Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes

Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet or synthesized endogenously. In addition to serving as an important source of energy, they produce a variety of both beneficial and detrimental effects. They play essential roles as structural components of all cell membranes and as signaling molecules regulating metabolic pathways through binding to nuclear or membrane receptors. However, under conditions of FFAs overload, they become toxic, inducing ROS production, ER stress, apoptosis and inflammation. SFAs (saturated fatty acids), unlike UFAs (unsaturated fatty acids), have recently been proposed as triggers of the NLRP3 inflammasome, a molecular platform mediating the processing of IL-1β in response to infection and stress conditions. Interestingly, UFAs, especially ω-3 FAs, inhibit NLRP3 inflammasome activation in various settings. We focus on emerging models of NLRP3 inflammasome activation with a special emphasis on the molecular mechanisms by which FFAs modulate the activation of this complex. Taking into consideration the current literature and FFA properties, we discuss the putative involvement of mitochondria and the role of cardiolipin, a mitochondrial phospholipid, proposed to be sensed by NLRP3 after release, exposure and/or oxidation. Finally, we review how this SFA-mediated NLRP3 inflammasome activation contributes to the development of both insulin resistance and deficiency associated with obesity/type 2 diabetes. In this context, we highlight the potential clinical use of ω-3 FAs as anti-inflammatory compounds.     

Arterial manifestations of Beh?et's disease. 12 cases

Out of 196 patients with Beh?et's disease, 12 (10 men and 2 women, mean age 34 +/- 7 years) had non-coronary arterial lesions. Beh?et's disease was complete in 4 patients. The arterial lesions had appeared 8.6 +/- 8 years on average (20 years at most) after the first sign of the disease. Three patients showed evidence of stenosis or occlusion involving one or several arteries. Eight patients had both stenotic and aneurysmal lesions. One patient had an arteriovenous fistula. Another developed a false aneurysm at the site of introduction of a femoral catheter. Yet another patient developed an anastomotic aneurysm one year after implantation of an abdominal aortic graft. In 2 cases histology showed fragmentation of the media associated with vasculitis of the vasa vasorum. Two patients with pulmonary aneurysm died of massive haemoptysis. In 2 patients combined corticosteroid and cyclophosphamide therapy failed to prevent the development of aneurysmal lesions. Phlebitis was associated with arterial involvement in 7 patients. Comparison between patients with or without arterial lesions showed no significant difference in time of onset of Beh?et's disease, sex, main clinical features and presence of HLA B5. Aneurysmal lesions respond poorly to medical treatment, and surgery is mandatory. Since recurrence at the site of anastomosis is possible, prolonged monitoring is required.     

Human parvovirus B19-induced vesiculopustular skin eruption

Erythema infectiosum, fifth disease, is a usually benign macular or maculopapular exanthem of childhood caused by the human parvovirus B19. A 27-year-old woman with a serologically documented human parvovirus infection who presented with a hemorrhagic exanthem and enanthem with areas of pustules and pseudo-pustules is described. The histologic findings were unusual because they combined the histologic features of morbilliform and vesiculopustular viral lesions. This case serves to underscore the occurrence of human parvovirus infection in adults. Further, it demonstrates the need to include parvovirus infection in the differential diagnosis of virally induced vesiculopustular skin eruptions.     

Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and receptors and are deleted in myeloid leukemias with a del(5q)

Interleukin-4 (IL-4) is a potent mediator of growth and differentiation of cells of several hematopoietic lineages. Interleukin-5 (IL-5) is a lineage-specific hematopoietic growth factor that stimulates the production of eosinophils and eosinophil colonies from normal human bone marrow cells. By using somatic cell hybrids and in situ chromosomal hybridization, we localized the IL-4 and IL-5 genes to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the IL-4 and IL-5 genes were found to be deleted in the 5q- chromosome of four patients with refractory anemia (RA) or therapy-related acute nonlymphocytic leukemia (t-ANLL), who had a del(5q). Thus a small segment of chromosome 5 contains IL-4, IL-5, IL- 3, and GM-CSF as well as other genes such as CD14 and EGR1. Our findings that each of these genes was deleted in the 5q- chromosome suggest that loss of function of one or more of these genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).     

Ultrastructural localization of human platelet thrombospondin, fibrinogen, fibronectin, and von Willebrand factor in frozen thin section

We have investigated the localization of thrombospondin (TSP), fibrinogen, fibronectin, and von Willebrand factor in human platelets by transmission electron microscopy of antibody-stained ultrathin frozen sections. In negatively stained thin sections, alpha granules were identified on the basis of their smooth, roughly spherical shape, size, single limiting electron-lucent 100 A membrane, and frequent presence of electron-dense nucleoid. In contrast, mitochondria exhibited characteristic double membranes and cristae. Sections were separately stained with affinity-purified polyclonal antibodies to these proteins as well as with three monoclonal anti-TSP antibodies. Antibody specificity was documented in radioimmunoassays, by immunofluorescent cross-blocking, and by staining of bands of appropriate mobility in Western blots of whole platelets. Bound antibody was visualized using a 5-nm colloidal gold-avidin conjugate. In resting cells, staining of virtually all alpha granules was observed for all four proteins. In contrast, consistent staining was absent from other organelles, including plasma membranes, mitochondria, and vacuolar structures that may represent the open canalicular system.     

Physician notification of their diabetes patients’ limited health literacy: A randomized,controlled trial

BACKGROUND: Many patients with chronic disease have limited health literacy (HL). Because physicians have difficulty identifying these patients, some experts recommend instituting screening programs in clinical settings. It is unclear if notifying physicians of patients' limited HL improves care processes or outcomes. OBJECTIVE: To determine whether notifying physicians of their patients' limited HL affects physician behavior, physician satisfaction, or patient self-efficacy. DESIGN: We screened all patients for limited HL and randomized physicians to be notified if their patients had limited HL skills. PARTICIPANTS: Sixty-three primary care physicians affiliated with a public hospital and 182 diabetic patients with limited HL. MEASUREMENTS: After their visit, physicians reported their management strategies, satisfaction, perceived effectiveness, and attitudes toward HL screening. We also assessed patients' self-efficacy, feelings regarding HL screening's usefulness, and glycemic control. RESULTS: Intervention physicians were more likely than control physicians to use management strategies recommended for patients with limited HL (OR 3.2, P=.04). However, intervention physicians felt less satisfied with their visits (81% vs 93%, P=.01) and marginally less effective (38% vs 53%, P=.10). Intervention and control patients' post-visit self-efficacy scores were similar (12.6 vs 12.9, P=.6). Sixty-four percent of intervention physicians and 96% of patients felt HL screening was useful. CONCLUSIONS: Physicians are responsive to receiving notification of their patients' limited HL, and patients support the potential utility of HL screening. However, instituting screening programs without specific training and/or system-wide support for physicians and patients is unlikely to be a powerful tool in improving diabetes outcomes.