Very Rapid Improvement in Extended Nitric Oxide Parameters Is Associated With Clinical and Functional Improvement in Patients With Chronic Rhinosinusitis With Nasal Polyps Treated With Dupilumab.

BACKGROUND AND OBJECTIVE: Dupilumab, an anti-IL-4 receptor a monoclonal antibody, was recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate-to-severe asthma. Onset of its clinical effects is rapid. CRSwNP is characterized by extended type 2 inflammatory involvement that can be assessed using extended nitric oxide analysis. We investigated whether dupilumab was associated with a rapid improvement in extended nitric oxide parameters, lung function, and clinical outcomes in patients with CRSwNP. METHODS: Consecutive patients with CRSwNP and an indication for dupilumab were evaluated for extended nitric oxide analysis (exhaled, FeNO; bronchial, JawNO; alveolar, CalvNO; nasal, nNO) and lung function 15 and 30 days after initiation of treatment and for clinical outcomes (nasal polyps score [NPS], quality of life questionnaires, visual analog scale [VAS] for the main symptoms, and the Asthma Control Test [ACT]) 30 days after initiation of treatment. RESULTS: We enrolled 33 patients. All extended nitric oxide and lung function parameters improved significantly after 15 days of treatment, remaining stable at 30 days. Scores on the NPS, VAS for the main RSwNP symptoms, quality of life questionnaires, and the ACT improved significantly 30 days after initiation of treatment. CONCLUSION: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway areas. This is associated with improved lung function and clinical parameters in patients with CRSwNP.

Very Rapid Improvement in Extended Nitric Oxide Parameters Is Associated With Clinical and Functional Improvement in Patients With Chronic Rhinosinusitis With Nasal Polyps Treated With Dupilumab

Background: Dupilumab, an anti–IL-4 receptor a monoclonal antibody, was recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate-to-severe asthma. Onset of its clinical effects is rapid. CRSwNP is characterized by extended type 2 inflammatory involvement that can be assessed using extended nitric oxide analysis. Objectives: We investigated whether dupilumab was associated with a rapid improvement in extended nitric oxide parameters, lung function, and clinical outcomes in patients with CRSwNP. Methods: Consecutive patients with CRSwNP and an indication for dupilumab were evaluated for extended nitric oxide analysis (exhaled, FeNO; bronchial, JawNO; alveolar, CalvNO; nasal, nNO) and lung function 15 and 30 days after initiation of treatment and for clinical outcomes (nasal polyps score [NPS], quality of life questionnaires, visual analog scale [VAS] for the main symptoms, and the Asthma Control Test [ACT]) 30 days after initiation of treatment. Results: We enrolled 33 patients. All extended nitric oxide and lung function parameters improved significantly after 15 days of treatment, remaining stable at 30 days. Scores on the NPS, VAS for the main CRSwNP symptoms, quality of life questionnaires, and the ACT improved significantly 30 days after initiation of treatment. Conclusions: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway areas. This is associated with improved lung function and clinical parameters in patients with CRSwNP. (AU)

Antecedentes: El dupilumab, un anticuerpo monoclonal anti-IL-4 receptor alfa, ha sido aprobado recientemente para el tratamiento de la rinosinusitis crónica con pólipos nasales (CRSwNP) y asma de moderada a grave, demostrando un inicio rápido de los efectos clínicos. La CRSwNP se caracteriza por un infiltrado extenso inflamatorio de tipo 2 que puede evaluarse mediante el análisis de óxido nítrico exhalado extendido. Objetivos: En este estudio, investigamos si dupilumab se asocia con una mejora rápida en los parámetros de óxido nítrico extendido, la función pulmonar y los resultados clínicos en pacientes con CRSwNP. Métodos: Se incluyeron pacientes consecutivos con CRSwNP e indicación para ser tratados con dupilumab y fueron evaluados mediante el análisis de óxido nítrico extendido (exhalado, FENO; bronquial, JawNO y alveolar, componentes CalvNO; nasal, nNO) y función pulmonar, 15 y 30 días después del inicio del tratamiento; y en el caso de las variables clínicas (puntuación del tamaño de los pólipos nasales [NPS]; cuestionarios de calidad de vida; escalas analógicas visuales [EVA] para los principales síntomas principales, prueba de control del asma [ACT]) solo después de 30 días de iniciado el tratamiento. Resultados: Se incluyeron 33 pacientes. Todos los parámetros del análisis extendido del óxido nítrico y la función pulmonar mejoraron significativamente después de 15 días de tratamiento, permaneciendo estables a los 30 días de tratamiento. El NPS, las EVA para los principales síntomas de CRSwNP, el cuestionario de calidad de vida y el ACT mejoraron significativamente después de 30 días de inicio del tratamiento. Conclusiones: En pacientes con CRSwNP, el tratamiento con dupilumab se asocia con una mejoría muy rápida en la inflamación tipo 2 en todos los compartimentos de las vías respiratorias y esto se asocia con una mejor función pulmonar y los parámetros clínicos. (AU)

