Involvement of Stat1 in the phagocytosis of M. avium.

Mycobacterium avium is an intracellular pathogen preferentially infecting human macrophages where they activate the JAK/STAT1 pathway. This activation enhances the survival of infected cells, but, at the same time, makes macrophages optimal targets for drugs development against p-tyr(701)stat1. In this study, we demonstrate that the fast and transient activity of the JAK/STAT1 pathway occurs immediately after macrophages internalization of heat-killed M. avium or inert particles. Furthermore, we show that a persistent Stat1 pathway activation occurs only when an intracellular M. avium infection is established in macrophages. These results strongly indicate different mechanisms of p-tyr(701)Stat1 activation. In particular, here we report findings aiming at explaining the short-time enhancement of p-tyr(701)Stat1 and shows its predominant relationship with FcγRs engagement during the internalization process. Furthermore, we demonstrate that opsonized live M. avium is phagocytosed by macrophages involving membrane receptors not related with JAK/STAT1 signalling pathway. On the contrary, heat-inactivated bacilli or latex particles seem to be internalized only after involvement of FcγRs and subsequent Stat1 phosphorylation.

Microtopography of Immune Cells in Osteoporosis and Bone Lesions by Endocrine Disruptors.

Osteoporosis stems from an unbalance between bone mineral resorption and deposition. Among the numerous cellular players responsible for this unbalance bone marrow (BM) monocytes/macrophages, mast cells, T and B lymphocytes, and dendritic cells play a key role in regulating osteoclasts, osteoblasts, and their progenitor cells through interactions occurring in the context of the different bone compartments (cancellous and cortical). Therefore, the microtopography of immune cells inside trabecular and compact bone is expected to play a relevant role in setting initial sites of osteoporotic lesion. Indeed, in physiological conditions, each immune cell type preferentially occupies either endosteal, subendosteal, central, and/or perisinusoidal regions of the BM. However, in the presence of an activation, immune cells recirculate throughout these different microanatomical areas giving rise to a specific distribution. As a result, the trabeculae of the cancellous bone and endosteal free edge of the diaphyseal case emerge as the primary anatomical targets of their osteoporotic action. Immune cells may also transit from the BM to the depth of the compact bone, thanks to the efferent venous capillaries coursing in the Haversian and Volkmann canals. Consistently, the innermost parts of the osteons and the periosteum are later involved by their immunomodulatory action, becoming another site of mineral reabsorption in the course of an osteoporotic insult. The novelty of our updating is to highlight the microtopography of bone immune cells in the cancellous and cortical compartments in relation to the most consistent data on their action in bone remodeling, to offer a mechanist perspective useful to dissect their role in the osteoporotic process, including bone damage derived from the immunomodulatory effects of endocrine disrupting chemicals.

Angiogenesis, tumor necrosis factor-alpha and procoagulant factors in coronary artery giant aneurysm of a fatal infantile Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an infantile febrile illness of unknown origin characterized by clinical, laboratory and histopathologic features of systemic vasculitis. METHODS AND RESULTS: We report a 3-month-old female infant with incomplete KD who suddenly died despite intravenous immunoglobulin, aspirin, steroid and heparin treatment. Postmortem examination confirmed the echocardiographically detected giant coronary aneurysms and showed occlusive thrombosis in the giant aneurysm of the left anterior descending coronary artery, associated with neoangiogenesis, macrophage infiltration and immunostaining for tissue factor (a strong initiator of the coagulation cascade), thrombopoietin receptor and tumour necrosis factor-alpha. CONCLUSIONS: These findings show the association of angiogenesis, tumor necrosis factor-alpha and procoagulant factors, with macrophage infiltration in coronary artery aneurysms of a fatal infantile KD.

Papillary thyroid carcinoma presenting as a solitary soft tissue arm metastasis in an elderly hyperthyroid patient. Case report and review of the literature.

