A multi-biomarker approach to lambda-cyhalothrin effects on the freshwater teleost matrinxa Brycon amazonicus: single-pulse exposure and recovery.

Effects of the pyrethroid lambda-cyhalothrin (LCH) were investigated in matrinxa Brycon amazonicus, a non-target freshwater teleost. The fish were submitted to a single-pulse exposure (10% of LC50; 96 h, 0.65 µg L-1), followed by 7 days of recovery in clean water. Hematologic parameters indicated impairments in oxygen transport, which were not recovered. Plasma [Na+], [Cl-], and protein were diminished, and only [Na+] remained low after recovery. Gill Na+/K+ATPase activity was increased and recovered to basal values. Brain acetylcholinesterase activity was not responsive to LCH. Liver ascorbic acid concentration was not altered, and reduced glutathione levels remained augmented even after recovery. LCH inhibited hepatic superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, while glutathione-S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PDH) activities were steady. After recovery, SOD remained low, and GPx was augmented. Liver depicted lipid peroxidation, which was not observed after recovery. Hepatic morphology was affected by LCH and was not completely recovered. These responses, combined with the persistence of changes even after recovery span, clearly show the feasibility of these biomarkers in evaluating LCH toxic potential to non-target organisms, highlighting the importance of pyrethroids' responsible use.

Altered burst swimming in rainbow trout Oncorhynchus mykiss exposed to natural and synthetic oestrogens.

Juvenile rainbow trout Oncorhynchus mykiss were exposed to two concentrations each of 17ß-oestradiol (E2; natural oestrogen hormone) or 17α-ethinyl oestradiol (EE2; a potent synthetic oestrogen hormone) to evaluate their potential effects on burst-swimming performance. In each of six successive burst-swimming assays, burst-swimming speed (Uburst ) was lower in fish exposed to 0.5 and 1 µg l(-1) E2 and EE2 for four days compared with control fish. A practice swim (2 days prior to exposure initiation) in control fish elevated initial Uburst values, but this training effect was not evident in the 1 µg l(-1) EE2-exposed fish. Several potential oestrogen-mediated mechanisms for Uburst reductions were investigated, including effects on metabolic products, osmoregulation and blood oxygen-carrying capacity. Prior to burst-swimming trials, fish exposed to E2 and EE2 for 4 days had significantly reduced erythrocyte numbers and lower plasma glucose concentrations. After six repeated burst-swimming trials, plasma glucose, lactate and creatinine concentrations were not significantly different among treatment groups; however, plasma Cl(-) concentrations were significantly reduced in E2- and EE2-treated fish. In summary, E2 and EE2 exposure altered oxygen-carrying capacity ([erythrocytes]) and an osmoregulatory-related variable ([Cl(-) ]), effects that may underlie reductions in burst-swimming speed, which will have implications for fish performance in the wild.

Italian WEEE management system and treatment of end-of-life cooling and freezing equipments for CFCs removal.

This study presents and analyzes the data of the Italian system for take-back and recovery of waste electrical and electronic equipments (WEEEs) in the start-up period 2008-2010. The analysis was focused particularly on the data about the treatment of end-of-life cooling and freezing equipments. In fact, the wastes of cooling and freezing equipments have a high environmental impact. Indeed, in their compressor oil and insulation polyurethane (PU) foams chlorofluorocarbon (CFC) ozone-depleting gases are still present. In the period 2001-2004 Northern Italy resulted the main source in Europe of CFCs. The European Directive on WEEE management was enacted in 2002, but in Italy it was implemented by the legislative Decree in 2005 and it became operational in 2008. Actually, in 2008 the national WEEE Coordination Centre was founded in order to organize the WEEE pick-up process and to control collection, recovery and recycling targets. As a result, in 2010 the average WEEE collection per capita exceeded the threshold of more than 4 kg per inhabitant, as well as cooling and freezing appliances represented more than one fourth of the Italian WEEE collection stream. During the treatment of end-of-life cooling and freezing equipments, CFCs were recovered and disposed principally by burner methods. The analyses of defined specimens collected in the treatment facilities were standardized to reliably determine the amount of recovered CFCs. Samples of alkaline solid salt, alkaline saline solution, polyurethane matrix and compressor oil collected during the audit assessment procedure were analyzed and the results were discussed. In particular, the analysis of PU samples after the shredding and the warm pressing procedures measured a residual CFCs content around 500-1300 mg/kg of CFCs within the foam matrix.