Very rapid improvement of extended nitric oxide parameters, associated with clinical and functional betterment, in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) treated with Dupilumab.

BACKGROUND AND OBJECTIVE: Background: Dupilumab, an anti-IL-4 receptor alpha monoclonal antibody, has been recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate to severe asthma, demonstrating a rapid onset of clinical effects. CRSwNP is characterized by an extended type-2 inflammatory involvement that can be assessed by extended nitric oxide analysis. Objective: In this study we investigated whether Dupilumab is associated with a rapid improvement in extended nitric oxide parameters, lung function and clinical outcomes in patients with CRSwNP. METHODS: : Consecutive patients with CRSwNP and indication to be treated with Dupilumab were evaluated for extended nitric oxide analysis (exhaled, FENO; bronchial, JawNO and alveolar, CalvNO components; nasal, nNO) and lung function 15 and 30 days after treatment initiation, and for clinical outcomes (nasal polyps score, NPS; quality of life questionnaires; visual analogue scales, VAS, for main symptoms, asthma control test, ACT) after 30 days of treatment initiation. RESULTS: 33 patients were enrolled. All extended nitric oxide and lung function parameters significantly improved after 15 days of treatment remaining stable at 30 days. NPS, VAS for main CRSwNP symptoms, quality of life questionnaires and ACT significantly improved after 30 days of treatment initiation. CONCLUSION: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway districts and this is associated with improved lung function and clinical parameters in patients with CRSwNP.

Occurrence of pyrethroid resistance mutation in Cydia pomonella (Lepidoptera: Tortricidae) throughout Argentina.

Pyrethroid insecticides were intensively used against Cydia pomonella in the Río Negro and Neuquén valley, main production area of pome fruits in Argentina. Therefore, the first objective was to evaluate lambda-cyhalothrin resistance levels in C. pomonella larvae from orchards in this area that are currently under pyrethroids treatments. The second objective was to evaluate the frequency of kdr mutation in C. pomonella across Argentina. High levels of resistance to lambda-cyhalothrin (resistance ratios > 30) were determined in all the populations evaluated. The L1014F (kdr) mutation was evaluated in 355 diapausing larvae collected in 12 orchards from San Juan to Santa Cruz provinces (1690 km away from each other). The highest frequency of kdr mutation was determined in larvae from the Río Negro and Neuquén valley (0.61), followed by those from Mendoza (0.36). The kdr allele was absent or present at very low frequencies in orchards subjected to low pyrethroid pressure. The frequency of detection of kdr mutation in C. pomonella from Argentina is related to the use of pyrethroids against this pest in different areas. Target-site insensitivity is, at least, one of the mechanisms involved in resistance to lambda-cyhalothrin in codling moth from the Río Negro and Neuquén valley.

Differential detoxifying responses to crude oil water-accommodated fraction in Hyallela curvispina individuals from unpolluted and contaminated sites.

Sublethal effects of water-accommodated fraction (WAF) from crude oil of Neuquén basin, Northern Patagonia-Argentina, were examined on both antioxidant and detoxification system of Hyalella curvispina adults collected in Los Barreales (LB) lake and in an oil-polluted stream (DS). The effects of WAF exposure during 6, 24 and 48 h were evaluated in the glutathione content (GSH) and glutathione S-transferase (GST), catalase (CAT) and cytochrome P450 (CYP450) activities. Populations from DS and LB showed not only different basal GSH content and enzyme activities but also different behavior to WAF exposure. LB population exposed to WAF showed a significant increase in GSH content, CAT and CYP450 activities, compared to control group. DS population presented high basal levels in CAT and CYP activity compared with LB population, but their response to WAF exposure was minor. Amphipods from DS, chronically exposed to hydrocarbons, were adapted to their environment.

