Sulodexide counteracts endothelial dysfunction induced by metabolic or non-metabolic stresses through activation of the autophagic program.

OBJECTIVE: Endothelial dysfunction (ED) predisposes to venous thrombosis (VT) and post-thrombotic syndrome (PTS), a long-term VT-related complication. Sulodexide (SDX) is a highly purified glycosaminoglycan with antithrombotic, pro-fibrinolytic and anti-inflammatory activity used in the treatment of chronic venous disease (CVD), including patients with PTS. SDX has recently obtained clinical evidence in the "extension therapy" after initial-standard anticoagulant treatment for the secondary prevention of recurrent deep vein thrombosis (DVT). Herein, we investigated how SDX counteracts ED. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were used. Metabolic and non metabolic-induced ED was induced by treating with methylglyoxal (MGO) or irradiation (IR), respectively. Bafilomycin A1 was used to inhibit autophagy. The production of reactive oxygen species (ROS), tetrazolium bromide (MTT) assay for cell viability, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, Real-time PCR and Western blot analysis for gene and protein expression were used. RESULTS: SDX protected HUVEC from MGO- or IR-induced apoptosis by counteracting the activation of the intrinsic and extrinsic caspase cascades. The cytoprotective effects of SDX resulted from a reduction in a) ROS production, b) neo-synthesis and release of pro-inflammatory cytokines (TNFα, IL1, IL6, IL8), c) DNA damage induced by MGO or IR. These effects were reduced when autophagy was inhibited. CONCLUSIONS: Data herein collected indicate the ability of SDX to counteract ED induced by metabolic or non-metabolic stresses by involving the intracellular autophagy pathway. Our experience significantly increases the knowledge of the mechanisms of action of SDX against ED and supports the use of SDX in the treatment of CVD, PTS and in the secondary prevention of recurrent DVT.

Mast cell, pro-inflammatory and anti-inflammatory: Jekyll and Hyde, the story continues.

IL-1 family members include inflammatory and anti-inflammatory cytokines. They can be beneficial or detrimental, not only in cancer, but also in inflammatory conditions. Mast cells (MCs) originate from CD34+/CD117+/CD13+ pluripotent hematopoietic stem cells, express c-Kit receptor (c-Kit-R), which regulates the proliferation and sustain the survival, differentiation and maturation of MCs. They are immune cells involved in innate and adaptive immunity, allergy, autoimmunity, cancer and inflammation. MCs along with T cells and macrophages release interleukin (IL)-10, which is a pleiotropic immunoregulatory cytokine with multiple biological effects. IL-10 inhibits Th1 inflammatory cells, in particular TNF mostly generated by macrophages and MCs, and down-regulates IFN-γ, IL-1 and IL-6. IL-37 is a family member cytokine which binds IL-18 receptor α chain and inhibits inflammatory mediators including TNF, IL-1, IL-6, IL-33 and nitric oxide (NO). IL-37 similar to IL-10 inhibits MC inflammatory cytokines in several disorders, including asthma, allergy, arthrtitis and cancer. Here we report a study comparing IL-10 with IL-37, two anti-inflammatory cytokines.

Fibromyalgia and bipolar disorder: extent of comorbidity and therapeutic implications.

Fibromyalgia (FM) is a syndrome that affects muscles and soft tissues. Presenting symptoms include chronic muscle pain, fatigue, sleep problems and psychological symptoms, including depression and anxiety. There exists strong evidence of a comorbidity between FM and Bipolar Disorder (BD). In this study, papers from 2006 to February 2016 that examined the comorbidity and etiological similarities of FM and BD were reviewed, as well as the therapeutic implications of these findings. The reviewed articles showed that an adequate psychiatric screening for BD is recommended in FM patients with depressive symptoms, in order to decrease administration of antidepressants for BD, due to the lack of proven efficacy, and to limit antidepressant-induced mania. Alternative therapies, such as agomelatine, memantine and psychotherapic treatment should be considered.

IL-37 a New IL-1 Family Member Emerges as a Key Suppressor of Asthma Mediated by Mast Cells.

