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Fosfomycin is a phosphonic acid derivative active against a wide spectrum of Gram-positive and Gram-negative pathogens. It is used for the treatment of uncomplicated urinary tract infections (uUTI) or severe infections by oral or intravenous (i.v.) administration. In order to improve its performance and robustness, the fosfomycin strip, an antibiotic gradient diffusion strip, was redeveloped and evaluated in the multicenter study summarized in this paper. ETEST fosfomycin (ETEST FO) clinical performance was evaluated by three study sites on 152 Enterococcus faecalis, 100 Staphylococcus spp. and 330 Enterobacterales in comparison with the CLSI and EUCAST agar dilution reference method. Referring to FDA performance criteria, the ETEST FO achieved 91.0% of essential (EA) and 99.0% of categorical agreement (CA) for Escherichia coli. In addition, 98.0% EA and 93.4% CA were achieved for E. faecalis, with no very major errors (VME) or major errors (ME). According to EUCAST breakpoints for intravenous fosfomycin use, Enterobacterales and Staphylococcus spp. also met ISO acceptance criteria for EA and CA (EA 91.5%, 94.0%, respectively, and CA 98.0% for both). A VME rate of 8.8% was observed for Enterobacterales but the MICs were within EA. A trend to predict lower MICs for Citrobacter spp., E. coli and Salmonella enterica and to predict higher MICs for Klebsiella pneumoniae MICs was observed, while ETEST FO should not be used for Enterobacter cloacae, because of low EA and a high VME rate. The study results support the efficiency of the novel ETEST FO, making it an easy-to-handle tool as a substitute to the classical agar dilution method.

Inflammaging is a low-grade inflammatory state generated by the aging process that can contribute to frailty and age-related diseases in the elderly. However, it can have distinct effects in the elderly living in endemic areas for infectious diseases. An increased inflammatory response may confer protection against infectious agents in these areas, although this advantage can cause accelerating epigenetic aging. In this study, we evaluated the inflammatory profile and the epigenetic age of infected and noninfected individuals from an endemic area in Brazil. The profile of cytokines, chemokines and growth factors analyzed in the sera of the two groups of individuals showed similarities, although infected individuals had a higher concentration of these mediators. A significant increase in IL-1ra, CXCL8, CCL2, CCL3 and CCL4 production was associated with leprosy infection. Notably, elderly individuals displayed distinct immune responses associated with their infection status when compared to adults suggesting an adaptive remodelling of their immune responses. Epigenetic analysis also showed that there was no difference in epigenetic age between the two groups of individuals. However, individuals from the endemic area had a significant accelerated aging when compared to individuals from São Paulo, a non-endemic area in Brazil. Moreover, the latter cohort was also epigenetically aged in relation to an Italian cohort. Our data shows that living in endemic areas for chronic infectious diseases results in remodelling of inflammaging and acceleration of epigenetic aging in individuals regardless of their infectious status. It also highlights that geographical, genetic and environmental factors influence aging and immunosenescence in their pace and profile.

Resume Introduction La thrombose veineuse d’effort est une cause rare de thrombose veineuse profonde du membre superieur (TVPMS) touchant les sujets jeunes et sans comorbidite. Le diagnostic n’est pas toujours facilement evoque. Cas clinique Nous rapportons le cas d’une jeune femme de 23 ans, professeur de francais, droitiere, sous contraception estroprogestative, violoniste, ayant recemment modifie sa facon de jouer, qui presentait un œdeme de la racine du bras droit associe a une erythrocyanose de declivite et a une circulation collaterale du moignon de l’epaule. Les D-dimeres etaient negatifs. La TVP sous-claviere droite n’etait objectivee que sur le deuxieme echo-Doppler. Le choix etait fait d’un traitement anticoagulant seul par heparine de bas poids moleculaire relaye par rivaroxaban, permettant une evolution tres satisfaisante a 48 heures, et ce jusqu’a 4 mois de l’episode, date ou la patiente a ete revue. Discussion Le diagnostic de TVPMS est avant tout un diagnostic clinique. Un score de probabilite clinique existe et permet d’introduire une anticoagulation meme si la TVP n’est pas objectivee par echo-Doppler, ce qui est possible compte tenu de la superposition claviculaire dans cette region. La suspicion de TVP d’effort doit faire rechercher une activite pouvant paraitre peu intense mais repetee (en hyper-abduction) comme ici la pratique du violon. Le traitement de ces thromboses repose sur les anticoagulants tandis que la place de la chirurgie et des methodes pharmaco-mecaniques doit encore etre precisee. Conclusion Devant une thrombose du membre superieur chez un sujet jeune et sans comorbidite, une thrombose d’effort (syndrome de Paget-Schroetter) doit etre evoquee facilement. Des etudes comparant les differentes options therapeutiques pourraient permettre d’homogeneiser les prises en charge, malgre l’heterogeneite des situations cliniques.

