 15.3 years old. Clinical and hematological data from the first visit to the oncology clinic were collected. The follow-up period was 12 months to 5 years. RESULTS: A significant difference in platelet counts was found between patients who died (187,000 ± 4000 µ/L) and those who were disease free for 5 years (248,000 ± 83,000 µ/L, P = 0.0001). A significant difference in platelet-to-lymphocyte ratio was found between patients who died and those with recurrence (192 ± 81 vs. 124 ± 71, P = 0.01). A negative correlation was found between age and lymph nodes (Ps = -0.305, P = 0.02) and staging and white blood cells count (Ps = -0.280, P = 0.04). A positive correlation was found between clinical staging and lymph nodes (Ps = 0.443, P = 0.001) and clinical staging and metastases (P = 0.308, P = 0.02). CONCLUSIONS: Platelet counts may be a prognostic marker for breast cancer. Patients who died within 1 year had lower pre-treatment platelet count, which could represent an insidious disseminated intravascular coagulopathy cancer related consumption process.

Vascular Reactivity of Adult-Onset Systemic Lupus Erythematosus Patients.

BACKGROUND: Cardiovascular disease (CVD) is more frequent in patients with systemic lupus erythematosus (SLE) compared with age- and sex-matched healthy subjects. SLE is an autoimmune disease that is more prevalent in women (9:1). Women tend to develop CVD in post-menopausal years; however, women with SLE may develop endothelial dysfunction and CVD at a younger age in the pre-menopausal years. OBJECTIVES: To study the endothelial function of adult-onset SLE patients from the north of Israel (the Galilee region) and to determine whether modern management (including biological treatments) changes the risk of developing CVD. METHODS: Thirteen females with adult-onset SLE without renal involvement were recruited to this prospective study. Clinical parameters (age, height, body mass index [BMI]), laboratory parameters (C-reactive protein [CRP] and hemoglobin level), and vascular responsiveness (flow mediated diameter percent change [FMD%]) were evaluated and compared to 11 age-matched healthy females. Student's t-test was used to find differences between the two groups. RESULTS: No difference was observed in adult-onset SLE female patients and their age- and sex-matched controls with regard to age (42.1 ± 11.8 years vs. 36.6 ± 10.8 years, P = NS), BMI (25 ± 1.8 kg/m2 vs. 25 ± 2.5 kg/m2, P = NS), and hemoglobin level (11.9 ± 0.9 gr% vs. 12.7 ± 1.2 gr%, P = NS). However, a significant difference was found in CRP (2.57 ± 2.2 mg vs. 0.60 ± 0.37 mg, P = 0.001), vascular responsiveness (0.94 ± 6.6 FMD% vs. 9.2 ± 8.1 FMD%, P = 0.012), and height (165.7 ± 4.5 cm vs. 171.6 ± 5.8 cm, P = 0.009). CONCLUSIONS: Adult-onset SLE females had impaired endothelial function even though they were treated by modern protocols.

Effects of Preoperative WBC Count on Post-CABG Surgery Clinical Outcome.

OBJECTIVE: White blood cells (WBCs) play a major role in inflammation, with effects on the vascular wall, the microvascular blood flow, and endothelial cells and endothelial function. Previous studies have shown that a high WBC count may increase the risk of cardiovascular complication rate and mortality after coronary artery bypass graft (CABG) surgery. The aim of the study was to evaluate the association between preoperative WBC count and the post-CABG clinical outcome. METHODS: A retrospective study that was based on 239 patients who underwent CABG surgery in our medical center. Statistical analysis estimated the effect of WBC count in postoperative clinical outcomes, including atrial fibrillation, length of stay, readmission rate, and death. RESULTS: The preoperative WBC count was associated with longer hospitalization length (B = 0.392, P < 0.01). A preoperative WBC count >8150/µL predicted a longer stay (Z = 2.090, P = 0.03). A low lymphocyte count was associated with atrial fibrillation (B = -0.543, P = 0.03). Female patients were older (Z = 2.920, P < 0.01), had impaired renal function (Z = -3.340, P < 0.01), and had a higher rate of postoperative atrial fibrillation (df 2 = 3.780, P = 0.05) and readmission (df 2 = 5.320, P = 0.02). CONCLUSIONS: Preoperative WBC count may have an effect on the postoperative clinical outcome in patients undergoing CABG. Surgeons should pay more attention to patients' WBC count and sex and plan surgery and postoperative management accordingly.

Rheumatoid Arthritis and Atherosclerosis.