Tracing sources of Listeria contamination in traditional Italian cheese associated with a US outbreak: investigations in Italy.

In 2012 a US multistate outbreak of listeriosis was linked to ricotta salata imported from Italy, made from pasteurized sheep's milk. Sampling activities were conducted in Italy to trace the source of Listeria monocytogenes contamination. The cheese that caused the outbreak was produced in a plant in Apulia that processed semi-finished cheeses supplied by five plants in Sardinia. During an 'emergency sampling', 179 (23·6%) out of 758 end-products tested positive for L. monocytogenes, with concentrations from <10 c.f.u./g to 1·1 × 106 c.f.u./g. Positive processing environment samples were found in two out of four processing plants. A 'follow-up sampling' was conducted 8 months later, when environmental samples from three out of six plants tested positive for L. monocytogenes and for Listeria spp. PFGE subtyping showed 100% similarity between US clinical strains and isolates from ricotta salata, confirming the origin of the outbreak. The persistence of strains in environmental niches of processing plants was demonstrated, and is probably the cause of product contamination. Two PFGE profiles from clinical cases of listeriosis in Italy in 2011, stored in the MSS-TESSy database, were found to have 100% similarity to one PFGE profile from a US clinical case associated with the consumption of ricotta salata, according to the US epidemiological investigation (sample C, pulsotype 17). However, they had 87% similarity to the only PFGE profile found both in the US clinical case and in 14 ricotta cheese samples collected during the emergency sampling (sample B, pulsotype 1). Sharing of molecular data and availability of common characterization protocols were key elements that connected the detection of the US outbreak to the investigation of the food source in Italy. Simultaneous surveillance systems at both food and human levels are a necessity for the efficient rapid discovery of the source of an outbreak of L. monocytogenes.

HIV-1 coreceptor usage in paired plasma RNA and proviral DNA from patients with acute and chronic infection never treated with antiretroviral therapy.

Although an independent evolution of viral quasispecies in different body sites might determine a differential compartmentalization of viral variants, the aim of this paper was to establish whether sequences from peripheral blood mononuclear cells (PBMCs) and plasma provide different or complementary information on HIV tropism in patients with acute or chronic infection. Tropism was predicted using genotypic testing combined with geno2pheno (coreceptor) analysis at a 10% false positive rate in paired RNA and DNA samples from 75 antiretroviral-naïve patients (divided on the basis of avidity index into patients with a recent or long-lasting infection). A high prevalence of R5 HIV strains (97%) was observed in both compartments (plasma and PBMCs) in patients infected recently. By contrast, patients with a long-lasting infection showed a quite different situation in the two compartments, revealing more (46%) X4/DM in PBMCs than patients infected recently (3%) (P = 0.008). As- a knowledge of viral strains in different biological compartments might be crucial to establish a therapeutic protocol, it could be extremely useful to detect not only viral strains in plasma, but also viruses hidden or archived in different cell compartments to better understand disease evolution and treatment efficacy in patients infected with HIV.

Characterization of placental cholinesterases and activity induction associated to environmental organophosphate exposure.

Although non-innervated, the placenta contains both cholinesterases (ChEs), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE). These enzymes are well-known for their multiple molecular forms. In a first approach, we used recognized specific inhibitors, substrate preferences and non-denaturating gel electrophoresis in order to characterize the ChE profile of term placenta from uncomplicated pregnancy. Results strongly suggest that the predominant cholinesterasic form present was tetrameric BChE. It is well established that both ChEs are targets of cholinesterase-inhibiting organophosphates (OP), one of the most important classes of chemicals actively applied to the environment. However, we have previously reported increased ChEs activity in placenta of rural residents exposed to OP. In the present work, we have studied: 1) whether this finding was reproducible and, 2) whether AChE or BChE up regulation is behind the increase of placental ChE activity. The population studied included forty healthy women who live in an agricultural area. Samples were collected during both the OP pulverization period (PP) and the recess period (RP). The placental ChEs activity increased in PP, evidencing reproducibility of previous results. The analysis of non-denaturating gels revealed that increased activity of total ChE activity in placenta from women exposed to OP may be attributable to tetrameric BChE up-regulation.

