Search

The RIETE Investigators., [Background] The optimal therapy of patients with acute subsegmental pulmonary embolism (PE) is controversial., [Methods] We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the rate of symptomatic PE recurrences during anticoagulation in patients with subsegmental, segmental, or more central PEs. [Results] Among 15 963 patients with a first episode of symptomatic PE, 834 (5.2%) had subsegmental PE, 3797 (24%) segmental, and 11 332 (71%) more central PE. Most patients in all subgroups received initial therapy with low‐molecular‐weight heparin, and then most switched to vitamin K antagonists. Median duration of therapy was 179, 185, and 204 days, respectively. During anticoagulation, 183 patients developed PE recurrences, 131 developed deep vein thrombosis (DVT), 543 bled, and 1718 died (fatal PE, 135). The rate of PE recurrences was twofold higher in patients with subsegmental PE than in those with segmental (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.16‐3.85) or more central PE (HR, 1.89; 95% CI, 1.12‐3.13). On multivariable analysis, patients with subsegmental PE had a higher risk for PE recurrences than those with central PE (adjusted HR, 1.75; 95% CI, 1.02‐3.03). After stratifying patients with subsegmental PE according to ultrasound imaging in the lower limbs, the rate of PE recurrences was similar in patients with DVT, in patients without DVT, and in those with no ultrasound imaging. [Conclusions] Our study reveals that the risk for PE recurrences in patients with segmental PE is not lower than in those with more central PE, thus suggesting that the risk of PE recurrences is not influenced by the anatomic location of PE.

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.

Essentials Recent randomized trials suggested fewer bleeding events in fragile patients with VTE receiving DOACs.The frequency, clinical characteristics and outcome of these patients have not been reported in real life.Fragile patients with VTE had a higher risk for major bleeding or death and a lower risk for recurrences than non‐fragile. Background Subgroup analyses from randomized trials suggested favorable results for the direct oral anticoagulants in fragile patients with venous thromboembolism (VTE). The frequency and natural history of fragile patients with VTE have not been studied yet. Objectives To compare the clinical characteristics, treatment and outcomes during the first 3 months of anticoagulation in fragile vs non‐fragile patients with VTE. Methods Retrospective study using consecutive patients enrolled in the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry. Fragile patients were defined as those having age ≥75 years, creatinine clearance (CrCl) levels ≤50 mL/min, and/or body weight ≤50 kg. Results From January 2013 to October 2016, 15 079 patients were recruited. Of these, 6260 (42%) were fragile: 37% were aged ≥75 years, 20% had CrCl levels ≤50 mL/min, and 3.6% weighed ≤50 kg. During the first 3 months of anticoagulant therapy, fragile patients had a lower risk of VTE recurrences (0.78% vs 1.4%; adjusted odds ratio [OR]: 0.52; 95% confidence intervals [CI]: 0.37‐0.74) and a higher risk of major bleeding (2.6% vs 1.4%; adjusted OR: 1.41; 95% CI: 1.10‐1.80), gastrointestinal bleeding (0.86% vs 0.35%; adjusted OR: 1.84; 95% CI: 1.16‐2.92), haematoma (0.51% vs 0.07%; adjusted OR: 5.05; 95% CI: 2.05‐12.4), all‐cause death (9.2% vs 3.5%; adjusted OR: 2.02; 95% CI: 1.75‐2.33), or fatal PE (0.85% vs 0.35%; adjusted OR: 1.77; 95% CI: 1.10‐2.85) than the non‐fragile. Conclusions In real life, 42% of VTE patients were fragile. During anticoagulation, they had fewer VTE recurrences and more major bleeding events than the non‐fragile.