BACKGROUND: Inflammation is the basic mechanism leading to many pathological processes, including degenerative diseases, atherosclerosis, and cancer. We found an interesting link connecting rheumatoid arthritis and atherosclerosis that may explain the high cardiovascular event rate among patients with rheumatoid arthritis, but also may lead to a new way of thinking and a better understanding of atherosclerosis. Rheumatoid arthritis could serve as a model of accelerated atherosclerosis. Understanding the basic mechanisms of rheumatoid arthritis may solve some of the complexity of atherosclerosis.

MicroRNA-423 may regulate diabetic vasculopathy.

To test the hypothesis that microRNAs may play a role in diabetic retinopathy, we measured the levels of different markers [microRNAs, vascular endothelial growth factor (VEGF), nitric oxide (NO), and total antioxidant capacity (TAO)] in patients with type 2 diabetes mellitus (T2DM) and microvascular complications. Sixty-nine patients were recruited: 22 healthy subjects, ten T2DM patients without retinopathy, 22 with nonproliferative diabetic retinopathy, and 15 with proliferative diabetic retinopathy (PDR). Serum levels of NO, VEGF, TAO and 16 candidate microRNAs were measured. Additionally, the mRNA levels of endothelial nitric oxide synthase (eNOS), induced NOS (iNOS), C reactive protein (CRP), VEGF, tumor necrosis factor α (TNFα), PON2, p22, and SOD2 were measured in human vascular endothelial cells cultured in the presence of pooled sera from the subject groups. Plasma miR-423 levels showed a significant ~ twofold decrease in patients with PDR compared to controls. P lasma NO levels were significantly higher in retinopathy, VEGF levels were significantly lower, and TAO was significantly decreased. eNOS mRNA levels were lower in the cells of T2DM patients without retinopathy, but higher in PDR. PON2, p22, and SOD2 mRNA levels were all significantly lower in PDR. CRP, TNFα, iNOS, and VEGF mRNA levels showed no significant association with disease status. Lowered miR-423 levels in diabetic patients showed a correlation with VEGF and an inverse correlation between NO and eNOS expression. Our findings suggest a cross talk between miR-423 and VEGF signaling, affecting eNOS function. miR-423 may be involved in the regulation of diabetic vascular retinal proliferation.

Erectile Dysfunction, Sleep Disorders, and Endothelial Function.

BACKGROUND: Erectile dysfunction (ED) is a syndrome associated with endothelial dysfunction, which may predict cardiovascular events in men presenting with this syndrome. It has been shown to be associated with a higher rate of acute myocardial infarction and cardiovascular mortality, vascular inflammation, and impaired endothelial function. In this review we present the literature findings and describe the mechanistic pathways that are known to be involved in this syndrome and its related clinical consequences.

Rheumatoid arthritis (RA) and cardiovascular disease.

Patients with rheumatoid arthritis (RA) suffer cardiovascular events 1.5-2 fold than the general population, and cardiovascular (CV) events are leading cause of death in patients with RA. It is known that patients with RA have endothelial dysfunction, related with impaired function of endothelial progenitor cells (EPCs). The mechanistic pathways leading to endothelial function are complicated, but understanding these mechanisms may open new frontiers of management and therapies to patients suffering from atherosclerosis. Inflammation is a key factor in atherosclerosis, including endothelial function, plaque stabilization and post infarct remodeling; thus, inhibition of TNF-α may affect the inflammatory burden and plaque vulnerability leading to less cardiovascular events and myocardial infarctions. An aggressive management of inflammation may lead to a significant improvement in the clinical cardiovascular outcome of patients with RA. The clinical evidence that showed a reduced risk of CV events following treatment with anti-inflammatory agents may suggest a new approach to treat atherosclerosis, i.e., inhibition of inflammation using biological medications that were primarily aimed to treat the high scale inflammation of RA and other autoimmune-inflammatory diseases, but may be useful also to prevent progression of atherosclerosis.

Inhibition of endothelial Progenitor Cells Inhibition in the first 24 hours of an Acute Ischemic Cerebrovascular Event.