Background: Clinical and molecular factors are essential to define the prognosis in patients with glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status, age, Karnofsky Performance Status (KPS), and extent of surgical resection are the most relevant prognostic factors. Our investigation of the role of gender in predicting prognosis shows a slight survival advantage for female patients. Methods: We performed a prospective evaluation of the Project of Emilia Romagna on Neuro-Oncology (PERNO) registry to identify prognostic factors in patients with GBM who received standard treatment. Results: A total of 169 patients (99 males [58.6%] and 70 females [41.4%]) were evaluated prospectively. MGMT methylation was evaluable in 140 patients. Among the male patients, 36 were MGMT methylated (25.7%) and 47 were unmethylated (33.6%); among the female patients, 32 were methylated (22.9%) and 25 were unmethylated (17.9%). Survival was longer in the methylated females compared with the methylated males (P = 0.028) but was not significantly different between the unmethylated females and the unmethylated males (P = 0.395). In multivariate analysis, gender and MGMT methylation status considered together (methylated females vs. methylated males; hazard ratio [HR], 0.459; 95% confidence interval [CI], 0.242-0.827; P = 0.017), age (HR, 1.025; 95% CI, 1.002-1.049; P = 0.032), and KPS (HR, 0.965; 95% CI, 0.948-0.982; P < 0.001) were significantly correlated with survival. Conclusions: Survival was consistently longer among MGMT methylated females compared with males. Gender can be considered as a further prognostic factor.

DNA methylation profiles of the 27 DMRs between WS and CTR. For each DMR, the title of the plot reports the name of the gene/genes in which the DMR maps, the not-adjusted P value of the ANOVA comparison between WS and CTR, and the length of the DMR in base pairs. Below the plot, the name of the CpG island and the position of the DMR respect to the CpG island are reported. (PDF 58Â kb)

OBJECTIVES: The anesthetic gas xenon is reported to preserve hemodynamic stability during general anesthesia. However, the effects of the gas during shock are unclear. The objective of this study was to evaluate the effect of Xe on hemodynamic stability and tissue perfusion in a canine model of hemorrhagic shock. METHOD: Twenty-six dogs, mechanically ventilated with a fraction of inspired oxygen of 21% and anesthetized with etomidate and vecuronium, were randomized into Xenon (Xe; n = 13) or Control (C; n = 13) groups. Following hemodynamic monitoring, a pressure-driven shock was induced to reach an arterial pressure of 40 mmHg. Hemodynamic data and blood samples were collected prior to bleeding, immediately after bleeding and 5, 20 and 40 minutes following shock. The Xe group was treated with 79% Xe diluted in ambient air, inhaled for 20 minutes after shock. RESULT: The mean bleeding volume was 44 mL.kg−1 in the C group and 40 mL.kg−1 in the Xe group. Hemorrhage promoted a decrease in both the cardiac index (p

Exercise-induced thrombosis is a rare cause of deep venous thrombosis (DVT) of the upper limb and usually affects young subjects without comorbid conditions. The diagnosis may be challenging.A 23-year-old female right-handed French teacher and amateur violin player presented with edema of the root of the right arm associated with erythrocyanosis of the extremity and collateral circulation of the shoulder. History taking revealed oral contraception and recent change in violin playing habits. D-dimers were negative. A second duplex-Doppler was required before visualization of a DVT in the right subclavian vein. The patient was given low-molecular-weight heparin alone, followed by rivaroxaban. The outcome was very favorable at 48h. The patient was seen at 4 months and had not had a recurrent episode.The diagnosis of DVT of the upper limb is basically clinical. There is a clinical probability score for the introduction of anticoagulation even if the duplex-Doppler fails to visualize DVT, a situation that can occur due to the clavicular superposition in this region. Exercise-induced DVT should be suspected in patients with minimally intense but repeated exercise (hyper-abduction), e.g. as here playing the violin. Anticoagulation is the treatment of choice. The role for surgery and pharmacomechanical strategies remains to be defined.Exercise-induced thrombosis (Paget-Schroetter syndrome) should be suspected in young patients free of any comorbidity who develop a thrombosis of the upper limb. Studies comparing different therapeutic options would be useful to achieve more homogeneous management practices despite the heterogeneous clinical presentations.