In 1986, we reported a multiple biological effect of IL-1 including immunological, inflammatory, and tumor killing activity. Since then other IL-1 family cytokines have been discovered, some with inflammatory and other with anti-inflammatory activity. In this review article, we speculate on the possible inhibitory effect of IL-37 in the light of new findings. IL-37, formerly termed IL-1 family member 7 (IL-1F7), binding IL-18 receptor α chain, acts as a cytokine with intracellular as well as extracellular functionality and as a natural inhibitor of immune responses and inflammation. IL-37 inhibits many pro-inflammatory cytokine and increases anti-inflammatory cytokines such as IL-10. Asthma pathogenesis involves multiple cell types including mast cells, which are important cellular constituents of the human innate and adaptive immunity. IL-37 has an impact on inflammatory cytokines generated by mast cells and is beneficial for and protective in asthma. However, the precise mechanism(s), safety, and tolerability of IL-37 are unclear and still remain a mystery. ABBREVIATIONS: GBP (Guanylate Binding Proteins); HMGB1 (High Mobility Group Box protein 1); NLRP (Nucleotide-like Receptor Pyrin domain 1); ASC (Apoptosis-associated Speck-like protein containing CARD, Caspase Recruitment Domain); FGF2 (Fibroblast Growth Factor 2).

ENOX2 (or tNOX): a new and old molecule with cancer activity involved in tumor prevention and therapy.

Cancer includes a number of related diseases due to abnormal cell proliferation that spreads to nearby tissues. Many compounds (physical, chemical and biological) have been used to try to halt this abnormal proliferation, but the therapeutic results are poor, due also to the side effects. It has been reported that ecto-nicotinamide adenine dinucleotide oxidase di-sulfide-thiol exchanger 2 (ENOX2), also known as tumor-associated nicotinamide adenine dinucleotide oxidase (tNOX), was found to be located on the cancer cell surface, essential for cancer cell growth. Capsaicin and other anti-oxidants are capable of inhibiting tNOX, causing apoptosis of cells, exerting anti-tumor activity. It is interesting that some authors reported that ENOX2 is present in the serum of cancer patients several years before the clinical symptoms of the tumor. However, this result has to be confirmed. In this article we discuss ENOX2 and its inhibition as a hope of improving cancer therapy.

Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment.

OBJECTIVE/BACKGROUND: Calf deep vein thrombosis (CDVT) is frequently found in symptomatic outpatients, but CDVT ultrasound diagnostic criteria are still debated. It has been proposed that only clots with ≥5 mm maximum diameter can be considered as CDVT. AIMS: To assess clot diameters and characteristics of CDVT, and to assess the recanalization rate of CDVT after anticoagulant treatment. METHODS: In a prospective, multicenter cohort study symptomatic outpatients in whom CDVT was diagnosed by ultrasound were enrolled. Posterior tibial, fibular, medial and lateral gastrocnemius, and soleal veins were compressed transversally over their entire length. Clot diameter was measured during maximum compression and ultrasound was repeated after 6 weeks of low molecular weight heparin treatment. RESULTS: In 172 patients (age 70 ± 1 y, male 32%) CDVT was detected in 132 (76.7%) muscle veins only, and in 24 (14%) axial veins only, while 16 (9.3%) patients had both muscular and axial CDVT. A total of 212 clots were found with a diameter of 5.8 ± 1.8 mm (IQR 4.5-6.8 mm) with the 10th percentile being ≥3.5 mm. A cut off value of ≥5 mm had a sensitivity of 0.76 (95% CI 0.69-0.82), whereas a value of ≥3.5 mm had a sensitivity of 0.94 (95% CI 0.89-0.97). Recanalization (i.e. residual vein obstruction ≤2 mm) was found in 51% of patients and the recanalization rate was not correlated with clot diameter at enrolment (rho -0.128 p = 0.93) or with type of CDVT (axial vs. muscular thrombosis). Patients with significantly reduced mobility had lower probability of CDVT recanalization. CONCLUSION: A clot diameter ≥5 mm is found in only 76% of CDVT patients and a clot diameter ≥3.5 mm may be more appropriate as a threshold for CDVT. After 6 weeks of anticoagulant treatment, half of CDVT patients had recanalization and recanalization was not correlated with clot characteristics at enrolment, but with mobility of the patients.

Endocrinology of the skin: intradermal neuroimmune network, a new frontier.

