First Demonstration of an Increased Serum Level of Reactive Oxygen Species During the Peripartal Period in the Ewes

Reactive Oxygen Species (ROS) are produced during oxidative metabolism, and regulate many biological processes. The acute inflammation characterizing parturition induces many physiological changes. Among them, there is evidence that ROS affect the synthesis of many factors involved in parturition. Our study aims to determine serum levels of ROS in periparturient ewes, as well as to establish a value of reference of their physiological concentration.

ROS determination was performed on blood collected every 12 hours in periparturient twin pregnant ewes. Our results will show a significant increase in ROS concentrations from the beginning to the end of the experiment. This increase may be due to the inflammatory process establishing during parturition.     

Biomechanical and clinical study of single posterior oblique cage POLIF in the treatment of degenerative diseases of the lumbar spine

Introduction

Aim of the study was to evaluate the biomechanical stability and the clinical efficacy of a lumbar interbody fusion obtained by single oblique cage implanted by a posterior approach.

Method

Through the realization of three finite element models (FEMs), the biomechanics of POLIF was compared to PLIF and TLIF. Ninety-four patients underwent interbody fusion by POLIF with instrumented posterolateral fusion. Clinical and radiographic outcomes were evaluated at regular intervals for at least 6 months.

Results

The FEMs showed no statistically significant differences in stability in compression and flexion–extension. Mean preoperative VAS score was 7.1, decreased to 2.1 at follow-up. Mean preoperative SF-12 value was 34.5 %, increased to 75.4 % at follow-up. All patients showed a good fusion rate and no hardware failure.

Discussion

POLIF associated to instrumented posterolateral fusion is a viable and safe surgical technique, which ensures a biomechanical stability similar to other surgical techniques.

     

Protective effect of erythropoietin and its carbamylated derivative in experimental Cisplatin peripheral neurotoxicity.

PURPOSE: Antineoplastic drugs, such as cisplatin (CDDP), are severely neurotoxic, causing disabling peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. Cotreatment with neuroprotective agents and CDDP has been proposed for preventing or reversing the neuropathy. Erythropoietin given systemically has a wide range of neuroprotective actions in animal models of central and peripheral nervous system damage. However, the erythropoietic action is a potential cause of side effects if erythropoietin is used for neuroprotection. We have successfully identified derivatives of erythropoietin, including carbamylated erythropoietin, which do not raise the hematocrit but retain the neuroprotective action exerted by erythropoietin. EXPERIMENTAL DESIGN: We have developed previously an experimental chemotherapy-induced peripheral neurotoxicity that closely resembles CDDP neurotoxicity in humans. The present study compared the effects of erythropoietin and carbamylated erythropoietin (50 microg/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo. RESULTS: CDDP given to Wistar rats significantly lowered their growth rate (P < 0.05), with slower sensory nerve conduction velocity (P < 0.001) and reduced intraepidermal nerve fibers density (P < 0.001 versus controls). Coadministration of CDDP and erythropoietin or carbamylated erythropoietin partially but significantly prevented the sensory nerve conduction velocity reduction. Both molecules preserved intraepidermal nerve fiber density, thus confirming their neuroprotective effect at the pathologic level. The protective effects were not associated with any difference in platinum concentration in dorsal root ganglia, sciatic nerve, or kidney specimens. CONCLUSIONS: These results widen the spectrum of possible use of erythropoietin and carbamylated erythropoietin as neuroprotectant drugs, strongly supporting their effectiveness.     

Binding and receptors for human albumin polymers and IgM/HBs circulating complex in HBsAg chronic carriers

Binding activity for polymerized human serum albumin (pHSA-binding), studied in passive haemoagglutination, receptors for polymerized human serum albumin (pHSA-receptors), studied in ELISA, as well as the circulating IgM/HBs complex were tested in 71 chronic carriers of HBsAg with and without liver pathology. We found that 73.2% of the sera were reactive for pHSA-binding while 45% were reactive for pHSA-receptors and 42.2% for the circulating IgM/HBs complex. The distribution and mode of association of these 3 markers showed a close correlation with the e-antigen in circulation (HBeAg) and with liver disease (p less than 0.05). We further observed that pHSA-binding can be present in the absence of pHSA-receptors, suggesting the possible existence of further reactants in the serum-pHSA reaction. We did not observe any correlations between the circulating IgM/HBs complexes, pHSA-binding and pHSA-receptors. Blocking experiments, in fact, confirmed the non-involvement of polymerized human serum albumin in the formation of the circulating IgM/HBs complex. Elution experiments showed that, in addition to HBsAg, class-G immunoglobulins are also directly involved in the serum-pHSA reaction.     