Bacteria and their products, such as LPS, act on mast cells (MCs) to induce the secretion of multiple cytokines, including IL-1, TNF, IL-18 and IL-33, which can be dosed in the site of infected tissues. Antigen-binding IgE cross-links FceRI on mast cells involves the generation and activation of PKCδ, ERK, tyrosine kinases (Syk and Lyn) and mitogen-activated protein kinases (MAPKs), inducing the release of chemical mediators which provoke inflammation and hypersensitive reaction. Other stimuli, including, cytokines, neuropeptides, chemical and physical activators, can also act on MCs to release a plethora of inflammatory compounds. Activated MCs produce a broad spectrum of inflammatory cytokines, chemokines, lipid compounds and vasoactive amines, all involved in immune response. By producing TNF, MCs have an antibacterial defense and a protective function; while pathogenic bacteria and their products, such as LPS, have an inflammatory response through MC activation. LPS binding TLR4 produce MC generation IL-1 family members, and chemokines, which may recruit inflammatory cells at the infection site; whereas in KitW/W-v mice, where MCs are genetically absent, the inflammatory effect is not present. We report for the first time a link between MCs and bacteria emphasizing the mediation of inflammatory cytokines/chemokines. We can conclude that mast cells fight bacteria, and their immune response is perfectly integrated in the immune network. We hope that the understanding of microbial and mast cell interaction leads to more efficient therapeutic development in relation to microbial resistance.

BACKGROUND: Low-molecular-weight heparin (LMWH) is the treatment of choice in cancer patients with venous thromboembolism. However, data on continuing LMWH treatment beyond 6 months remain scanty. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to compare the rate of venous thromboembolism recurrences and major bleeding appearing beyond the first 6 months of anticoagulant therapy in cancer patients with venous thromboembolism, according to therapy with LMWH or vitamin K antagonists (VKA). We performed a propensity score-matched cohort study. RESULTS: After propensity matching, 482 cancer patients continued to receive LMWH and 482 switched to VKA. During the course of anticoagulant therapy (mean 275.5 days), 57 patients developed venous thrombosis recurrences (recurrent pulmonary embolism 26, recurrent deep vein thrombosis 29, both 2), 28 had major bleeding, 38 had nonmajor bleeding, and 129 died. No patient died of recurrent venous thrombosis, and 5 patients died of bleeding (2 were on LMWH, 3 on VKA). Patients who continued with LMWH had a similar rate of deep vein thrombosis recurrences (relative risk [RR] 1.41; 95% confidence interval [CI], 0.68-2.93), pulmonary embolism recurrences (RR 0.73; 95% CI, 0.34-1.58), major bleeding (RR 0.96; 95% CI, 0.51-1.79), or nonmajor bleeding (RR 1.15; 95% CI, 0.55-2.40), compared with those who switched to VKA, but a higher mortality rate (RR 1.58; 95% CI, 1.13-2.20). CONCLUSIONS: In cancer patients with venous thromboembolism who completed 6 months of LMWH therapy, switching to VKA was associated with a similar risk of venous thrombosis recurrences or bleeding when compared with patients who continued LMWH. (C) 2018 Elsevier Inc. All rights reserved.

Diabetes is a metabolic disorder characterized by hyperglycemia and associated with microvascular and macrovascular syndromes mediated by mast cells. Mast cells are activated through cross-linking of their surface high affinity receptors for IgE (FcRI) or other antigens, leading to degranulation and release of stored inflammatory mediators, and cytokines/chemokines without degranulation. Mast cells are implicated in innate and acquired immunity, inflammation and metabolic disorders such as diabetes. Histamine and tryptase genes in mast cells are overexpressed in pancreatic tissue of type 2 diabetes mellitus (T2DM) patients. Histamine is a classic inflammatory mediator generated by activated receptors of mast cells from the histamine-forming enzyme histidine decarboxylase (HDC), which can be activated by two inflammatory chemokines, RANTES and MPC1, when injected intramuscularly or intradermally in mice. This activation is inhibited in genetically mast cell-deficient W/Wv mice, which show higher insulin sensitivity and glucose tolerance. This study contributes to understanding the mechanism by which mast cells profoundly affect diabetes, and their manipulation could represent a new therapeutic strategy. However, further studies are needed to clarify the role of mast cells in inflammation and metabolic disorders such as diabetes.

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.

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.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).

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.

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, β2--adrenoreceptor (β2AR) 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.

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.

Calf deep vein thrombosis (CDVT) ultrasound diagnostic criteria are still debated. A clot >= 3.5 mm may be an appropriate threshold for CDVT diagnosis. Six week heparin treatment is associated with recanalization in half of patients with CDVT. 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 = 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. (C) 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.