The replication of human immunodeficiency virus type 1 in macrophages is enhanced after phagocytosis of apoptotic cells

Clearance of apoptotic cells increases macrophage secretion of antiinflammatory mediators and might modulate viral replication in human immunodeficiency virus (HIV) type 1-infected macrophages. To study this, primary macrophages were infected with HIV-1 and exposed to apoptotic cells. It was found that phagocytosis of apoptotic cells potently enhanced HIV-1 growth. The peptide Arg-Gly-Asp-Ser, which binds to integrin receptors, inhibited the uptake of apoptotic cells and the subsequent enhancement of HIV-1 replication. Viral replication was preceded by increased secretion of transforming growth factor (TGF)-beta1 and partially reverted by anti-TGF-beta1 antibodies. Moreover, anti-TGF-beta1 antibodies inhibited HIV-1 replication in macrophages not exposed to apoptotic cells. A positive correlation was observed between TGF-beta1 production and HIV-1 growth, and the addition of TGF-beta1 amplified HIV-1 replication in macrophages from low TGF-beta1 producers. The findings suggest that TGF-beta1 favors HIV-1 replication in macrophages and that the clearance of apoptotic cells by HIV-1-infected macrophages contributes to persistent viremia in patients infected with HIV-1.     

Biological and clinical features of acute lymphoblastic leukaemia with cytoplasmic granules or inclusions: description of eight cases

We describe eight patients (four children and four adults) with an acute lymphoblastic leukaemia (ALL) with cytoplasmic granules or inclusions. The incidence of this variant of acute leukaemia in our whole series of patients with ALL is 1.8%. The granules or inclusions were usually positive for aspecific esterases (ANAE) and/or acid phosphatase, and the immunophenotype was in all cases typical of a CALLA positive B-lineage ALL (CD10+, CD19+ and/or CD24+, DR+, TdT+, anti-T-, anti-My-, SIg-). In one paediatric case, CD33 was unusually coexpressed. Ultrastructural investigations were performed in one case and demonstrated large granules containing vesicles, usually membrane bound, in the majority of blast cells. In the two cases analysed, Ig heavy chain gene rearrangement was detected. In this series of patients prognosis was poor since three never achieved a complete remission, four relapsed and only one is still in first continuous remission.     

DARC (Duffy) and BCAM (Lutheran) reduced expression in thyroid cancer

Duffy or DARC (Duffy Antigen Receptor for Chemokines) is a glycosylated membrane protein that selectively binds angiogenic chemokines. Previous in vivo and in vitro studies of DARC function in cancer have associated DARC over expression with better prognosis, decreased metastatic potential, and inhibition of tumor-associated neovascularization. Another carcinogenesis-associated antigen is Lutheran or BCAM (basal cell adhesion molecule), a surface glycoprotein that acts as a receptor for the extracellular matrix protein, laminin. BCAM is a protein related to tumor progression; and, its over expression is associated with skin, ovarian and pancreatic cancers. We explored DARC and BCAM functions and investigated whether or not their expressions were altered in thyroid cancer. The expression of DARC and BCAM were evaluated by quantitative real-time PCR (qPCR) in a set of 18 normal thyroid tissues (NT), 15 follicular adenomas (FTA), 17 follicular carcinomas (FTC), and 122 papillary thyroid carcinomas (PTC), including 78 classical (CVPTC) and 44 follicular variant (FVPTC). RNA was isolated, reverse transcribed to cDNA, and used in qPCR reactions containing SYBR Green. The relative expression value was calculated using ribosomal protein S8 as an internal control. When we compared benign (NT and FTA) versus malignant samples (FTC, CVPTC and FVPTC) we observed a significant decrease of DARC and BCAM relative expression in malignant cases. Additionally, we correlated clinic-pathological features (tumor size, presence of metastasis, presence of lymphocyte infiltrate) with DARC and BCAM expression. We found a diminished expression of DARC in PTC samples, which was correlated with tumor size and presence of a lymphocyte infiltrate. We, also, found a correlation between decreased BCAM expression and tumor size or presence of metastasis. DARC and BCAM expression was associated with pathogenesis of thyroid carcinoma and correlated with clinical–pathological features.     

Effects of mitochondrial ferritin overexpression in normal and sideroblastic erythroid progenitors

In myelodysplastic syndromes with ring sideroblasts (MDS‐RS), the iron deposited in the mitochondria of RS is present in the form of mitochondrial ferritin (FTMT), but it is unknown whether FTMT overexpression is the cause or the result of mitochondrial iron deposition. Lentivirus FTMT‐transduced CD34⁺ bone marrow cells from seven healthy donors and CD34⁺ cells from 24 patients with MDS‐RS were cultured according to a procedure that allowed the expansion of high numbers of erythroid progenitors. These cells were used to investigate the possible influence of experimentally‐induced FTMT overexpression on normal erythropoiesis and the functional effects of FTMT in sideroblastic erythropoiesis. In MDS‐RS progenitors, FTMT overexpression was associated with reduced cytosolic ferritin levels, increased surface transferrin receptor expression and reduced cell proliferation; FTMT effects were independent of SF3B1 mutation status. Similarly, FTMT overexpressing normal erythroid progenitors were characterized by reduced cytosolic ferritin content and increased CD71 expression, and also by higher apoptotic rate in comparison with the FTMT‐ controls. Significantly lower levels of STAT5 phosphorylation following erythropoietin stimulation were found in both sideroblastic and normal FTMT⁺ erythroid cells compared to the FTMT‐ cells. In conclusion, experimental overexpression of FTMT may modify mitochondrial iron availability and lead to ineffective erythropoiesis.     