Therapeutic implications of resistance to molecular therapies in metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) patients carrying KRAS mutated tumors do not benefit from epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies. Indeed, the mutational status of KRAS is currently a validated predictive biomarker employed to select mCRC patients for EGFR targeted drugs. When patients fail standard 5-fluorouracil-, oxaliplatin-, irinotecan- and bevacizumab-based therapies, EGFR-targeted salvage therapy can be prescribed only for those individuals with KRAS wild-type cancer. Thus, clinicians are now facing the urgent issue of better understanding the biology of KRAS mutant disease, in order to devise novel effective therapies in such defined genetic setting. In addition to KRAS, recent data point out that BRAF and PIK3CA exon 20 mutations hamper response to EGFR-targeted treatment in mCRC, potentially excluding from treatment also patients with these molecular alterations in their tumor. This review will focus on current knowledge regarding the molecular landscape of mCRC including and beyond KRAS, and will summarize novel rationally-developed combinatorial regimens that are being evaluated in early clinical trials.

MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis: experience on seven patients.

BACKGROUND: Adult Langerhans cell histiocytosis (LCH) is a rare disease. The combination of vinblastine and prednisone, given in a 6-month course, is the standard of care but prospective randomized trials are lacking. PATIENTS AND METHODS: We report our monocentric experience in the treatment of seven adult patients with multisystem (MS) LCH (n = 3) or single-system multifocal (SS-m) LCH (n = 4) with the short-course intensive chemotherapy regimen methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomicin (MACOP-B). RESULTS: The overall response rate was 100% [five complete response (CR), two partial response (PR)]. After a median follow-up of 6.5 years, four patients are in first continuous CR and three patients relapsed after 5, 8 and 62 months, respectively. Four patients were evaluated with positron emission tomography (PET) scan: all three PET-negative patients at the end of treatment had a long-lasting response with only one patient relapsing after 5 years. PET scan detected additional bone lesions at diagnosis in two of four patients, changing the treatment program in one of them. CONCLUSIONS: MACOP-B regimen seems to be very active in the treatment of adult MS or SS-m LCH, with long-lasting responses in five of seven patients. PET scan merits further evaluation in the initial staging and in the evaluation of the response to chemotherapy.

Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome.

BACKGROUND: Peripheral T-cell lymphoma unspecified (PTCLU) and mycosis fungoides (MF) often show resistance to conventional chemotherapy. Gemcitabine should be considered a suitable option. We report the long-term update of 39 pretreated T-cell lymphoma patients treated with gemcitabine. PATIENTS AND METHODS: From May 1997 to September 2007, 39 pretreated MF and PTCLU patients received gemcitabine. Inclusion criteria were as follows: histologic diagnosis of MF or PTCLU; relapsed/refractory disease; age > or =18 years; and World Health Organization performance status of two or less. Nineteen patients had MF and 20 PTCLU. All patients with MF had a T3-T4, N0, and M0 disease and patients with PTCLU had stage III-IV disease. Gemcitabine was given on days 1, 8, and 15 on a 28-day schedule (1200 mg/m(2)/day) for a total of three to six cycles. RESULTS: Overall response rate was 51% (20 of 39 patients); complete response (CR) and partial response (PR) rates were 23% (9 of 39 patients) and 28% (11 of 39 patients), respectively. Patients with MF had a CR rate of 16% and a PR rate of 32% compared with a CR rate of 30% and a PR rate of 25% of PTCLU patients. Among the CR patients, 7 of 9 are in continuous complete response with a variable disease-free interval (15-120 months). CONCLUSION: In our experience, gemcitabine proved to be effective in pretreated MF and PTCLU patients, even in the long term.

Transfer of spectral weight and symmetry across the metal-insulator transition in VO(2).

We present a detailed study of the valence and conduction bands of VO2 across the metal-insulator transition using bulk-sensitive photoelectron and O K x-ray absorption spectroscopies. We observe a giant transfer of spectral weight with distinct features that require an explanation which goes beyond the Peierls transition model as well as the standard single-band Hubbard model. Analysis of the symmetry and energies of the bands reveals the decisive role of the V 3d orbital degrees of freedom. Comparison to recent realistic many body calculations shows that much of the k dependence of the self-energy correction can be cast within a dimer model.

Experimental observation and theoretical description of the pure Fano effect in the valence-band photoemission of ferromagnets.

The pure Fano effect in angle-integrated valence-band photoemission of ferromagnets has been observed for the first time. A contribution of the intrinsic spin polarization to the spin polarization of the photoelectrons has been avoided by an appropriate choice of the experimental parameters. The theoretical description of the resulting spectra reveals a complete analogy to the Fano effect observed before for paramagnetic transition metals. While the theoretical photocurrent and spin-difference spectra are found in good quantitative agreement with experiment in the case of Fe and Co, only a qualitative agreement could be achieved in the case of Ni by calculations on the basis of plain local spin-density approximation. Agreement with experimental data could be improved in this case in a very substantial way by a treatment of correlation effects on the basis of dynamical mean field theory.

Dynamical properties of charged stripes in La2-xSrxCuO4.