Rationale The purpose of this paper is to explore new perspectives about difficulties academicians may have communicating with clinicians, obtaining subjects, and gaining compliance for their research. Aims and Objectives Evidence-based medicine (EBM) has been defined as an integration of best research evidence, clinical expertise, and patient values; however, clinical observation and experience are placed last in the evidence hierarchy with the randomized controlled trial held as the standard for clinical intervention. This paper describes how the hierarchical model of power in the research community obstructs new areas of knowledge, and how clinicians create resistance. Methods Foucault gave new perspectives describing how power circulates through individuals within organizational discourse. Drawing on literature and experience, and using a framework based on postmodern theoretical concepts, this paper examines patterns of discourse, subjectivity, resistance, and power/knowledge within the physical therapy profession. Results The hierarchical discourse of medical knowledge produces opposition rather than collaboration between researcher, clinician, and patient. Alleviating perceptions of dominance and creating connections produces cohesion within medical communities. Conclusions Evidence to practice and practice to evidence redefines EBM as a circular integration of best research evidence, clinical expertise, and patient values.

This study investigated features of skeletal muscle ageing in elderly individuals having previously undergone unilateral total knee arthroplasty (TKA) and whether markers of sarcopenia could be mitigated by a 12-week alpine skiing intervention. Novel biomarkers agrin, indicative of neuromuscular junction (NMJ) degeneration, tumor suppressor protein p53, associated with muscle atrophy, and a new ultrasound-based muscle architecture biomarker were used to characterize sarcopenia. Participant details and study design are presented by Kösters et al. (2015). The results of this study show that NMJ degeneration is widespread among active septuagenarians previously subjected to TKA: all participants showed elevated agrin levels upon recruitment. At least 50% of individuals were identified as sarcopenic based on their muscle architecture, supporting the hypothesis that NMJ alterations precede sarcopenia. Notably, sarcopenia was strongly associated with the expression of p53, which seems to confirm its validity as a biomarker of muscle atrophy. Training did not significantly modify any of these biomarkers. In view of the lack of accretion of muscle mass in response to the alpine skiing intervention, we hypothesize that local muscle inflammation and oxidative stress may have blunted the anabolic response to training and promoted muscle breakdown in this elderly post-TKA population.

In previous investigations we pursued the hypothesis that lifelong, chronic antigenic load (CAL) is the major driving force of immunosenescence, which impacts on human lifespan by reducing the number of virgin antigen-non experienced (ANE) T cells, and filling the immunological space with expanded clones of memory and effector, antigen-experienced (AE) T cells. A model has been proposed to relate CAL with the conversion rate from ANE to AE CD8+ T cells. In addition, in order to account for individual variations of immunosenescence and lifespan, a noise term has been introduced to describe the individual fluctuations of CAL. This model was able to follow with a reasonable approximation the age-related decrease of ANE CD8+ T cells, as well as human survival curves. In this paper we extend this approach to historical survival curves, starting from 1750 until present days, and show that the quality of the fit of historical demographic data improves as we approach the recent, quantitative and qualitative decrease of CAL. Indeed, the almost linearity in the increase of lifespan and in the decrease of the noise fluctuation amplitude within this historical period suggests that the improvement of life conditions has steadily lowered the intensity of CAL and restricted the variability which results from the interaction between the individuals and their immunological environment. On the whole, this approach allows to appreciate when and how immunosenescence has started to impact on survivorship, and predicts its increasing, crucial role in explaining human mortality in hygienized, economically developed societies.

Background As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. Methods Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. Results Two hundred sixty-seven GBM patients (median age, 64 y; range, 29–84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2–12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0–18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248–0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388–0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328–0.986; P = .0446). Conclusions The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.

L’hemodynamique veineuse cerebro-spinale (HVCS) depend des memes parametres que la circulation veineuse systemique, a savoir les diverses pressions intraveineuses (PIV) et extraveineuses (PEV) qui modulent le facteur cle du drainage qu’est la pression transmurale (PTM) ainsi que la compliance parietale qui, autorisant d’importantes variations de volume veineux, permet d’amortir les variations de pression (capacitance ou effet reservoir). Elle s’en singularise par des valeurs specifiques de ces parametres et de leur regulation.

