Mitoresilience: Hormesis, Psycho-physical Resilience, Mitochondria and Heart Rate Variability as Relevant Interplaying Elements in Longevity Medicine.

Psycho-biological resilience is considered one of the most important factors in the epigenetics of aging. Cell senescence exhibits a series of possible biochemical derangements concerning mitochondria, proteasome, genome and membranes. Research has shown that resilience can be acquired through hormesis, a set of conservative and adaptive processes based on biphasic doseresponse to specific mild stressors, such as fasting, intake of polyphenols, exercising, physical and chemical stress and mental engagement. These stimuli were shown to elicit beneficial cellular metabolic pathways, such as sirtuin activation, mechanistic target of rapamycin and insulin growth factor- 1 downregulation, nuclear related factor 2 upregulation and autophagy. The complex of these resilience-building processes plays a documented role in longevity. Mitochondria are regarded as one of the core actors of aging processes and represent the main target of hormetic approaches [mitohormesis]; furthermore, the influence of the mind on mitochondria, and thus on the balance of health and disease has been recently established, leading to the so-called mitochondria psychobiology. Hence, psychologic and physical stress that reflects on these organelles may be regarded as a relevant factor in cell senescence, and thus the proposed "mitoresilience" denomination may be pertinent within the biomedical science of aging. Finally, the quantification of individual resilience is becoming increasingly important in aging science, and the investigation of the autonomic nervous system through heart rate variability (HRV) proved to be a valid method to quantify this parameter. In conclusion, an integrated approach targeting hormetic pathways to improve psychophysical resilience (namely mitoresilience), supported by the monitoring of HRV, may represent a valuable option in longevity medicine.

New Perspectives in Phlebology and Lymphology.

The recent research on chronic degenerative diseases (CDD), such as obesity, diabetes, neurodegeneration, atherosclerosis, autoimmune diseases, cancer and aging itself, has shown that Venous and Lymphatic Diseases (VLD) may play an important role in their development, de facto pushing phlebology and especially lymphology under a spotlight in biomedical research [...].

An Overview of Systematic Reviews of the Role of Vitamin D on Inflammation in Patients with Diabetes and the Potentiality of Its Application on Diabetic Patients with COVID-19.

Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.

Medicine and Phlebolymphology: Time to Change?

Biomedical science is undergoing a reappraisal of its scientific advancement process and of the related healthcare management. Progress in medicine should combine improvements of knowledge, efficacy, and safety of diagnostic/therapeutic procedures, with adequate cost-effectiveness profiles. This narrative review is aimed at assessing in medicine, more specifically in phlebology and lymphology: (a) scientific literature possible biases, (b) the level of evidence, comprehensiveness, and cost-effectiveness of the main therapeutic options, and (c) the possible contribution of integrative and translational medicine. Current medical research may have cognitive biases, or industry-tied influences, which impacts clinical practice. Some reductionism, with an increasing use of drugs and technology, often neglecting the understanding and care of the root causative pathways of the diseases, is affecting biomedical science as well. Aging brings a relevant burden of chronic degenerative diseases and disabilities, with relevant socio-economic repercussions; thus, a major attention to cost-effectiveness and appropriateness of healthcare is warranted. In this scenario, costly and innovative but relatively validated therapies may tend to be adopted in venous and lymphatic diseases, such as varicose veins, leg venous ulcer, post-thrombotic syndrome, pelvic congestion syndrome, and lymphedema. Conversely, a more comprehensive approach to the basic pathophysiology of chronic venous and lymphatic insufficiency and the inclusion of pharmacoeconomics analyses would benefit overall patients' management. Erroneous lifestyle and nutrition, together with chronic stress-induced syndromes, significantly influence chronic degenerative phlebo-lymphatic diseases. The main active epigenetic socio-biologic factors are obesity, dysfunctions of musculo-respiratory-vascular pumps, pro-inflammatory nutrition, hyperactivation of stress axis, and sedentarism. An overall critical view of the scientific evidence and innovations in phebolymphology could be of help to improve efficacy, safety, and sustainability of current practice. Translational and integrative medicine may contribute to a patient-centered approach. Conversely, reductionism, eminence/reimbursement-based decisional processes, patients' lack of education, industry-influenced science, and physician's improvable awareness, may compromise efficacy, safety, appropriateness, and cost-effectiveness of future diagnostic and therapeutic patterns of phlebology and lymphology.

COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review.

Coronavirus disease-19 (COVID-19) has been regarded as an infective-inflammatory disease, which affects mainly lungs. More recently, a multi-organ involvement has been highlighted, with different pathways of injury. A hemoglobinopathy, hypoxia and cell iron overload might have a possible additional role. Scientific literature has pointed out two potential pathophysiological mechanisms: i) severe acute respiratory syndrome-coronavirus-2 (SARS-CoV- 2) interaction with hemoglobin molecule, through CD147, CD26 and other receptors located on erythrocyte and/or blood cell precursors; ii) hepcidin-mimetic action of a viral spike protein, inducing ferroportin blockage. In this translational medicinebased narrative review, the following pathologic metabolic pathways, deriving from hemoglobin denaturation and iron metabolism dysregulation, are highlighted: i) decrease of functioning hemoglobin quote; ii) iron overload in cell/tissue (hyperferritinemia); iii) release of free toxic circulating heme; iv) hypoxemia and systemic hypoxia; v) reduction of nitric oxide; vi) coagulation activation; vii) ferroptosis with oxidative stress and lipoperoxidation; viii) mitochondrial degeneration and apoptosis. A few clinical syndromes may follow, such as pulmonary edema based on arterial vasoconstriction and altered alveolo-capillary barrier, sideroblastic-like anemia, endotheliitis, vasospastic acrosyndrome, and arterio- venous thromboembolism. We speculated that in COVID-19, beyond the classical pulmonary immune-inflammation view, the occurrence of an oxygen-deprived blood disease, with iron metabolism dysregulation, should be taken in consideration. A more comprehensive diagnostic/therapeutic approach to COVID-19 is proposed, including potential adjuvant interventions aimed at improving hemoglobin dysfunction, iron over-deposit and generalized hypoxic state.

A Polyphenol-Based Multicomponent Nutraceutical in Dysmetabolism and Oxidative Stress: Results from a Pilot Study.

To assess short-term efficacy and safety of a multicomponent nutraceutical (MCN) on dysmetabolism and oxidative stress, a pilot prospective observational study was performed on 21 individuals (12 men and 9 women) who took, for 60 days, 2 tablets per day of an MCN based on antioxidants and metabolism regulators: hydroxytyrosol (15 mg), maqui (300 mg), amla (200 mg), monacolin K (10 mg), berberine (245 mg), astaxanthin (0.5 mg), coenzyme Q10 (100 mg), and folic acid (200 mcg). On day 0 (T0) and day 60 (T60), all participants underwent laboratory tests related to lipid profile, carbohydrate metabolism, oxidative stress, and cellular inflammation. Statistical analysis was applied to the resulting data. A significant improvement of most atherogenesis and oxidative stress biomarkers was recorded (mean figure at T0 and T60, p value): total cholesterol 243.50/194.83 mg/dl, p =.0002; low-density lipoproteins 174.50/124.58 mg/dl, p =.0001; glycemia 96.25/88.50 mg/dl, p =.035; total free radicals 306.44/280.93 U.Carr., p =.036; serum antioxidant capacity 2103.00/2246.06 umol/l, p =.0042; oxidized cholesterol 680.33/597.25 uEq/l, p =.0511. Insulinemia, microalbuminuria, high-density lipoproteins, C-reactive protein, and triglycerides had no statistically significant variation. Body weight and systo-diastolic pressure showed no significant change from T0 to T60. No relevant side effects were reported. The investigated MCN (Eonlipid), based on polyphenols, significantly improved the oxidative stress parameters and decreased the majority of atherogenesis parameters at short term. No significant side effects were reported. Further placebo-controlled studies should possibly corroborate the promising results of this pilot study.