Endocrinology systems exert an important effect on vascular function and have direct actions on blood vessels. Estrogens provoke an increase in skin elasticity, epidermal hydration, skin thickness, reduce skin wrinkles and augment the content of collagen and the level of vascularisation. Therefore, there is an intricate cross-talk between skin conditions and stress. In stress, ß2--adrenoreceptor (ß2AR) pathway, cortisol, epinephrine and norepinephrine increase DNA damage and interfere with the regulation of the cell cycle, contributing to aging and skin diseases. Substance P is a neuropeptide released in the skin from the peripheral nerve and is related to stress and inflammation. SP provokes infiltration of inflammatory cells in the skin and induces a variety of cytokines/chemokines. Corticotropin-releasing hormone (CRH), produced by mast cells, is a neuropeptide also expressed in skin and responds to stress. CRH initiates diverse intracellular signaling pathways, including cAMP, protein kinase C, and mitogen-activated protein kinases (MAPK). Under stress, CRH, glucocorticoids, epinephrine and cytokines are generated. Moreover, the release of ACTH binds the receptor MC2-R and stimulates the generation of glucocorticoids such as corticosterone and cortisol, which interact with the transcription factors AP-1 and NF-kB. In skin keratinocytes, ACTH promotes the generation of pro-inflammatory cytokines, which enhances T-cell activity. Cortisol is immunosuppressive by inhibiting Th1 and Th2 cell response, antigen presentation, antibody and cytokine/chemokine production. However, glucocorticoids are certainly helpful in Th1-mediated autoimmune disorders. On the other hand, cytokines, such as TNF, IL-1 and IL-6, stimulate the generation of CRH and activate HPA axis in inflammatory states. Here, we describe for the first time a cross-talk between endocrinology and skin, including pro-inflammatory cytokines and neurogenic inflammatory pathways.

Efficacy of pulsed low-intensity electric neuromuscular stimulation in reducing pain and disability in patients with myofascial syndrome.

Myofascial pain syndrome (MPS) is characterized by chronic pain in multiple myofascial trigger points and fascial constrictions. In recent years, the scientific literature has recognized the need to include the patient with MPS in a multidimensional rehabilitation project. At the moment, the most widely recognized therapeutic methods for the treatment of myofascial syndrome include the stretch and spray pressure massage. Microcurrent electric neuromuscular stimulation was proposed in pain management for its effects on normalizing bioelectricity of cells and for its sub-sensory application. In this study, we tested the efficacy of low-intensity pulsed electric neuromuscular stimulus (PENS) on pain in patients with MPS of cervical spine muscles. We carried out a prospective-analytic longitudinal study at an outpatient clinic during two weeks. Forty subjects (mean age 42±13 years) were divided into two groups: treatment (TrGr, n=20) and control group (CtrlGr, n=20). Visual-analog scale (VAS) values, concerning the spontaneous and movement-related pain in the cervical-dorsal region at baseline (T0) and at the end of the study (T1), showed a reduction from 7 to 3.81 (p < 0.001) in TrGr. In the CtrlGr, VAS was reduced from 8.2 to 7.2 (n.s.). Moreover, the pressure pain threshold at T0 was 2.1 vs 4.2 at T1 (p < 0.001) in TrG. In the CtrlGR we observed no significant changes. Modulated low-intensity PENS is an innovative therapy permitting to act on the transmission of pain and on the restoration of tissue homeostasis. It seems to affect the transmission of pain through the stimulation of A-beta fibers. The above results show that low-intensity PENS can be considered as an effective treatment to reduce pain and disability in patients with MPS.

Is vitamin E an anti-allergic compound?

Vitamin E is found in eight forms in nature which include four tocopherols (alpha, beta, gamma and delta) and four tocotrianols (alpha, beta, gamma and delta). The classic effect of vitamin E is to reduce and prevent oxygen damage to the tissue and is useful for the treatment of pain, inflammation and allergic reactions. In addition to antioxidant activity, vitamin E also has a number of different and related functions. It protects against cancer, improves immune response, lowers the incidence of infectious diseases, cardiovascular diseases and is protective in allergy and asthma risk, and other disorders. Vitamin E increases n-6 polyunsaturated fatty acid (PUFA) and decreases n-3 PUFA, an effect that diminishes asthma and allergic diseases. Moreover, vitamin E regulates vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration through its oxidant and non-antioxidant effect. Furthermore, vitamin E modulates the endothelial function by altering VCAM-1-induced oxidative activation of endothelial cell PKCα. However, vitamin E is not consistently associated with asthma and/or allergy, and in some cases there are conflicting results on allergy and inflammatory diseases. The association of vitamin E and allergy appears to be very complex, and further study needs to clarify this dilemma.