Evaluation of cytochrome P450 activity in field populations of Cydia pomonella (Lepidoptera: Tortricidae) resistant to azinphosmethyl, acetamiprid, and thiacloprid.

The Río Negro and Neuquén Valley is the most important apple and pear growing region in Argentina. Cydia pomonella L. (Lepidoptera: Tortricidae), the main fruit-tree pest is being controlled by azinphosmethyl (AzMe), acetamiprid (Acet), and thiacloprid (Thia) among other insecticides. The objective of this study was to evaluate the response of neonate larvae of codling moth to these three insecticides and on the role of cytochrome P450 monooxygenase in their toxicity. All field populations presented significantly lower mortality to a discriminating concentration (DC) of Acet and AzMe. In addition, 13 of the 14 populations showed significantly lower mortality to DC of Thia. Most of the field populations (71%) showed significantly higher 7-ethoxycoumarine O-deethylase activity compared with the laboratory-susceptible strain. While positive significant correlation (gamma = 0.59) was found between Thia and AzMe mortalities at the DC level, no significant correlations were detected between Acet and Thia (gamma = 0.35) or Acet and AzMe (gamma = 0.12). However, Acet and Thia mortalities were significantly correlated to the percentage of individuals exhibiting 7-ethoxy-coumarine O-deethylase activity activities higher than the mean upper 95% confidence limit of the susceptible strain (gamma = -0.52 and gamma = -0.63, respectively).

Reticulon1-C modulates protein disulphide isomerase function.

Endoplasmic reticulum (ER) is the primary site for the synthesis and folding of secreted and membrane-bound proteins. Accumulation of unfolded and misfolded proteins in ER underlies a wide range of human neurodegenerative disorders. Hence, molecules regulating the ER stress response represent potential candidates as drug targets for tackling these diseases. Protein disulphide isomerase (PDI) is a chaperone involved in ER stress pathway, its activity being an important cellular defense against protein misfolding. Here, we demonstrate that human neuroblastoma SH-SY5Y cells overexpressing the reticulon protein 1-C (RTN1-C) reticulon family member show a PDI punctuate subcellular distribution identified as ER vesicles. This represents an event associated with a significant increase of PDI enzymatic activity. We provide evidence that the modulation of PDI localization and activity does not only rely upon ER stress induction or upregulation of its synthesis, but tightly correlates to an alteration in its nitrosylation status. By using different RTN1-C mutants, we demonstrate that the observed effects depend on RTN1-C N-terminal region and on the integrity of the microtubule network. Overall, our results indicate that RTN1-C induces PDI redistribution in ER vesicles, and concomitantly modulates its activity by decreasing the levels of its S-nitrosylated form. Thus RTN1-C represents a promising candidate to modulate PDI function.

Analysis of intracellular human immunodeficiency virus (HIV)-1 drug resistance mutations in multi-failed HIV-1-infected patients treated with a salvage regimen: 72-week follow-up.

The human immunodeficiency virus (HIV) mutational archive of proviral DNA was monitored during a 72-week follow-up in 20 multidrug-experienced HIV-1-infected patients treated with a darunavir/ritonavir-based salvage therapy. At the beginning of the study, all patients harboured a number of intracellular drug resistance-associated mutations (RAMs) in peripheral blood mononuclear cells. In some patients, a significant fluctuation in the number of RAMs was observed during the observation period. However, all patients, notwithstanding the presence or the fluctuation of intracellular RAMs, showed a persistently undetectable viraemia. The data suggest that the archived resistant viral variants change during suppressive therapy, but that the variants are unable to re-emerge and to affect virological response.

A new diagnostic algorithm for Burkitt and diffuse large B-cell lymphomas based on the expression of CSE1L and STAT3 and on MYC rearrangement predicts outcome.