Ageing is associated with complex remodelling in the phenotypic and functional profiles of T lymphocytes. We investigated whether expression of CD28 antigen on T cells is conserved throughout adulthood and ageing in humans. For this purpose we analysed T cells obtained from peripheral blood of 102 healthy people of ages ranging from 20 to 105 years. We found an age-related increase of CD28- T cells in percentage and absolute number, predominantly among CD8+ T cells. CD28- T cells from aged donors analysed by flow cytometry appeared as resting cells (not expressing CD25, CD38, CD69, CD71, DR), bearing markers of cytotoxic activity (CD 11b and CD 57) and with a phenotype compatible with 'memory' cells (up-regulated CD2 and CD11a; CD62L absent). At the functional level, freshly isolated purified CD28- CD8+ T cells showed high anti-CD3 redirected cytotoxic activity against Fc-bearing P815 cells. The same activity tested on freshly isolated bulk T lymphocytes was significantly augmented with age. We found a positive correlation between age, number of CD8+ CD28- T cells and anti-CD3 redirected cytotoxicity by freshly isolated T cells. These data suggest that an activation of unknown nature within the cytotoxic arm of the immune system occurs with age. We speculate that these cytotoxic T lymphocytes (CTL) in vivo may constitute armed effector cells for immediate killing of targets bearing peptides from pathogens of intracellular origin.

Stress can be seen as the body's most important and complex reaction to ensure survival involving the neuroendocrine systems and a variety of other organs. The investigation of the evolutionary bases of stress argues that the basic mechanisms and molecules involved in stress (CRH, ACTH, glucocorticoids, biogenic amines and cytokines) are fundamentally similar and well preserved throughout evolution in different species and taxa. A review of available data highlights that the involvement of immunity during stress response has a strong evolutionary basis and is not a mere consequence of glucocorticoid hormone release. We propose that the evolutive cellular bases of stress are to be identified in immune cells, such as invertebrate hemocytes, producing a variety of cytokine-like molecules, capable at the same time of producing a variety of hormone- and neuropeptide-like molecules and of performing a proto-stress response (release of biogenic amines). We conclude that stress, a highly conserved reaction remarkably similar in different species and taxa, is a fundamentally positive type of adaptive reaction.

Quebec City - Quebec - Canada

Epidemiological studies have suggested, but not demonstrated, a role of exposure to 50/60-Hz magnetic fields in increasing cancer risk in man (workers and the general population). A possible target of magnetic fields is the immune system. In particular, it is known that an important defence against cancer is represented by natural killer (NK) cells capable of killing cancer cell targets. To test this hypothesis, human NK cells, stimulated or not with phytohaemagglutinin or interleukin 2, were exposed to 50-Hz sinusoidal magnetic fields before or during the cytotoxicity test, and then mixed with a variety of target cancer cell lines (Daudi, Raji, U937, H14, IGROV, SW626, K562, HL60). The experiments were performed in two laboratories (Rome and Modena) by means of two different exposure systems. The results of both laboratories suggest that 50-Hz sinusoidal magnetic fields with flux densities up to 10 mT do not affect the cytotoxic activity of human NK cells.

Continuous radio-wave monitoring of the Geminid activity in December 1992 and 1993 by using a forward scatter (FS) bistatic radar over the Bologna-Lecce baseline (700 km) in Italy, reveals peculiar structural aspects of the stream in terms of signal amplitude-rate and duration-rate dependence. The observational results of the Geminid display obtained in the two consecutive years with differentiated peak levels of transmitted power, exhibit different time distributions of underdense meteors against the signal received power. Both sets of the data relative to the peak activity in December 12–14, show reflection properties of Geminids which are atypical if compared with echoes from cometary-type showers, with really high echo counts at mid-upper levels of the peak received power. An assymmetric curve of activity of the Geminids complex is evidenced, with the peak flux of smaller particles occurring earlier than that of larger ones.