Catheter Foam Sclerotherapy of the Great Saphenous Vein, with Perisaphenous Tumescence Infiltration and Saphenous Irrigation.

OBJECTIVES: This was a prospective observational study to assess the short- to mid-term efficacy and safety of catheter foam sclerotherapy (CFS) of the great saphenous vein (GSV), including peri-saphenous tumescence infiltration (PST) and intra-saphenous saline irrigation (ISI), in combination with phlebectomy of the varicose tributaries. METHODS: Eighty-eight limbs in 82 patients (19 male, 63 female, mean age 55.7 years) affected by varices related to GSV incompetence were submitted to CFS of the refluxing GSV segment after PST and ISI, combined with phlebectomy of the varicose tributaries. Sodium tetradecylsulfate (STS) 3% + CO2/O2 sclerosant foam (SF) (median 7 mL) was injected in the GSV trunk (median caliber 7.1 mm) by means of a 4F catheter. Clinical and colour duplex ultrasound (CDU) investigation was performed pre-operatively, and 40 days, 6, 12, and 36 months post-operatively. A visual analogue scale (VAS) was used to assess procedure related symptoms and venous symptoms before and 40 days after the treatment. RESULTS: Clinical recurrence (visible varices) at 40 days, 6 and 12 months was 0%, whereas at 36 months it was 4.7%; VAS pre-operative score of heaviness, pain, and cramps/paraesthesiae decreased from 6 (IQR 6-8) to 1 (IQR 0-3), from 3 (IQR 0-7) to 0 (IQR 0-1), and from 3 (IQR 0-7) to 0 (IQR 0-1) respectively at 40 days. The CDU based occlusion rate at 40 days, 6, 12, and 36 months was 100% (88/88), 100% (88/88), 94.3% (83/88), and 89.4% (76/85) respectively. Six of the nine patent saphenous veins (average diameter 1.4 mm) had anterograde flow (overall 96.5% reflux free GSVs). One superficial venous thrombosis was recorded without any further relevant complication. CONCLUSIONS: GSV treatment by means of CFS and adjuvant PST + ISI, combined with phlebectomy of varicose tributaries, proved to be safe and effective in terms of clinical and duplex based outcomes at short/mid-term follow-up.

Sclerosing foam in the treatment of varicose veins and telangiectases: history and analysis of safety and complications.

OBJECTIVE: To review the use of sclerosing foam in the treatment of varicose veins, to describe the different techniques of foam preparation, and to report the complications of our 3-year experience with this treatment. METHOD: From November 1997 to the end of October 2000, 453 patients were treated with a sclerosing foam for large, medium, and minor varicosities with sodium tetradecylsulfate (STS) or polidocanol (POL). A first group of 257 patients (90 for minor varicosities and 167 for medium to large veins) received a sclerosing foam according to the Monfreux technique. From December 1999 to October 2000, 196 patients were treated with a sclerosing foam prepared according to Tessari's method (36 for minor size veins or teleangectasias and 170 for medium-large veins). Every patient was studied with (color-flow) duplex scanning before and after the treatment and large vein injections were administered under duplex guide. RESULTS: The immediate success rate was 88.1% in the first group for the medium-large veins. In the same districts we registered an early success rate in 93.3% for the patients treated with the Tessari's method. The complication rate (mostly minor complications) was 8.5% in the first group and 7.1% in the second group. CONCLUSION: The use of sclerosing foam may become an established therapy in the treatment of varicose veins with a high success rate, low cost, and low major complication rate. According to our actual experience and knowledge, the safe amount of foam should not exceed the 3-ml limit, but further advancements could come from standardization of the foam preparation technique.