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The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in rat ventral PAG (vPAG) that encode fear memory through signalling the onset and offset of an auditory conditioned stimulus during presentation of the unreinforced conditioned tone during retrieval. Some units only display CS+ onset or offset responses and the two signals differ in extinction sensitivity, suggesting they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that: (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to: (a) disruption of the temporal precision of vPAG offset, but not onset responses to the unreinforced conditioned tone, and (b) an increase in duration of freezing behaviour. And (ii) chemogenetic manipulation of the MCN-vPAG projection during fear acquisition: (a) reduces the occurrence of fear- related ultrasonic vocalisations and (b) during subsequent retrieval, slows the extinction rate of fear- related freezing. These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways; raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities.Impact StatementCerebellar-periaqueductal grey interactions contribute to fear conditioned processes and, as such, provide a novel target for treating psychological conditions including post-traumatic stress disorder.

Background and objectives A randomized trial was conducted in Tuscany, Italy, to evaluate the effectiveness of HPV vaccination for 25 year old (yo) women who attend at the first time cervical cancer screening. The trial also evaluated immune response after vaccination, reductions of cytological abnormalities and the impact of vaccination on screening activity. Study design During 2010–2011, all 25 yo women who were invited to the Florence cervical cancer screening programme were also asked to participate in the trial. Enrolled women were randomized into study and control groups. Those in the study group were offered HPV vaccination after the usual Pap test. The cytology distribution and prevalence for any high risk (hr) HPV type were compared at the subsequent screening round in an intention-to-treat analysis. The impact of HPV vaccination was evaluated per protocol comparing vaccinated women with the control group. Results Our results showed a reduction in HPV prevalence at recall for any hr-HPV type but it was not statistically significant, being 17.1% vs 21.4%, p = 0.20 in the study and control groups, respectively. If we restricted the analysis to vaccinated women, strong reductions of the HPV 16,18,31,33,45 and HPV 31,33,45 infections were observed, being 5.3% vs 12.8%, p < 0.01 and 2.1% vs 6.5%, p = 0.02, respectively. Significant reductions for any hr-HPV infection and for HPV 16 infection were also observed in women HPV 16/18 negative at enrolment, being 12% vs 21.4%, p < 0.01 and 0.6% vs 6.7%, p-value < 0.01, respectively. In women hr-HPV negative at enrolment no infections due to HPV 16 or HPV 18 were observed and there was a big reduction for any hr-HPV infection (7.1% vs 21.4% p < 0.01). A strong antibody response was observed not only for HPV 16 & 18 but also for their related types. Conclusions Our findings suggest that HPV vaccination at the age 25 is beneficial if it is offered to hr-HPV negative women. Our data will assist in developing a cost effectiveness model for choosing the best strategy to integrate screening and vaccination for the coming years. Clinical trial registration number is NCT02296255. (Less)

Table S1. Characteristics of the screening programmes, and design and results of studies of the impact of mammography screening on the incidence of advanced breast cancer. (See the full text of the article for abbreviations) [45â 48]. (DOC 197 kb)