The key goal of diabetes management is to prevent complications. While the patho-physiological mechanisms responsible for diabetes complications have been extensively studied, at present it is impossible to predict which patient with diabetes could develop complications. In recent years, the role of leukocyte telomere length in the pathogenesis of cardiovascular disease and Type 2 diabetes has been investigated. However, studies aiming to investigate the role of telomeres in the development and progression of Type 2 diabetes, as well as diabetic complications, are still lacking. As a consequence, this study aimed to verify whether leukocyte telomere length is associated with the presence and the number of diabetic complications in a sample of patients with Type 2 diabetes.This is a cross-sectional study. Nine hundred and one subjects were enrolled, including 501 patients with Type 2 diabetes, of whom 284 had at least one complication and 217 were without complications, and 400 control subjects. Leukocyte telomere length was measured by quantitative real-time PCR.Patients with diabetes complications had significantly shorter leukocyte telomere length than both patients without diabetes complications and healthy control subjects. Moreover, among patients with diabetes complications, leukocyte telomere length became significantly and gradually shorter with the increasing number of diabetes complications. The magnitude of the effect of the decrease of the abundance of telomeric template vs. a single-copy gene length (T/S ratio) on complications is described by the estimated odds ratio OR=5.44 (95%CI 3.52-8.42).The results of the study support the hypothesis that telomere attrition may be a marker associated with the presence and the number of diabetic complications.

A new method for the cytofluorimetric analysis of mitochondrial membrane potential in intact cells has been developed by using the lipophilic cationic probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1), whose monomer emits at 527 nm after excitation at 490 nm. Depending on the membrane potential, JC-1 is able of forming J-aggregates that are associated with a large shift in emission (590 nm). The color of the dye changes reversibly from green to greenish orange as the mitochondrial membrane becomes more polarized. In two human cell lines (K562 and U937), we have studied by flow cytometry the changes in membrane potential provoked by the K+ ionophor valinomycin, a drug known to affect mitochondrial membrane potential, while the K+/H+ ionophor nigericin, known to affect intracellular pH but not mitochondrial membrane potential, was used as control. The incubation with valinomycin for 10 min. at 37 degrees C in a low K+ medium provoked a marked and dose-dependent reduction in JC-1 greenish orange fluorescence, while nigericin had no effect.

The distribution of the energy reflected by a meteor trail is strongly connected to the ionization density distribution across and along a meteor trail. Recent forward-scatter observations over the Bologna-Lecce baseline in Italy carried out in 1991–92, show that the number of underdense meteor trails (with electron line densityq≤2.1014 electrons/mvs. peak signal amplitudes decreases more rapidly with the increasing signal level than what predicted. An exponential (simple and/or log-normal) model is proposed, by taking into account different signal-to-noise ratio thresholds and the Kolmogorov-Smirnov (K-S) procedure is used to test the overall goodness of fit between the set of observations and specified theoretical distributions. It is shown that this model provides a better fit to data mainly for middle-high levels of received power and for values ofq≥1013 electrons/m.

This work investigates the variability of planetary-scale waves from motion field observations in the middle atmosphere carried out at the Budrio radar station near Bologna (45°N; 12°E) in the 1989–1990 winter during DYANA (DYnamics Adapted Network for the Atmosphere). Meso-thermospheric zonal winds associated with long-period waves give evidence of significant energy input from below mainly in the course of the two strat-warmings recorded at the end of January and in mid February 1990. Amplification of 10-day waves in the upper mesosphere and lower thermosphere just a few days before the temperature peak at the 10hPa stratospheric level, and the effects induced by these waves on tidal and mean fields, are here taken into account to clarify the influence and the evolution of strat-warmings in the middle atmosphere. Nonlinear mixing processes between planetary and tidal oscillations are indicated to be responsible for the short-term variability pointed out in the amplitude variations of tides.

The present paper summarizes the main findings related to aging and immune neuroendocrine responses in invertebrates. In particular, the functional aspects and the genes involved are examined. A possible mechanism of correlation between aging and functioning of immune-neuroendocrine related genes is also discussed.

The immune system in conjunction with the neuroendocrine circuit form the ‘immune-neuroendocrine suprasystem,’ which is able to integrate immunity, stress response, and inflammation. This network is conserved in invertebrates and vertebrates, and a pool of well-known molecules (pro-opiomelanocortin-derived peptides, cytokines, biogenic amines, glucocorticoids, and nitric oxide) act as information mediators. The macrophage is the principal actor in regulating and integrating responses in this complex system. In this article, we discuss the evolution of the immune-neuroendocrine system, the principal age-related modifications, and the association with important inflammatory-based disorders such as Alzheimer’s disease, major depression, frailty, as well as other age-related pathologies.

