SV-IV Peptide1–16 reduces coagulant power in normal Factor V and Factor V Leiden

Background

Alefacept (anti-CD2) biological therapy selectively targets effector memory T cells (Tem) in psoriasis vulgaris, a model Type 1 autoimmune disease.

Methods

Circulating leukocytes were phenotyped in patients receiving alefacept for moderate to severe psoriasis.

Results

In all patients, this treatment caused a preferential decrease in effector memory T cells (CCR7^- CD45RA^-) (mean 63% reduction) for both CD4⁺ and CD8⁺ Tem, while central memory T cells (Tcm) (CCR7⁺CD45RA^-) were less affected, and naïve T cells (CCR7⁺CD45RA⁺) were relatively spared. Circulating CD8⁺ effector T cells and Type 1 T cells (IFN-γ-producing) were also significantly reduced.

Conclusion

Alefacept causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis.     

Anti-GOR in hepatitis D: specific association with hepatitis C virus superinfection

Summary A group of 113 patients with chronic hepatitis D was investigated for the presence of anti-GOR and liver kidney microsomal antibodies. Eight patients were anti-GOR positive and also positive for hepatitis C virus-infection. In sera from 16 patients liver-kidney microsomal antibodies were detectable by immunofluorescence. They were classified as LKM-3 due to their fluorescence pattern. Two of the LKM-3-positive sera were also anti-hepatitis C virus and anti-human immunodeficiency virus positive. None of these patients were positive for anti-GOR. Fourteen sera from LKM-3-positive patients reacted in Western blot with a microsomal protein at 55 kDa that differs from the 50-kDa LKM-1 (cytochrome P450IID6) antigen. Our studies demonstrate that hepatitis D virus itself does not induce an autoimmune reaction against the GOR antigen and that autoimmunity to the LKM-3 antigen induced by hepatitis D virus infection does not correlated with anti-GOR. These studies support the specificity of the anti-GOR response for hepatitis C virus infection.     

Construction, training and clinical validation of an interpretation system for genotypic HIV-1 drug resistance based on fuzzy rules revised by virological outcomes

OBJECTIVES: To evaluate whether fuzzy operators can be usefully applied to the interpretation of genotypic HIV-1 drug resistance by experts, and to improve the prediction of salvage therapy outcome by adapting interpretation rules of genotypic resistance on the basis of their association with virological response data. METHODS: We used a clinical dataset of 231 patients failing highly active antiretroviral therapy (HAART) and starting salvage therapy with baseline resistance genotyping and virological outcomes after 3 and 6 months. A set of rules predicting genotypic resistance was initially derived from an expert (ADL). Rules were implemented using a fuzzy logic approach and the virological outcomes dataset used for the training phase. The resulting algorithm was validated using a separate set of 184 selected patients by correlating the resulting predicted activity with observed virological response at 3 months. For comparison, the expert systems from the drug resistance group of the Agence Nationale de Recherches sur le SIDA (ANRS-AC11) and the algorithm from the Stanford's HIV drug resistance database (Stanford HIVdb) were evaluated on the same set. RESULTS: The starting algorithm had a correlation with virological outcomes of R2=0.06 (P=0.0001). After the training phase the correlation with virological outcomes increased to R2=0.19 (P<0.000001). In the validation set of patients, the activity of the salvage regimen predicted by the fuzzy algorithm was the only variable independently predictive of the 3-month viral load change even after adjusting by the activity predicted by the two expert systems and baseline viral load (for each 10% salvage regimen's activity increase, mean HIV RNA change from baseline: -0.27 log10 copies/ml; 95% CI -0.39, -0.15). CONCLUSION: Using fuzzy operators in a virological outcomes training database to implement a rules-based algorithm for genotypic resistance interpretation, significant improvements of outcomes prediction were obtained. The resulting algorithm showed an independent predictive capability of virological outcomes over that of two rules-based interpretation algorithms made by experts. Although the system was trained and validated on a limited number of cases, the approach deserves further evaluation.     

Treatment of a pituitary metastasis from a neuroendocrine tumour: case report and literature review

Herein we report a rare case of a pituitary metastasis from a neuroendocrine tumour mimicking an adenoma. Moreover, starting from this unusual case, the relevant literature concerning the diagnosis and management of patients with metastasis at pituitary level is reviewed. A 69-year-old woman was admitted to our Unit for severe headache, diplopia, and critical visual field impairment. MRI showed a large pituitary mass compressing the optic chiasm and infiltrating the cavernous sinus. Trans-sphenoidal biopsy revealed a pituitary metastasis from a neuroendocrine tumour, in line with the multiple liver lesions that were already considered metastases from an ileal primary neuroendocrine tumour. In vitro receptor characterisation of both pituitary and liver tissues by immunohistochemistry showed a heterogeneous somatostatin receptor subtype pattern, with a predominant expression of sst₂ within the pituitary lesion. However, the liver metastasis receptor profile was completely different from the pituitary. Octreotide LAR was administered first, followed by receptor radiometabolic therapy with radiolabelled somatostatin analogues (⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE). After 16 months, MRI showed a significant shrinkage of the sellar mass. Moreover, disappearance of diplopia and visual defects, together with a considerable improvement in quality of life were gradually recorded. To our knowledge, this is the first case of combined treatment using “cold” and radiolabelled octreotide in a pituitary metastasis from a neuroendocrine tumour. Umberto Goglia and Diego Ferone contributed equally.     