The debate about the overall benefits and harms of breast cancer screening continues. Sceptics continue to question the likely breast cancer mortality reduction and emphasise the potential harms, including over-diagnosis and over-treatment. These issues will be debated following presentations on the current evidence. There is also continuing interest in the benefits and harms of targeting screening to women at increased risk. Current thoughts and evidence on this will be presented. 1. The Benefits and Risks of Screening Mammography − A Debate Update on the evidence for breast cancer screening in 50−70-year-old women (L. Nystrom) Population-based breast cancer screening programmes (BSPs) using mammography have been implemented in most counties in West Europe in accordance with the European Guidelines using the results of the various randomised controlled trials (RCTs) as the justification. The efficacy of these RCTs has been questioned, and as a result the effectiveness of the BSPs has been re-evaluated. A number of different approaches has been applied. Initially, simple analysis of the trends in breast cancer mortality before and after the introduction of the BSP was used. This approach has significant limitations as the majority of those dying from breast cancer in the early years after the start of the BSP were diagnosed before the introduction of the BSP. Several more sophisticated approaches have since been applied. A crucial issue is being able to link the cancer registry data with the cause-of-death registry on an individual basis to be able to calculate the incidencebased breast cancer mortality, making comparisons over time or between geographical areas with and without BSPs. The results from studies based on incidencebased mortality, case-referent approach and trend analysis using Poisson regression and/or joinpoint analysis will be presented, summarised and discussed. Evidence for screening women under 50 and over 70 years (H.J. de Koning) While the majority interpret the results of the screening trials as showing a significant breast cancer mortality benefit for women aged 50−70 years, there is much less agreement about the benefits of screening in older and younger women. The evidence that is available from both trials and trial-based modelling studies suggests that there is a benefit, although at a significantly lower level. In younger women earlier diagnosis appears to have less benefit because of the greater likelihood of aggressive characteristics of the cancer typical in younger women; in older women the opposite is true and the exponential increase in competing causes of death becomes more important. The data will be presented and discussed. A randomised trial in one million UK women to assess the benefits of adding one extra screening visit (R. Peto) Continuing with the theme of screening older and younger women and the lack of data from randomised trials in the UK a population-based trial of offering screening to half of all women in the age ranges 47−50 and 70−73 has been started. This is the largest randomised trial in the world. The aims, methodology and means of assessment of the results will be discussed. The adverse effects of screening (E. Paci) With medical interventions such as screening there is always a need to balance the benefits and harms. This issue has been taken into consideration particularly in the evaluation of the performance of breast cancer screening, with special attention being given to the risk of falsepositive results. Excess in cancer diagnosis (over-diagnosis) in screened compared to unscreened populations is well known in breast, lung and prostate screening. This over-diagnosis is recognised only at the population level. Estimates of over-diagnosis were possible in the few RCTs that did not offer screening to the control group and is reported to be between 7 and 14%. Estimates of over-diagnosis from 0959-8049/$ – see front matter © 2012 ECCO − the European CanCer Organisation. All rights reserved. Extended Abstracts S9 observational studies vary widely, in the UK programme for example varying from the 4% reported by Duffy to the 52% estimated by Jorgensen and Gotzsche. Considering only the studies which have taken into consideration adjustment for underlying incidence and lead time, the range of the estimates of observational studies which considered underlying trends and lead time adjustment in Europe are between 0 and 11%. Recall rate is one the most important performance parameters in breast screening. In the European Guidelines positive and negative predictive value and the level of false positive assessment are the subject of quality evaluation of screening programmes. The cumulative risk of false positives in women undergoing biennial screening has been estimated at 20.8% in Norway and 15.2% in Italy, substantially different from that in the United States where up to 50% of women screened may experience a false-positive recall. 2. Screening Higher-Risk Groups? Pathological risk factors and screening (A. Salomon) Much more attention has been given to the increased risks of breast cancer associated with family history than to other factors − such as lifestyle, hormone therapy and breast density − and pathological risk factors. Pathological risks associated with entities such as atypical ductal hyperplasia (ADH) and lobular neoplasia (lobular carcinoma in situ, LCIS, and atypical lobular hyperplasia, ALH) have risks that are equal to and higher than family history, and strategies for screening should always include these. The range of pathological risk factors and the mechanism for this underlying risk will be discussed. The evidence for mammography screening after breast cancer treatment? Health technology assessment (F. Gilbert) Following treatment for primary breast cancer disease can recur either following conservation surgery − ipsilateral breast tumour recurrence (IBTR) or in the opposite breast − metachronous contralateral breast cancer (MCBC). Recurrence rates are between 0.4 and 0.8% each year and are higher than the rate of breast cancer in the normal unaffected population. Young age ( 15% LTR) reported sensitivities ranging from 71 to 93%. This is twice as high as the sensitivity of mammography. Although breast MRI also detects more benign disease, the positive predictive value of MRIinduced biopsies is 0.35–0.45 and is not different from mammographic screening. However, there are some substantial drawbacks to screening with breast MRI. We do not know if all of the extra cancers detected are clinically relevant, although retrospective comparisons suggest that they might be, and recent screening trials indicate better disease-free survival and overall survival for MRI-screendetected breast cancer. There is also uncertainty about the cost effectiveness of MRI as a breast screening tool. Current recommendations are to reserve MRI screening for women with substantially increased risk, but in the future we might select women for MRI screening when the performance of mammographic screening is expected to be poor (e.g. in women with very dense breasts). Evidence-based higher-risk screening (L. Holmberg) The Department of Health in the UK has decided to introduce breast screening for younger women ( 8) should be offered screening with MRI from the age of 30, while those at moderate risk should be offered mammographic screening from the age of 40. The data analyses and rationale for these recommendations will be discussed. Conflict of interest statement