The exposure of human polymorphonuclears to an extremely low frequency (3 Hz) electromagnetic field for 1 hour had an enhancing effect on thromboxane A2 release stimulated by A23187 calcium ionophore. On the contrary, IL-1 stimulation of TxA2 production was not affected by an electromagnetic field, suggesting that interleukin-1 influence on thromboxane synthesis is not due to a calcium ionophore-like action.

Recent stratospheric warmings are herewith examined in association with the influence of long-period planetary waves. Investigations on height and time variations of geopotential and wind data obtained in the winters of 1980–87 at different tropo-stratospheric levels from messages of the radiosondes situated in the Central Europe take necessarily into account the propagation of quasi-stationary and free planetary waves which in proper conditions mutually interfere with each other. The definition and evolution of the different types of warming are connected with the structure of these waves and enable one to interpret more completely coupling phenomena among different regions of the neutal atmosphere during the most disturbed winters. Distinct spectral analysis methods permit to extract from geopotential data series prominent wave periods within 1÷3 weeks. Westerly winds in the stratosphere reach unusual amplitudes before a sudden stratospheric warming, and this amplification is seen to be in connection with transient normal modes which are able to interact even with the mean circulation of the mesosphere and lower thermosphere.

The development of a chronic, low grade, inflammatory status named "inflammaging" is a major characteristic of aging which plays a critical role in the pathogenesis of age-related diseases. The NU-AGE rationale is that a one year Mediterranean whole diet (considered by UNESCO a heritage of humanity), newly designed to meet the nutritional needs of the elderly, will reduce inflammaging in fully characterized subjects aged 65-79 year of age, and will have systemic beneficial effects on health status (physical and cognitive). Before and after the dietary intervention a comprehensive set of analyses, including omics (transcriptomics, epigenetics, metabolomics, metagenomics) will be performed to identify the underpinning molecular mechanisms. NU-AGE will set up a comprehensive database as a tool for a systems biology approach to inflammaging and nutrition. NU-AGE is highly interdisciplinary, includes leading research centres in Europe on nutrition and aging, and is complemented by EU multinational food industries and SMEs, interested in the production of functional and enriched/advanced traditional food tailored for the elderly market, and European Federations targeting policy makers and major stakeholders, from consumers to EU Food & Drink Industries.

Plasminogen activator inhibitor type 1 (PAI-1) is an independent cardiovascular risk factor and increases in patients with Type 2 diabetes mellitus. The 4G/5G polymorphism of PAI-1 has been reported to be involved in the incidence of cardiovascular disease by regulation of PAI-1 levels, but this relation is still under debate. The aim of the study was to test the effect of 4G/5G polymorphism on the lowering of PAI-1 levels in Type 2 diabetic patients during vitamin E supplementation. Ninety-three Type 2 diabetic subjects (age +/- SD, 62.1 +/- 6.1 yr) were enrolled and treated with vitamin E (500 IU/die) for 10 weeks. We determined the 4G/5G polymorphism and PAI-1 activity at baseline, during (5th and 10th week) and after (30th week) vitamin E supplementation. No significant differences were found in PAI-1 and its determinants among the three genotypic groups at baseline. Decrements were detected in the whole group in PAI-1 at the 5th and the 10th week from baseline followed by an increase at the 30th week (p0.001). Patients with 4G/4G and 4G/5G genotypes showed a different trend with respect to those with 5G/5G in PAI-1. In particular, there was a decrease in 4G/4G and 4G/5G PAI-1 levels from the 10th week, while a decrease in 5G/5G PAI-1 was observed from the 5th week (p0.01). The delayed decrease, found in patients with at least one 4G allele with respect to those with 5G/5G genotype, demonstrates that 4G/5G polymorphism mainly influences the rate of decrease of PAI-1 after supplementation with vitamin E in Type 2 diabetic subjects.