A case of papillary thyroid carcinoma (PTC) presenting as a solitary metastasis in the right arm muscle is described in an elderly hyperthyroid male patient. A 2-cm nodule in the right bycipites muscle was found to be a papillary carcinoma of thyroid origin and a primary, 3.5-cm tumor was subsequently found in the left lobe of a hyperfunctioning gland due to toxic goiter. Both tumors were well differentiated PTC, follicular variant. No high grade features, nor extrathyroidal spread, nor regional lymph node metastases were found, but histology evidenced intrathyroidal vascular invasion. After radical surgery and radioiodine therapy, the patient is currently disease-free 4 years after diagnosis. This is the third reported case of PTC manifesting as a single soft tissue metastasis and the first associated with hyperthyroidism. Hematogenous spread of differentiated PTC is rare, although less unusual in PTC follicular variant. Histological vascular invasion, hypervascularity and increased blood flow in the hyperfunctioning thyroid gland might have facilitated the dissemination of malignant tumor cells through the bloodstream. Literature data indicate that PTC in elderly patients is increasing and is often clinically aggressive. Radical surgical and radiometabolic treatments are required also in this age group to improve clinical outcome.

In vivo coronary plaque histology in patients with stable and acute coronary syndromes: relationships with hyperlipidemic status and statin treatment.

OBJECTIVES: Aim of the study was to investigate whether maintained moderate statin treatment influence atheroma, macrophage content, neoangiogenesis and/or haemorrhage in coronary plaques from patients with non-fatal coronary syndromes. METHODS: A total of 48 patients underwent elective directional coronary atherectomy on "de novo" culprit lesions; 16 patients had non-treated hypercholesterolemia, 16 patients received maintained moderate statin treatment for hypercholesterolemia and 16 had no lipoprotein abnormalities. These three patients groups were matched for age and clinical diagnosis of stable angina (SA) or unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI). Atherectomy specimens were stained with antibodies against macrophages, endothelial cells and glycophorin A. Results of histology and immunohistochemistry were morphometrically analyzed by using computer-assisted image analysis. RESULTS: Atheroma and fibrous tissue, neoangiogenesis, macrophage and haemorrhage (i.e., glycophorin A) differed between the three groups (P<0.05). Statin-treated group showed significantly decreased atheroma (P=0.016), fibrous tissue (P=0.42), macrophage content (P=0.012), neoangiogenesis (P=0.00048) and haemorrhage (P=0.0092) as compared with the non-treated hyperlipidemic group. CONCLUSIONS: The present findings show that maintained moderate statin treatment may contribute to plaque stabilization in non-fatal coronary syndromes by decreasing intraplaque neoangiogenesis and haemorrhage, lipid burden and macrophage content, and, on the other hand, by increasing plaque collagenization.

Pharmacokinetic and antiretroviral activity in mice of oral [P(1),P(2)-bis[2-(adenin-9-yl)ethoxymethyl]phosphonate], a prodrug of 9-(2-phosphonylmethoxyethyl)adenine.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is an antiviral drug with activity against herpes viruses, Epstein-Barr virus and retroviruses, including the human immunodeficiency virus. Unfortunately, oral PMEA administration, as required for long-term therapy, is hindered by its low bioavailability. In the present study, the synthesis, oral bioavailability and antiretroviral activity of a new prodrug of PMEA, consisting of two molecules of PMEA bound together by a P-O-P bond (Bis-PMEA), are reported. Pharmacokinetic experiments in mice showed that the oral bioavailabilities of PMEA following oral gavage of Bis-PMEA or PMEA (at a dose equivalent to 28 mg of PMEA/kg) were 50.8 and 13.5%, respectively. These results correlate with the antiviral efficacy of Bis-PMEA administered orally at a dose equivalent to 50 mg/kg of PMEA in C57 BL/6 mice infected with the retroviral complex LP-BM5. Oral treatment with Bis-PMEA proved to be more effective than oral treatment with PMEA given at equimolar doses. Moreover, oral Bis-PMEA was more effective than intraperitoneal PMEA (50 mg/kg) in reducing lymphoadenopathy, hypergammaglobulinaemia and lymph node proviral DNA content, overall in the first weeks post virus inoculation. Bis-PMEA thus appears to be an efficient oral prodrug of PMEA without significant toxicity, at least in this mouse model.