BACKGROUND: Aggressive mature B-cell non-Hodgkin's lymphomas (BCL) sharing features of Burkitt's lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) (intermediate BL/DLBCL) but deviating with respect to one or more characteristics are increasingly recognized. The limited knowledge about these biologically heterogeneous lymphomas hampers their assignment to a known entity, raising incertitude about optimal treatment approaches. We therefore searched for discriminative, prognostic, and predictive factors for their better characterization. PATIENTS AND METHODS: We analyzed 242 cytogenetically defined aggressive mature BCL for differential protein expression. Marker selection was based on recent gene-expression profile studies. Predictive models for diagnosis were established and validated by a different set of lymphomas. RESULTS: CSE1L- and inhibitor of DNA binding-3 (ID3)-overexpression was associated with the diagnosis of BL and signal transduction and transcription-3 (STAT3) with DLBCL (P<0.001 for all markers). All three markers were associated with patient outcome in DLBCL. A new algorithm discriminating BL from DLBCL emerged, including the expression of CSE1L, STAT3, and MYC translocation. This 'new classifier' enabled the identification of patients with intermediate BL/DLBCL who benefited from intensive chemotherapy regimens. CONCLUSION: The proposed algorithm, which is based on markers with reliable staining properties for routine diagnostics, represents a novel valid tool in separating BL from DLBCL. Most interestingly, it allows segregating intermediate BL/DLBCL into groups with different treatment requirements.

Meal replacement with a low-calorie diet formula in weight loss maintenance after weight loss induction with diet alone.

BACKGROUND/OBJECTIVES: Weight loss in obesity can reduce morbidity and mortality and benefits persist as long as weight loss is maintained. Weight maintenance is difficult in the long term and new strategies need to be developed to achieve this goal. We aimed to evaluate the efficacy of substituting a low-calorie diet formula for a meal in a weight loss program during the maintenance phase. METHODS: Randomized paralleled clinical trial including 62 adult patients with at least a 5% weight loss with diet alone for 6 months, randomized to two groups: daily replacement of one meal with a low-calorie diet formula, or dieting alone for another 6 months (weight maintenance phase). RESULTS: Weight maintenance or further weight loss occurred in 83.9% of patients in the intervention group, whereas only in 58.1% in the control group (P=0.025). As a whole, patients in the intervention group lost a further 3.2+/-3.7% of initial weight compared with a 1.3+/-3.6% in the control group (P=0.030). Body fat mass diminished in both groups, with no differences between them (1.6+/-3.5 vs 1.0+/-9.3 kg, respectively, P=0.239), and the same happened with free fat mass (0.9+/-3.3 vs 0.4+/-6.7 kg, respectively, P=0.471). A multivariate logistic regression analysis (R (2)=0.114, P=0.023) retained only the intervention as a predictor of the achievement of weight maintenance with an odds ratio (95% confidence interval) of 3.756 (1.138-12.391). CONCLUSIONS: Substitution of a low-calorie diet formula for a meal is an effective measure for weight loss maintenance compared with dieting alone.

EpiSouth: a network for communicable disease control in the Mediterranean region and the Balkans.

The countries around the Mediterranean Sea share epidemiological characteristics and public health problems. In 2006 the EpiSouth Project was started as a framework for collaboration for communicable diseases surveillance and training in the Mediterranean Basin. As of December 2008, 26 countries from southern Europe, the Balkans, North Africa and the Middle-East are members of EpiSouth and several international organisations and institutions collaborate: the European Commission (EC), the European Centre for Disease Prevention and Control (ECDC), the Italian Ministry of Work, Health and Social Policies and the World Health Organization (WHO). The project is coordinated by the Italian national public health institute and three work packages (WPs) Cross-border epidemic intelligence, vaccine preventable diseases and migrants and Cross-border emerging zoonoses are operated by the national institutes of France, Bulgaria and Greece. These WPs constitute technical pillars on which the project develops. Networking and Training are WPs dedicated to capacity building and are run by the Padua Teaching Hospital (Italy) and the Spanish national public health institute. A steering committee guides EpiSouth's activities while all countries collaborate through WP steering teams and focal points. A number of outcomes have been accomplished and documents with results are available from the EpiSouth website which hosts a public website and a restricted area for direct sharing of information among the participants. Five electronic bulletins were published, two trainings for 63 participants performed, national epidemic intelligence systems were evaluated, a preliminary survey on vaccine-preventable diseases and migrants performed, and a list of priorities for emerging zoonoses in the Mediterranean area was selected. Overall the network succeeded in creating cohesion, mutual trust and concrete collaboration on cross-border public health issues in a geographical area that is not addressed as a whole by any other initiative or organisation.