Mast cell and cancer with special emphasis on il-37 an anti-inflammatory and inhibitor of innate immunity: new frontiers.

Mast cells (MCs) are mediators of allergy and inflammation and participate in the growth of cancer cells. MCs can promote both neoangiogenesis and tumor growth. They increase in the stroma of certain tumors where they can be recruited by tumor-derived chemoattractants, such as monocyte chemotactic protein-1 (MCP-1), RANTES and stem cell factor (SCF) to selectively secrete inflammatory molecules including chemical mediators and cytokines (TNF, IL-6 and IL-1). However, MC differentiation pathways and heterogeneity in cancer are still poorly understood. Human interleukin 1 (IL-1) plays a pivotal role in the pathogenesis of many diseases and functions, including host response to microbial invasion, injury inflammatory processes, immunologic challenges and cancer. Inflammation around the tumor includes the infiltration of mast cells and facilitates cancer growth. MCs are activated by IL-1 which can be produced by certain cancer cells and stimulate the stromal cells to selectively release IL-6, contributing to the development of Th-17 cells and increasing inflammation. IL-37, mainly generated by macrophage cell line, is an IL-1 family member which binds IL-18 receptor α (IL-18Rα) chain, and acts as a natural inhibitor of immune responses. IL-37 down-regulates cJun induced by IL-1, pro-inflammatory signals and reduces the expression of the mitogen-activated protein kinase (MAPK) p38α, STAT transcription factors and p53, affecting cellular differentiation and proliferation. In the present study we report the relationship between inflammatory mast cells, cancer and the beneficial effect of IL-37.

Lymphatic edema of the lower limbs after orthopedic surgery: results of a randomized, open-label clinical trial with a new extended-release preparation.

The lymphedema is a high interstitial protein concentration edema, caused by impaired lymphatic transport capacity. It can be primary or secondary. The secondary form may be caused by a lesion of the lymphatic vessels and/or lymph nodes during diagnostic or therapeutic procedures such as surgical interventions. Often, in clinical practice, there is lymphedema after orthopedic surgery, even in minor orthopedic surgery. Lymphedema, typically presents symptoms of swelling, pain, inflammation, and itching, and it can generate, over the years, acute disability in the affected limbs. The standard therapy is mainly represented by medical treatment, such as manual lymphatic drainage and compression with bandages and stockings. In literature it is documented that lymphedema is responsive to alpha and the gamma benzopyrones. The aim of this study was to determine the effectiveness of delayed extended-release formulation of a compound containing apha-benzo-pyrone (Coumarin), benzo-gamma-pyrone (Troxuretina) and oligomeric proanthocyanidins from Vitis vinifera (OPC), in addition to compression therapy, in the reduction of lymphatic edema after prosthetic hip and knee surgery. In the group treated, after 30 days, a reduction was observed of the edema of 4.8% in the ankle area (p less than 0.008) and 2.7% in the calf area (p less than 0.013). The control group showed no significant reduction. The treated group showed a marked reduction of all the secondary symptoms considered in the study, although variations were not significant. The results show that the compound used was effective in reducing edema after major orthopedic surgery, and consequently in alleviating some related symptoms, such as pain, itching, and burning. As an edema has extensive inflammatory components in patients with reduced mobility, the final data seems interesting, however, further investigations and a better follow-up are required.

Venous insufficiency and foot dysmorphism: effectiveness of visco-elastic rehabilitation systems on veno-muscle system of the foot and of the calf.