Inelastic light-scattering spectra of underdoped La2-xSrxCuO4 single crystals are presented which provide direct evidence of the formation of quasi-one-dimensional charged structures in the two-dimensional CuO2 planes. The stripes manifest themselves in a Drude-like peak at low energies and temperatures. The selection rules allow us to determine the orientation to be along the diagonals at x=0.02 and along the principal axes at x=0.10. The electron-lattice interaction determines the correlation length which turns out to be larger in compound classes with lower superconducting transition temperatures. Temperature is the only scale of the response at different doping levels demonstrating the importance of quantum critical behavior.

Angle resolved photoemission from Nd1.85Ce0.15CuO4 using high energy photons: a fermi surface investigation.

We have performed an angle resolved photoemission study on a single crystal of the optimally electron doped (n-type) cuprate superconductor Nd2-xCexCuO4 (x=0.15) at a photon energy of 400 eV. The Fermi surface is mapped out and is, in agreement with earlier measurements, of hole-type with the expected Luttinger volume. However, comparing with previous low energy measurements, we observe a different Fermi surface shape and a different distribution of spectral intensity around the Fermi surface contour. The observed Fermi surface shape indicates a stronger electron correlation in the bulk as compared to the surface.

Observation of an unconventional metal-insulator transition in overdoped CuO2 compounds.

The electron dynamics in the normal state of Bi(2)Sr(2)CaCu(2)O(8+delta) is studied by inelastic light scattering over a wide range of doping. A strong anisotropy of the electron relaxation is found which cannot be explained by single-particle properties alone. The results strongly indicate the presence of an unconventional quantum-critical metal-insulator transition where "hot" (antinodal) quasiparticles become insulating while "cold" (nodal) quasiparticles remain metallic. A phenomenology is developed which allows a quantitative understanding of the Raman results and provides a scenario which links single- and many-particle properties.

Clinical trials in Italy: focus on the protocols submitted to ethics committees.

OBJECTIVE: To describe the main characteristics of clinical research protocols submitted to Italian local ethics committees (LECs). DESIGN: Prospective survey on all research protocols evaluated during the period from 1 September 1998 to 31 July 1999. Data were prospectively collected for each individual study containing information on: general characteristics of the study; study design; population under study; LEC decision; and study monitoring. SETTING: Twenty Italian LECs from nine regions in Italy. MAIN OUTCOME MEASURES: Type of protocols, diseases and drugs under investigation, population under study, methodological characteristics (e.g. sponsorship, multicentricity, presence of a control group). RESULTS: Data on 449 protocols corresponding to 625 evaluations were received. The majority of protocols (83.1%, n=373) were investigational studies on drugs, sponsored 76.8% (n=345) and multicentre 86.4% (n=388). The majority of the drug protocols were on antineoplastic drugs (27.7%, n=104), cardiovascular agents (15.4%, n=58) and systemic anti-infective agents (13.8%, n=52). A few of the drugs investigated were new entities. A few studies focused on subpopulations, e.g. elderly and children (10 and 16, respectively). Early development phases (I and II) were less likely to be sponsored and multicentre. The most represented drug category in phase I-II trials was the antineoplastic agents. CONCLUSION: A small portion of research protocols submitted to LECs in Italy relate to innovative research. The new Italian legislation, which decentralizes approval of clinical trials from central to local levels, will lead to shorter approval times and should stimulate more original research. Surveys on LECs activity give important information on active research areas, methodological quality of current studies and outcome of the studies in terms of trial closure and publication of the results. The latter information may be obtained through a follow-up of the cohort of studies included in the present cross-sectional survey.

A critical evaluation of the methodology of the literature on medication compliance.

OBJECTIVE: To develop a simple evaluation tool to assess methodologic rigor of the literature on patient compliance with medications, and to apply the tool to a sample of the literature. METHODS: A computerized search of the MEDLINE database (January 1980-December 1996) was performed. All English-language articles on compliance with medications were identified, using the MeSH terms patient-compliance and drug-therapy. A 10% sample was then randomly selected for review. Methodologic rigor was assessed on eight standards: study design, specification of patient sample, power analysis, specification of disease, specification of therapeutic regimen, duration of follow-up, definition of compliance, and compliance measurement. The raw scores of the eight standards were then combined in three summary scores, standardized from 0 to 100: study design, disease-related features, and compliance issues. RESULTS: Seventy-two articles from 719 identified were reviewed. The majority of the research articles were descriptive (63.9%), and patients in these studies were selected mainly from a convenience sample (41.7%). Just nine studies were multicenter studies, and three employed power analysis. The compliance definition was replicable in 41.7% of the studies. In 22 articles neither the compliance measure nor the criteria were stated. One-quarter of the studies (18) used a nonvalidated measure of compliance. Only two studies reached a score of 6 in the compliance measure, and eight studies used two different measures of compliance simultaneously. The median values in the summary scores were: study design 8.3, disease 42.9, compliance issues 50. CONCLUSIONS: The quality of the compliance research was generally poor. These low scores reflect very important shortcomings in the methodology. Such oversights make it difficult for the reader to critically assess the validity of the conclusions.