Anti-proliferative and pro-apoptotic activities of hydroxytyrosol on different tumour cells: the role of extracellular production of hydrogen peroxide

Purpose

Several recently published data suggest that the anti-proliferative and pro-apoptotic properties of hydroxytyrosol [3,4-dihydroxyphenyl ethanol (3,4-DHPEA)] on HL60 cells may be mediated by the accumulation of hydrogen peroxide (H₂O₂) in the culture medium. The aim of this study was to clarify the role played by H₂O₂ in the chemopreventive activities of 3,4-DHPEA on breast (MDA and MCF-7), prostate (LNCap and PC3) and colon (SW480 and HCT116) cancer cell lines and to investigate the effects of cell culture medium components and the possible mechanisms at the basis of the H₂O₂-producing properties of 3,4-DHPEA.

Methods

The proliferation was measured by the MTT assay and the apoptosis by both fluorescence microscopy and flow cytometry. The concentration of H₂O₂ in the culture medium was measured by the ferrous ion oxidation–xylenol orange method.

Results

It was found that the H₂O₂-inducing ability of 3,4-DHPEA is completely prevented by pyruvate and that the exposure of cells to conditions not supporting the H₂O₂ accumulation (addition of either catalase or pyruvate to the culture medium) inhibited the anti-proliferative effect of 3,4-DHPEA. Accordingly, the sensitivity of the different cell lines to the anti-proliferative effect of 3,4-DHPEA was inversely correlated with their ability to remove H₂O₂ from the culture medium. With regard to the mechanism by which 3,4-DHPEA causes the H₂O₂ accumulation, it was found that superoxide dismutase increased the H₂O₂ production while tyrosinase, slightly acidic pH (6,8) and absence of oxygen (O₂) completely prevented this activity. In addition, different transition metal-chelating compounds did not modify the H₂O₂-producing activity of 3,4-DHPEA.

Conclusions

The pro-oxidant activity of 3,4-DHPEA deeply influences its ‘in vitro’ chemopreventive activities. The main initiation step in the H₂O₂-producing activity is the auto-oxidation of 3,4-DHPEA by O₂ with the formation of the semiquinone, superoxide ions (O₂ ^?) and 2H⁺.     

Presepsin (soluble CD14 subtype) and procalcitonin levels for mortality prediction in sepsis: data from the Albumin Italian Outcome Sepsis trial

Introduction

Sepsis, a leading cause of death in critically ill patients, is the result of complex interactions between the infecting microorganisms and the host responses that influence clinical outcomes. We evaluated the prognostic value of presepsin (sCD14-ST), a novel biomarker of bacterial infection, and compared it with procalcitonin (PCT).

Methods

This is a retrospective, case–control study of a multicenter, randomized clinical trial enrolling patients with severe sepsis or septic shock in ICUs in Italy. We selected 50 survivors and 50 non-survivors at ICU discharge, matched for age, sex and time from sepsis diagnosis to enrollment. Plasma samples were collected 1, 2 and 7 days after enrollment to assay presepsin and PCT. Outcome was assessed 28 and 90 days after enrollment.

Results

Early presepsin (day 1) was higher in decedents (2,269 pg/ml, median (Q1 to Q3), 1,171 to 4,300 pg/ml) than in survivors (1,184 pg/ml (median, 875 to 2,113); P = 0.002), whereas PCT was not different (18.5 μg/L (median 3.4 to 45.2) and 10.8 μg/L (2.7 to 41.9); P = 0.31). The evolution of presepsin levels over time was significantly different in survivors compared to decedents (P for time-survival interaction = 0.03), whereas PCT decreased similarly in the two groups (P = 0.13). Presepsin was the only variable independently associated with ICU and 28-day mortality in Cox models adjusted for clinical characteristics. It showed better prognostic accuracy than PCT in the range of Sequential Organ Failure Assessment score (area under the curve (AUC) from 0.64 to 0.75 vs. AUC 0.53 to 0.65).

Conclusions

In this multicenter clinical trial, we provide the first evidence that presepsin measurements may have useful prognostic information for patients with severe sepsis or septic shock. These preliminary findings suggest that presepsin may be of clinical importance for early risk stratification.     

Associations between γ-glutamyl transferase, metabolic abnormalities and inflammation in healthy subjects from a population-based cohort: A possible implication for oxidative stress

AIM: To examine the relationships between γ -glutamyltransferase (GGT), alanine-aminotransferase (ALT),aspartate-aminotransferase (AST) and various metabolic parameters, C-reactive protein (CRP) and an oxidative stress marker (nitrotyrosine, NT) in subjects without any metabolic abnormalities from a population-based sample.METHODS: Two hundred and five subjects with normal body mass index (BMI), glucose tolerance, and without any metabolic abnormality were studied out of 1339subjects, without known liver diseases, alcohol abuse or use of hepatotoxic drugs, who are representative of the 45-64 aged population of Asti (north-western Italy).RESULTS: In all patients metabolic parameters and hs-CRP levels linearly increase from the lowest to the highest ALT and GGT tertiles, while in subjects without metabolic abnormalities, there is a significant association between fasting glucose, uric acid, waist circumference,hs-CRP, triglyceride values, and GGT levels. In these subjects, male sex, higher hs-CRP and glucose levels are associated with GGT levels in a multiple regression model, after adjustments for multiple confounders.In the same model, median NT levels are significantly associated with the increasing GGT tertile (β = 1.06;95%CI 0.67-1.45), but not with the AST and ALT tertiles.In a multiple regression model, after adjusting for age,sex, BMI, waist, smoking, and alcohol consumption, both NT (β = 0.05; 95%CI 0.02-0.08) and hs-CRP levels (β =0.09; 95%CI 0.03-0.15) are significantly associated with fasting glycemia.CONCLUSION: GGT, an easy, universally standardized and available measurement, could represent an early marker of sub-clinical inflammation and oxidative stress in otherwise healthy individuals. Prospective studies are needed to establish if GGT could predict future diabetes in these subjects.