Chronic venous disease is very common and widespread. Chronic Venous Insufficiency (CVI) is a condition characterized by hypertension of the venous system of the lower limbs which manifests itself through a large range of symptoms. The main cause of CVI is hypertension of the venous system of lower limbs, which in most cases is due to reflux for the incontinence of the valvar system of veins. Other causes are related to obstruction of the venous outflow, or at a reduced venous emptying due to inefficiency of the system of the veno-muscular pumps of the calf and of the foot. The purpose of this study was to evaluate if the use of a non-invasive rehabilitative mode to improve the efficiency of the veno-muscular pumps of the foot and of the calf using photoplethysmography in reflected light. Fifty (50) patients suffering from flatfoot and ped cavus, were studied doing a stabilometric and baropodometric test to evaluate the angle of the foot and the podalic angle. Patients were evaluated by examining vascular examination and venous reography in basal condition, using corrective visco-elastic insoles for the correction of dysmorphisms that we were studying. An improvement of the angle of the Right and Left axis (p<0.05) and the podalic angle (p<0.001), using the right insole both in the flatfoot and cavus foot, was shown by the podobarographic examination. A not important tendency to improvement was also shown by the use of non-specific insole in both pathologies. The vascular examination showed an improvement of 38 percent in venous emptying capacity of the foot/calf veno-muscular pump in cavus foot with the specific B insole (p<0.002). An important improvement of 24 percent, using the specific A insole (p<0.05), was documented in flatfoot. The photoplethysmography examination documented a significant improvement of the venous emptying capacity of foot-calf veno-muscular system due to the use of specific insoles for the studied dysmorphism, with an improving tendency even with the use of non-specific insoles. The hemodynamic improvement is correlated with the improvement of the analyzed biomechanical parameters: contact time, lenght of the halfstep, podalic angle and angle of the foot. The partial normalization of biomechanical parameters allows a reorganization of relationships of forces between ground and foot, as well as the improvement of the function of the subtalar joint, causing a partial recovery of the complex physiological mechanism of activation of the veno-muscular pumps of the foot and of the calf.

Isolated distal deep vein thrombosis: efficacy and safety of a protocol of treatment. Treatment of Isolated Calf Thrombosis (TICT) Study.

AIM: The optimal treatment of isolated distal deep vein thrombosis (ID-DVT) is still controversial. A complete anticoagulation as soon as the diagnosis is made is recommended by some authors. Alternatively, other authors suggest to perform serial ultrasonography assessments to detect the possible extension of DVT towards proximal veins. Only in this case the treatment should be initiated. Furthermore, the optimal duration of treatment is far from established. The Treatment of Isolated Calf Thrombosis (TICT) study was set up to assess the efficacy and safety of a particular treatment regimen of ID-DVT based on low molecular weight heparins (LMWH). METHODS: The drug treatment consisted of a twice-daily subcutaneous administration of a full dose of weight-adjusted LMWH for one week, followed by a half dose of LMWH administered once-daily for another three weeks. At the end of the four-week period of treatment, a colour-coded Doppler ultrasonography (CCDU) assessment was scheduled and after three months a follow-up visit was performed. If a patient was unable to attend the visit, he was contacted by a phone-call to assess if any adverse events occurred. The study enrolled 192 outpatients with ID-DVT confirmed by CCDU. Twenty-one out of 192 patients (10.9%) were excluded for violation of protocol. Thus 171 (39.9% men, mean age of 60.45 years ) were eligible and were included in the study. Sixty-one patients (36.6%) presented an unprovoked ID-DVT. RESULTS: Events during the period of treatment (4 weeks). Ten out of 171 patients (5.8%) had complications: five patients showed an extension proximal to the knee (2.9%) all with an unprovoked ID-DVT; two showed an extension of thrombus within the distal veins. Three patients (1.7%) suffered from minor bleeding; there was no major bleeding. Further events during three months of observation occurred. Five patients had thrombus recurrences: four patients showed a proximal DVT (3 with a previous unprovoked ID-DVT, 1 with a previous ID-DVT secondary to a traumatic leg fracture, with persistent difficulty of deambulation); one, with a previous secondary thrombosis, showed a ID-DVT. CONCLUSIONS: In our study only 2.9% of patients with ID-DVT showed a progression of thrombosis to proximal deep veins; the majority of thrombus progression, during the treatment period, was observed in patients with unprovoked ID-DVT. Our results support the usefulness of a prolonged treatment in unprovoked ID-DVT.