Disruption of contactin 4 in three subjects with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder of the central nervous system of largely unknown aetiology. The prevalence of the syndrome underscores the need for biological markers and a clearer understanding of pathogenesis. For these reasons, a genetic study of idiopathic ASD was undertaken. METHODS AND RESULTS: Array based comparative genomic hybridisation identified a paternally inherited chromosome 3 copy number variation (CNV) in three SUBJECTS: a deletion in two siblings and a duplication in a third, unrelated individual. These variations were fluorescence in situ hybridisation (FISH) validated and the end points further delineated using a custom fine tiling oligonucleotide array. Polymerase chain reaction (PCR) products unique to the rearrangements were amplified and sequence analysis revealed the variations to have resulted from Alu Y mediated unequal recombinations interrupting contactin 4 (CNTN4). CONCLUSION: CNTN4 plays an essential role in the formation, maintenance, and plasticity of neuronal networks. Disruption of this gene is known to cause developmental delay and mental retardation. This report suggests that mutations affecting CNTN4 function may be relevant to ASD pathogenesis.

An improved method for generating BAC DNA suitable for FISH.

Fluorescence in situ hybridization (FISH) is commonly used to identify chromosomal aberrations such as translocations, deletions, duplications, gene fusions, and aneuploidies. It relies on the hybridization of fluorescently labeled DNA probes onto denatured metaphase chromosomes or interphase nuclei. These probes are often generated from DNA sequences cloned within bacterial artificial chromosomes (BACs). Growing these BACs in adequate amounts for FISH can be demanding. We describe FISH performed with bacteriophage Phi29 DNA polymerase amplified BAC DNA. Generating this material required significantly smaller cultures and less time than standard methods. The FISH results obtained were comparable with those obtained from standard BAC DNA. We believe this method of BAC DNA generation is useful for the entire FISH community as it improves considerably on prior methods.

Dieta y ejercicio / Diet and exercise

El tratamiento no farmacológico de la diabetes tipo 2 consiste en medidas precisas y escalonadas en el estilo de vida: alimentación y actividad física. La estrategia nutricional, cuando coexiste obesidad, estriba en la aplicación de una dieta moderadamente hipocalórica que consiga pérdidas modestas de grasa (especialmente visceral), y el mantenimiento de dicha pérdida, conservando la masa magra. El reparto energético entre lípidos, proteínas e hidratos de carbono tiene un margen muy amplio, y debe individualizarse según la edad, la presencia o no de sobrepeso y otras comorbilidades (dislipemia, hipertensión, etc.). En diabéticos tipo 2no obesos el tratamiento es el mismo, pero sin restricción calórica. Estas medidas se acompañarán de un incremento en la actividad física diaria y la recomendación individualizada de ejercicio físico más intenso semanal, por el potente efecto de mejora de la sensibilidad a la insulina y los factores de riesgo cardiovascular asociados. En esta exposición se aportan algunas propuestas de prescripción individualizada de ambos elementos del estilo de vida, basándonos en las evidencias científicas del momento (AU)

Non-pharmacological treatment of type 2diabetes consists of well-defined and progressive lifestyle measures: diet and exercise. In obese diabetic patients, the nutritional strategy consists of a moderatelyhypocaloric diet to achieve modest fat loss(especially visceral fat) and to maintain this loss while conserving lean tissue mass. Calorie distribution among lipids, proteins and carbohydrates has a wide margin and should be individually tailored according to age and the presence or absence of overweight and other comorbidities (dyslipidemia, hypertension etc.). Treatment is the same in non-obese type 2 diabetics, but without calorie restriction. These measures should be accompanied by an increase in daily physical exercise and individualized recommendations for more intense weekly physical activity due to its strong effect on improving insulin sensitivity and associated cardiovascular risk factors. The present article discusses some recommendations for the individualized prescription of both types of lifestyle modification, based on the latest scientific evidence (AU)

Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality.