A considerable public concern about cancer risk from acrylamide-rich foods followed the announcement that high concentrations of acrylamide are found in fried potatoes and potato chips and, more generally, in starch-containing foods cooked at high temperatures. From a series of hospital-based case-control studies conducted in Italy and Switzerland between 1991 and 2000, we have analyzed the relation between intake of fried/baked potatoes and cancer risk. The cancer sites considered were oral cavity and pharynx (749 cases, 1,772 controls), esophagus (395 cases, 1,066 controls), larynx (527 cases, 1,297 controls), large bowel (1,225 colon and 728 rectum cases, 4,154 controls), breast (2,569 cases, 2,588 controls) and ovary (1,031 cases, 2.411 controls). All cancer cases were incident and histologically confirmed. Controls were subjects admitted to the same network of hospitals of cases for acute, non-neoplastic conditions. All the odds ratios (OR) for the highest vs. the lowest tertile of intake ranged between 0.8-1.1. We found no evidence of interaction with age, gender, alcohol and tobacco use. Our data provide reassuring evidence for the lack of an important association between consumption of fried/baked potatoes and cancer risk. (C) 2003 Wiley-Liss, Inc.

A new method based on the recently developed relative risk approach is introduced, and applied to data from Italian centenarian study (965 subjects aged from 13 to 109 years old) for investigating influences on longevity by Tyrosine Hydroxylase (TH) gene variability. The strategic parameterization enables the model to disentangle the various ways by which HUMTHO1.STR alleles (alleles 6, 7, 8, 9, 10*, 10, as defined according to the number of repeats) may contribute in reducing or increasing the hazard of death with different patterns of influences. Among all the alleles, we have found that allele 10* (10 imperfect repeats) shows a remarkable dominant and beneficial effect that reduces the log hazard of death in an additive manner. The results confirm that HUMTHO1.STR polymorphism is involved in the modulation of human longevity.

We instituted a low-repetition, high-intensity inspiratory muscle strength training (IMST) program and progressively longer spontaneous breathing periods (SBPs) in a group of medically complex patients who were dependent on mechanical ventilation (MV) and had failed to wean.IMST was provided to 10 consecutive patients (four men, six women; mean [+/- SD] age, 59 +/- 15 years) who had failed to wean from MV by conventional methods foror= 7 days. Prior to initiating IMST, patients had received MV support for a mean of 34 +/- 31 days. Daily IMST consisted of four sets of six breaths through a threshold inspiratory muscle trainer that had been set at an intensity to yield an exertion rating of 6 to 8 of a maximal value of 10. At the start of IMST, patients were tolerating 2.1 +/- 3.4 consecutive hours of SBPs. The duration of the SBPs was increased daily, as tolerated. Patients were considered to have been weaned from MV when they were able to breathe without MV support for 24 consecutive hours.After 44 +/- 43 days of IMST, 9 of 10 patients were weaned from MV. The initial IMST pressure was 7 +/- 3 cm H(2)O, and it was increased to 18 +/- 7 cm H(2)O (p0.05).These results indicate that an IMST protocol that produces significant increases in threshold training pressure, in combination with progressive SBPs, aids in weaning patients from MV. Although promising, these preliminary observations must be tested in a controlled trial.

Female transgenic FVB mice transfected with the mammary erbB-2/neu oncogene were injected 0.1 ml 0.9% solution of sodium chloride (control), 1 meg Vilon peptide (Lys-Glu) or Epitalon peptide (Ala-Glu-Asp-Glu), s.c., 5 days in succession once a month, beginning from the age of 2 months. The characteristics of mammary tumor induction in the control and experimental groups did not differ until the age of 9 months. Later on, Epitalon-treated mice revealed distinct inhibition of carcinogenesis. One tumor per animal was detected in 7% (control), 4% (Vilon) and 16% (Epitalon) (p0.05). Two or more tumors per animal were in 75%, 95% and 56%, respectively (p0.05). Largest diameter of mammary adenocarcinoma in the Epitalon group was smaller than in controls by 33% (p0.05). Although the number of mice with metastases to the lung in all three groups was practically identical, their incidence in the Vilon group was 2.6 times higher than in Epitalon-treated animals (p0.05). Largest diameter of metastasis in the Epitalon group was the smallest, too. Our data point to inhibition of mammary carcinogenesis by Epitalon in transgenic erbB-2/neu mice.

The logistic regression model is a popular model for data analysis in epidemiological research. In this paper, we use this model to analyze genetic data collected from gene-longevity association studies. This new approach models the probability of observing one genotype as a function of the age of investigated individuals. Applying the model to genotype data on the TH and 3'ApoB-VNTR loci collected from an Italian centenarian study, we show how it can be used to model the different ways that genes affect survival, including sex- and age-specific influences. We highlight the advantages of this application over other available models. The application of the model to empirical data indicates that it is an efficient and easily applicable approach for determining the influences of genes on human longevity.