Compliance with sulfonylureas in a health maintenance organization: a pharmacy record-based study.

OBJECTIVE: To determine which factors affect compliance with sulfonylureas in a population served by a health maintenance organization in Southern California. METHODS: Retrospective analysis of pharmacy records and healthcare utilization data for two years (April 1993-March 1995), and a survey mailed to patients. Patients treated with sulfonylureas were selected for analysis on the basis of their prescription profile. Compliance was measured from the pharmacy records as the proportion of days the patient was in possession of the prescribed medications. Patient compliance with sulfonylureas was modeled as a function of four clusters of determinants: patient-related attributes, drug regimen characteristics and complexity, health status and disease-related variables, and characteristics of the interaction with healthcare providers. RESULTS: 786 patients were identified for analysis (49.1% women, mean age 59 y). The mean compliance rate was 83% +/- 22% SD. Compliance was significantly positively related with age and self-reported level of medication-taking compliance at baseline. Factors shown to have an inverse relationship with compliance were treatment complexity, perception of general health, and being a newly treated patient (adjusted R2 for the final model = 0.148). CONCLUSIONS: Our results suggest that factors found to be associated with noncompliant behavior (e.g., being a newly treated patient, self-reported compliance, regimen complexity) can be assessed by physicians and pharmacists as a routine practice.

Kinetic selection of HPV 16 E6/E7-directed antisense nucleic acids: anti-proliferative effects on HPV 16-transformed cells.

The E6/E7-coding sequences of the human papillomavirus type 16 (HPV 16) were probed for kinetic accessibility in vitro by pools of catalytic antisense RNA. Only long-chain complementary RNA and very few antisense sequences with a 3' portion complementary to a 10 nt window within unspliced and spliced E6-coding target sequences showed fast annealing with k(ass) values of up to 10(4) M-1s-1 indicating that the majority of E6/E7 RNA sequences are unfavourable targets for antisense inhibitors and ribozymes. Fast-annealing antisense oligodeoxyribonucleotides directed against the window of 10 nt inhibited cell proliferation of HPV 16-transformed SiHa cells but not slow-annealing antisense species. Antisense RNA of several hundred nucleotides in length also showed significant anti-proliferative activity. Biological effects of antisense oligodeoxyribonucleotides were specific for the antisense sequence, could only be found in HPV-positive but not in HPV-negative cell lines, and were related to decreased levels of E7 protein and E6/E7-specific transcripts. This work suggests that HPV 16 E7/E6 sequences exhibit a low accessibility for antisense oligonucleotides. This can be overcome, however, by exploiting the relationship between fast annealing of antisense species and their increased efficacy in human cells.

Patterns of practice for acute myocardial infarction in a population from ten countries.

BACKGROUND: There is conclusive evidence from large scale randomized clinical trials (RCTs) that several treatments administered in the acute phase of a myocardial infarction (AMI) reduce mortality. However, only a minority of patients admitted with AMI receives at the appropriate treatments. OBJECTIVES: This study aims at (1) describe the utilization patterns for AMI; (2) determine the appropriateness of prescribing, measured as adherence to the ACC/ AHA guidelines; and (3) determine which factors are associated with the administration of thrombolytic agents. METHODS: The study was a multi-center survey carried out in ten countries (nine European and one Canadian province) over a 3-month period. Data were prospectively collected by clinical pharmacists. All consecutive patients admitted to the participating hospitals during the study period with a diagnosis of suspected AMI were included in the study. Rates of use were calculated as "overall utilization" and "adjusted utilization" (e.g., accounting for eligibility). RESULTS: Data were available on 1976 patients from 56 participating centers. The mean age of the patients was 65 years (range 25 95, SD = 12.6) and 29.7% were women. Adjusted utilization rates were 63.7% for thrombolysis, 88% for aspirin, and 65.9% for beta-adrenergic blocking agents. The most utilized thrombolytic agent was streptokinase (65.9%). The main reasons given by physicians for not administering thrombolysis was the delay from chest pain onset to admission. Patients admitted to teaching hospitals were less likely to receive aspirin than patients admitted to general hospitals (adjusted rate 90.1% vs 86%, P = 0.007), but they were more likely to undergo a primary invasive procedure (11.0% vs 2.5% P = 0.001). Multivariate analysis showed that age greater than 74 years, delay, prior myocardial infarction, and Killip scale were correlated with the non-utilization of thrombolysis. CONCLUSION: Recommended treatments are still under-utilized in patients with AMI. Increased utilization is required, particularly for elderly people. There is a wide variability among hospitals with different affiliations (teaching vs non teaching), demonstrating the different patterns of practice in various settings.