BACKGROUND: Endothelial progenitor cells may have a role in ongoing endothelial repair. Impaired mobilization or depletion of these cells may contribute to progression of vascular disease. Our hypothesis was that endothelial progenitor cells would be suppressed in patients with acute cerebrovascular event based on our previous study that found severe endothelial dysfunction in those patients. OBJECTIVES: To study the ability of patients with acute stroke to build colonies of endothelial progenitor cells. METHODS: We studied the number of colony-forming units of endothelial progenitor cells (CFU-EPCs) from the peripheral blood of 22 male patients with a first-time acute stroke (age 58.09 ± 9.8 years) and 13 healthy men (34 ± 6.7 years), 8 female patients with a first-time acute stroke (54.6 ± 10.3 years) and 6 healthy women (38.3 ± 11.6 years). Endothelium-dependent function was assessed by high-resolution ultrasonography of the brachial artery that measured the change in diameter of the artery by flow-mediated diameter percent change (FMD%). All patients had strokes demonstrated by a brain computed tomography (CT) scan done on admission. Peripheral blood was drawn soon after admission and was processed for endothelial progenitor cells in culture. RESULTS: Thirty patients without known cardiovascular risk factors and who did not take any medications were admitted with a first-time acute stroke. All demonstrated a strong correlation between CFU-EPCs grown in culture and endothelial dysfunction (r = 0.827, P < 0.01). Endothelial dysfunction with an FMD% of -2.2 ± 9.7% was noted in male patients vs. 17.5 ± 6.8% in healthy males (P = 0.0001), and -7.2 ± 10.1% in female patients vs. 25.1 ± 7.1% in healthy females (P = 0.0001). CFU-EPCs were 5.5 ± 6.3 in men with stroke vs. 23.75 ± 5.3 in healthy males (P = 0.0001), and 7.6 ± 4.9 in women with stroke vs. 22.25 ± 6.7 in healthy females (P = 0.0004).

Serum miR-122 levels correlate with diabetic retinopathy.

Diabetic retinopathy is the most severe ocular complication of diabetes and may lead to visual disability and blindness. Proliferative diabetic retinopathy (PDR) is characterized by ischemia-induced neovascularization with associated complications. An association was established between the presence of PDR, cardiovascular disease, and mortality among patients with type 1 diabetes mellitus and type 2 diabetes mellitus in epidemiological studies. However, the mechanism underlying increased cardiovascular risk in patients with PDR is still unknown. In recent years, a group of miRNAs has been linked to the pathology of diabetes mellitus. Besides, miRNAs in biofluids such as serum have been suggested as potential minimally invasive biomarkers of diabetes and vascular complications. This was a prospective study that recruited 40 human subjects: 10 healthy subjects, 10 with diabetes but without retinopathy (NDR), 10 with diabetic non-proliferative retinopathy (NPDR), and 10 with proliferative diabetic retinopathy (PDR). To examine whether serum miRNAs show altered levels at different stages of diabetic retinopathy, seven specific miRNA candidates (miR-126-3p, miR-130a-3p, miR-21-1, let-7f-5p, miR-122, miR-30c and miR-451a) were measured by qRT-PCR in RNA isolated from sera of all subjects. miR-122 levels increased in parallel with retinopathy severity: from healthy controls to NDR and from NDR to NPDR. However, when the disease progressed to PDR a marked decrease in miR-122 level was noted. This decrease was significant both compared to NPDR samples (p = 0.016) and to all non-PDR samples (p = 0.0002). Additionally, a positive trend was observed comparing miR-122 levels and the number of endothelial progenitor cells in the sera of all subjects. A significant increase in miR-122 was found in patients with diabetic retinopathy that may be related to its role in preventing angiogenesis and proliferation. The dramatic decline in patients with PDR may represent an inhibition or exhaustion of the anti-angiogenic anti-proliferative defense system. Further studies are needed to understand whether miRNA-122 has a role in the pathogenesis of diabetic retinopathy.

Association Between the Frank Sign and Cardiovascular Events.

Clinicians have attempted to find early preclinical physical diagnosis signs to detect vascular diseases at the preclinical stage and to prevent clinical deterioration in time. An interesting example of such signs is the Frank sign, which was first described by Dr Sonders T. Frank in 1973. Our goal was to summarize the clinical trials and observational studies that had examined the association between the Frank sign and cardiovascular diseases. Summarizing the 57 studies we found showed that this association could be used for early diagnosis of coronary and vascular diseases in the preclinical stage and that they were found in different populations around the world. Autopsy studies also found a strong association between the Frank sign and cardiovascular causes of death in both sexes. Cardiovascular causes of death included ischemic and hypertensive heart disease, calcific valvular stenosis, ruptured dissecting aneurysm of the thoracic aorta, and ruptured atheromatous aneurysm of the abdominal aorta. The Frank sign was correlated with increased intima-media thickness and stroke and was found in patients with peripheral vascular disease and with cardiovascular risk factors. The Frank sign could serve as a physical sign to help clinicians diagnose cardiovascular diseases.