Factors Affecting the Strength of Denture Repairs

Fracture of dentures is a common clinical finding in daily prosthodontic practice, resulting in great inconvenience to both patient and dentist. A satisfactory repair should be cost-effective, simple to perform, and quick; it should also match the original color and not cause distortion to the existing denture. Different repair materials, surface designs, and mechanical and chemical surface treatments have been recommended in order to obtain stronger repairs. This article reviews some of the available literature with regard to the most important factors that may influence the strength of denture repairs.     

Glucocorticoid resistance in dialysis patients may impair the kidney allograft outcome.

This study examines in vitro steroid sensitivity in chronic renal failure (CRF) patients and its influence on the allograft outcome. We determined the inhibitory effect of dexamethasone (DEX) on concanavalin A (Con-A)-stimulated peripheral blood mononuclear cell (PBMC) proliferation, and glucocorticoid receptor' (GR) number of binding sites (B(max)) and affinity (K(d)) in 28 CRF patients and 40 normal healthy controls. Based on K(d) values >95th percentile from controls, patients were divided into two groups: glucocorticoid resistant (n = 11) and glucocorticoid sensitive (n = 17). Patients were followed during 18 months post-transplantation observing acute rejection episodes (ARE), chronic allograft nephropathy (CAN), allograft failure and death. The DEX concentration that caused 50% inhibition of Con-A-stimulated PBMC proliferation (IC(50)) was higher in CRF than in healthy controls (2.2 x 10(-5) +/- 1.0 x 10(-5) versus 8.3 x 10(-6) +/- 4.2 x 10(-6) mol/L, P = 0.02). Values of K(d) (12.4 +/- 1.8 versus 7.2 +/- 0.9 nM) and B(max) (7.7 +/- 1.1 versus 4.1 +/- 0.3 fmol/mg protein) were higher in CRF patients (P = 0.02 and P = 0.001, respectively). There were higher incidences of ARE (P = 0.02) and CAN (P = 0.002) in the glucocorticoid-resistant group. Univariate and multivariate logistic regression showed that K(d) was an independent predictor of ARE (OR 8.8, P = 0.03) as well as of CAN (OR 16.5, P = 0.01). In conclusion, we observed glucocorticoid resistance in a subgroup of CRF patients undergoing dialysis, which led to a higher morbidity due to ARE and CAN in an 18-month follow-up period.     

Is haemodynamic depression during carotid stenting a predictor of peri-procedural complications?

OBJECTIVE: The clinical significance of Haemodynamic Depression (HD) during carotid stenting (CAS) remains unclear. The aim of this study was to analyze the frequency and predictors of HD during CAS in a single centre experience. METHODS: A prospective protocol for CAS was applied in a 15-month interval. Patients with restenosis, on betablockers, or with arrhythmias were excluded. A standardized dose of atropine (0.4mg) was given prior to stent deployment. Changes in heart rate, blood pressure, and neurological status were monitored and recorded. HD was defined as systolic pressure <90mmHg and/or heart rate <50 beats/min. Fifteen potential predictors of HD (age, gender, hypertension, smoking, diabetes, coronary artery disease, previous myocardial infarction, symptoms, degree of carotid stenosis contralateral CEA or CAS, calcified/hyperechoic plaque, plaque length, stent oversizing and type of stent) were tested in multivariate analysis. RESULTS: Two hundred and twenty three consecutive patients were enrolled. HD occurred in 98 cases (44%): in 68 cases HD required additional pharmacological support. At 30 days, any stroke rate was 3.1% (3 major and 4 minor), TIA rate 1.8%, myocardial infarction rate 0.4%. No deaths were recorded. No difference in complication rates were found in patients with or without HD. From regression analysis only the presence of calcified plaque (HR 9.5; 95% CI 5.0 to 18.2; p<0.0001) and the plaque length (HR 1.77; 95% CI 1.03 to 3.06; p=0.038) were associated significantly with HD. CONCLUSIONS: HD during CAS is a common, relatively benign event, without increased risk of peri-operative complications. Careful pharmacological treatment is necessary to decrease HD and the potential complications, especially in patients with more severe calcified lesions. These results require confirmation in a separate, larger cohort.     

Metabolic genotypes as modulators of asbestos-related pleural malignant mesothelioma risk: a comparison of Finnish and Italian populations

The role of CYP1A1, GSTM1, GSTT1, EPHX1, and NAT2 genotypes in susceptibility to malignant mesothelioma (MM) was compared in two case-control studies, previously conducted in two countries where different types of asbestos fibers have been used [Hirvonen et al., 1995. Inherited GSTM1 and NAT2 defects as concurrent risk modifiers in asbestos-related human malignant mesothelioma. Cancer Res. 55, 2981-2983; Hirvonen et al., 1996. Glutathione S-Transferase and N-Acetyltransferase genotypes and asbestos-associated pulmonary disorders. J. Natl. Cancer Inst.88, 1853-1856; Neri et al., 2005. Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure. Mutat. Res. 592, 36-44]. Fifty-seven asbestos-exposed MM patients and 255 controls were recruited in Italy, 48 cases and 121 controls in Finland. In order to make the two studies comparable, they have been updated and new genotyping analyses have been performed. The NAT2 fast acetylator and EPHX1 low-activity genotypes were positively associated with MM in the Italian study, while they were negatively associated with this malignancy in the Finnish one. A combined significant effect was also observed in the Italian study for the NAT2 fast acetylator and EPHX1 low-activity genotypes, while this combination was protective in the Finnish study. Combination of NAT2 fast acetylator and GSTM1 null genotype posed a significantly increased risk of MM in the Italian, but not in the Finnish study. The opposite results obtained in Finland and Italy may be ascribed to random chance, but a role may be hypothesized for the fact that different types of asbestos have been used in the two countries.