The breast tumor associated gene-1 (BRCA1) and poly(ADP-ribose) polymerase-1 (PARP1) are both involved in DNA-damage response and DNA-damage repair. Recent investigations have suggested that inhibition of PARP1 represents a promising chemopreventive/therapeutic approach for specifically treating BRCA1- and BRCA2-associated breast cancer. However, studies in mouse models reveal that Parp1-null mutation results in genetic instability and mammary tumor formation, casting significant doubt on the safety of PARP1 inhibition as a therapy for the breast cancer. To study the genetic interactions between Brca1 and Parp1, we interbred mice carrying a heterozygous deletion of full-length Brca1 (Brca1(+/Delta11)) with Parp1-null mice. We show that Brca1(Delta11/Delta11);Parp1(-/-) embryos die before embryonic (E) day 6.5, whereas Brca1(Delta11/Delta11) embryos die after E12.5, indicating that absence of Parp1 dramatically accelerates lethality caused by Brca1 deficiency. Surprisingly, haploinsufficiency of Parp1 in Brca1(Delta11/Delta11) embryos induces a severe chromosome aberrations, centrosome amplification, and telomere dysfunction, leading to apoptosis and accelerated embryonic lethality. Notably, telomere shortening in Brca1(Delta11/Delta11);Parp1(+/-) MEFs was correlated with decreased expression of Ku70, which plays an important role in telomere maintenance. Thus, haploid loss of Parp1 is sufficient to induce lethality of Brca1-deficient cells, suggesting that partial inhibition of PARP1 may represent a practical chemopreventive/therapeutic approach for BRCA1-associated breast cancer.

Prevalence, molecular characterization and antimicrobial resistance of thermophilic campylobacter isolates from cattle, hens, broilers and broiler meat in south-eastern Italy.

Eleven cattle farms, 8 layer farms, 7 broiler farms and 30 broiler meat samples were investigated in south-eastern Italy throughout 2003 to evaluate the prevalence, the molecular type and antimicrobial resistance of thermophilic Campylobacters. A total of 398 samples were analysed. One Campylobacter isolate for each positive faecal swab and three isolates per positive broiler meat sample were selected for further analysis. Multiplex PCR was performed for species-level identification and PCR-RFLP of the flagellin A gene for genotyping. Resistance to 14 antimicrobials was studied in 188 Campylobacter isolates. Prevalence of campylobacters was high both on farms (100%) and in food samples (73%). On 4/11 cattle farms and on 10/15 poultry farms more than one species was isolated. The presence of more than one genotype was found on 8/11 cattle farms, on 10/15 poultry farms and in 8/22 Campylobacter-positive food samples. High rates of resistance to quinolone were observed: 9/31 (29%) C. jejuni bovine isolates, 4/22 (18%) C. jejuni poultry isolates, and 14/26 (54%) C. coli poultry isolates. Resistance to sulphamethoxazole-trimethoprim was also observed frequently: 18/26 (69%) of the avian C. coli strains, 25/31 (80%) of the C. jejuni strains isolated from poultry and 15/22 (68%) of those isolated from cattle were resistant. There was a significant difference between the rate of resistance to macrolides of C. coli and C. jejuni isolated in poultry, which amounted to 23% and 3%, respectively. This study provided data on the prevalence and antimicrobial resistance of thermophilic campylobacters in south-eastern Italy and confirmed that flaA-typing is an efficient tool to study the epidemiology of Campylobacter strains in short-term investigations.

[Probesci strategy: a cheaper therapeutic approach for obese patients]. / Estrategia probesci: un abordaje terapéutico de menor coste para el paciente obeso.

Obesity has become epidemic in Western countries. From clinical practice, obestity may be considered as a disease characterized by an excess of body fat mass, but patients usually demonstrate different responses to the same therapeutic strategy. It could be possible that the latter may be a consecuence of different pathophysiological factors among obese patients. Therefore, a detailed and thorough phenotyping of patients may enable clinitians to establish groups of patients that may respond in a homogeneous and effective way to a specific treatment for obesity. However, this type of approach can be especially time-consuming and may increase costs. In this study we describe the "PROBESCI" strategy, which is a novel system of studying the obese patient at the first visit, performed in groups of patients, aimed to the collection and analysis of data in order to categorize phenotypic profiles which may achive homogeneous responses to a specific therapy. We also analyze the costs of this new strategy compared to those of an individual consultation, showing a decrease of 58% for the first visit, and of 21% of the total costs throughout treatment.