Introduction Le syndrome du bebe secoue (SBS) est un probleme de sante publique actuel. En avril 2016, la HAS a lance un appel a la candidature d’experts afin d’elaborer un groupe de travail dans le but d’etablir des recommandations de bonnes pratiques [1] . Le secouement de l’enfant est responsable de diverses sequelles neurologiques, qu’elles soient transitoires ou definitives, et perturbe frequemment le developpement moteur de l’enfant. D’autres deficiences (sensitives, sensorielles, cognitives) peuvent survenir. Certaines atteintes vont s’aggraver avec la croissance, d’autres vont apparaitre plus tardivement, revelant principalement des troubles de l’apprentissage et du comportement [2] , [3] . L’objectif de cette etude est d’analyser l’evolution clinique depuis sa decouverte en 1970 par M. Caffey jusqu’a nos jours. Le but est d’informer de facon preventive les masseurs-kinesitherapeutes sur cette maltraitance infantile et ses consequences afin d’adapter leurs prises en charge therapeutiques. Materiel, population et methode Nous avons realise une revue de la litterature en interrogeant principalement les bases de donnees suivantes : HAS, Medline, EMConsulte et PEDro. D’autres supports bibliographiques manuels et informatises orientes exclusivement sur le SBS ont ete utilises. La majorite des ressources selectionnees datent des 15 dernieres annees et traitent des programmes preventifs mis en place dans differents pays tels que le Canada et les Etats-Unis. Resultats En 2011, une audition publique organisee par la SOFMER a permis la publication d’un document faisant office de recommandations de la HAS [4] . Il en conclut que le SBS se definit frequemment comme une association de signes cliniques, regroupant un hematome sous-dural et des hemorragies retiniennes. Des lesions neurologiques, osseuses et cutanees peuvent s’ajouter. Conclusion ou discussion Les autorites competentes s’interessent de plus en plus au SBS. La complexite du diagnostic retarde la prise de soins adaptee a l’enfant. L’evaluation pluridisciplinaire est importante afin de determiner la gravite du traumatisme. Dans nos pratiques, il est important de prendre en consideration les sequelles du secouement de l’enfant et non le SBS en tant que tel. Cet acte, conscient ou non, ne doit pas interferer sur le regard du therapeute vis-a-vis des parents et de l’enfant. La vigilance quant a l’evolution des deficiences doit s’effectuer depuis le traumatisme et se prolonger sur plusieurs mois.

In the Province of Florence (central Italy), the Center for Cancer Prevention (CSPO) runs a breast clinic for early diagnosis of breast cancer at which women can present as self-referrals or be referred by a general practitioner. About 55% of breast cancers incident in the area were diagnosed at CSPO. This paper evaluates the differences observed in 10-year observed and relative survival between hospitals and breast clinic cases. A population-based data set of 1182 invasive cases diagnosed in the years 1985 and 1986 (Tuscany Cancer Registry) was analyzed. Cox models were used to evaluate the effects of place of diagnosis on observed survival. In comparison to hospital cases, breast clinic cases showed a significantly higher frequency of localized cancer (55% vs 37%) and a better relative survival, persistent at 10 years of follow-up (69% vs 58%). The better survival of breast clinic cases persisted after age adjustment (hospitals cases; RR = 0.71, 95% CI: 0.60-0.84) and after age + diffusion of disease adjustment (RR = 0.79, 95% CI: 0.66-0.93). For regionally diffused cancers, breast clinic cases showed a 10-year survival significantly better than hospital cases. In conclusion, even if some bias (i.e. lead-time and length bias) could affect the comparison, breast clinic cases showed a better survival persistent until 10 years after diagnosis. An earlier stage distribution explained, at least partly, the different prognosis.