Levels of house-dust-mite allergen in homes of nonallergic people in Pavia, Italy

BACKGROUND: HDM distribution varies between geographic areas and may be affected by housing characteristics. We quantified Der p 1 and Der f 1 and assessed the relationships between their levels and housing characteristics in homes of nonallergic subjects. METHODS: Der f 1 and Der p 1 were measured by ELISA in dust samples from living-room floors and mattresses of 44 homes of nonallergic subjects in Pavia. Information about household characteristics was obtained by questionnaire. RESULTS: Der p 1 and Der f 1 concentrations (microg/g dust, median) were 0.34 and 7.8 on mattresses, and 0.15 and 0.83 on living-room floors. Higher Der f 1 levels on mattresses were associated with synthetic pillows (P<0.05), and (only when expressed as microg/m2) with bedding washing temperature of < or = 60 degrees C (P<0.05). Der f 1 levels were higher on the living-room floors of homes located on lower (< or =first) floors (P<0.05). Good correlations were found between Der p 1 and Der f 1 expressed as microg/g dust and microg/m2 on both mattresses and living-room floors. CONCLUSIONS: In homes of nonallergic subjects in northern Italy, Der f 1 exceeded the threshold for sensitization in a high proportion of mattress samples.     

Stochasticity and bistability in horizontal transfer control of a genomic island in Pseudomonas

Genomic islands (GEI) comprise a recently recognized large family of potentially mobile DNA elements and play an important role in the rapid differentiation and adaptation of bacteria. Most importantly, GEIs have been implicated in the acquisition of virulence factors, antibiotic resistances or toxic compound metabolism. Despite detailed information on coding capacities of GEIs, little is known about the regulatory decisions in individual cells controlling GEI transfer. Here, we show how self-transfer of ICEclc, a GEI in Pseudomonas knackmussii B13 is controlled by a series of stochastic processes, the result of which is that only a few percent of cells in a population will excise ICEclc and launch transfer. Stochastic processes have been implicated before in producing bistable phenotypic transitions, such as sporulation and competence development, but never before in horizontal gene transfer (HGT). Bistability is instigated during stationary phase at the level of expression of an activator protein InrR that lays encoded on ICEclc, and then faithfully propagated to a bistable expression of the IntB13 integrase, the enzyme responsible for excision and integration of the ICEclc. Our results demonstrate how GEI of a very widespread family are likely to control their transfer rates. Furthermore, they help to explain why HGT is typically confined to few members within a population of cells. The finding that, despite apparent stochasticity, HGT rates can be modulated by external environmental conditions provides an explanation as to why selective conditions can promote DNA exchange.     

mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.     

Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex

Objectives:To define the maximum tolerated dose (MTD), thetoxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods:Fourteen patients with advanced solid tumorsnot responsive to previous antitumor treatments received BBR 3464 on a daily× 5 schedule every twenty-eighth day. The drug was given as a one-hourinfusion with pre-and post-treatment hydration (500 ml in one hour) and noantiemetic prophylaxis. The starting dose was 0.03 mg/m²/day. Amodified accelerated titration escalation design was used. Total and freeplatinum (Pt) concentrations in plasma and urine were assessed by ICP-MS ondays 1 and 5 of the first cycle. Results:Dose was escalated four times up to 0.17mg/m²/day. Short-lasting neutropenia and diarrhea of late onsetwere dose-limiting and defined the MTD at 0.12 mg/m². Nausea andvomiting were rare, neither neuro- nor renal toxic effects were observed.BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-lifeof several days. At 0.17 mg/m² plasma Cmax and AUC on day 5 werehigher than on day 1, indicating drug accumulation. Approximately 10%of the equivalent dose of BBR3464 (2.2%–13.4%) wasrecovered in a 24-hour urine collection. Conclusions:The higher than expected incidence of neutropenia andGI toxicity might be related to the prolonged half-life and accumulation oftotal and free Pt after daily administrations. Lack of nephrotoxicity and thelow urinary excretion support the use of the drug without hydration. Thesingle intermittent schedule has been selected for clinical development.