The hardening of metals involves the immersion of hot components in mineral oil with production of aerosols containing PAHs, to wich workers can be exposed. The determination of airborne PAHs and urinary 1-hydroxypyrene (1-OHPy) was performed for a group of workers and the latter resulted within the reference values. However, the average 1-OHPy concentration on metal workers (0.07 microg/g creatinine) was statistically different from the average value obtained for a group of employees (0.03 microg/g creatinine), highlighting the risk of exposure to PAHs. Therefore, being these potentially carcinogenic compounds, interventions were prescribed in order to reduce the risk of occupational exposure.

This study is aimed at testing the cochlear functionality using otoacoustic emissions, analyzing the synergistic effects of simultaneous exposure to noise and organic solvents EBTx on workers of a glass-reinforced plastic products factory. Exposure to organic solvents was assessed using ambiental measurements and evaluation of the salivary concentration. Biological monitoring was performed evaluating the urinary concentration of the styrene metabolites. Statistical analysis shows that otoacoustic tests can discriminate between different exposure groups. Significant differences were found between controls and subjects exposed to high styrene and low noise levels, showing the ototoxic effect (at sub-clinical level) of the styrene exposure.

Styrene is used in manufacturing fiberglass reinforced plastics: and occupational exposure was related to neurotoxicology and genotoxicity. The sum of the metabolites mandelic and phenylglyoxylic acids is the ACGIH biomarker for occupational exposure with a BEI of 400 mg/g of creatinine in end shift urine corresponding to a airborne styrene concentration of 85 mg/m3. There are two main molding processes, open and closed, the last more effective at controlling worker's styrene exposure.To compare the open molding process to the compression of fiber reinforced resin foils, a kind of closed molding, monitoring the styrene exposure of workers in two production sites (A and B).Environmental Monitoring was carried out by Radiello samplers and Biological Monitoring by means of the determination of MA and PGA with HPLC/MS/MS in 10 workers at Site A and 14 at Site B.The median values for styrene exposure resulted 31.1 mg/m3 for Site A and 24.4 mg/m for Site B, while the medians for the sum of the two metabolites in the end shift urine were 86.7 e 33.8 mg/g creatinine respectively. There is a significant linear correlation between personal styrene exposure and the excretion of styrene metabolites (R = 0.74).As expected the exposure markers of the workers of the two production sites resulted higher in the open process. The analytical results of both environmental and biological monitoring were all below the occupational exposure limits, confirming the efficacy of the protective devices.

Item does not contain fulltext OBJECTIVE: Analysing trends in population breast cancer mortality statistics appears a simple method of estimating the effectiveness of mammographic screening programmes. We reviewed such studies of population-based screening in Europe to assess their value. METHODS: A literature review identified 17 papers, of which 12 provided quantitative estimates of the impact of screening. Due to differences in comparisons and outcome measures, no pooled estimate of effectiveness was calculated. RESULTS: Comparisons included breast cancer mortality before and after the introduction of screening, trends in early and late starting areas and trends in age groups affected and unaffected by screening. Studies that calculated the percentage annual change after the start of screening found reductions of 1-9% per year (1%, 2.3-2.8% and 9% for those with adequate follow-up). Of studies that compared mortality in time periods before and after introduction of screening, three single country studies all had adequate follow-up and estimated mortality reductions ranging from 28% to 36%. Limitations of studies of population mortality rates include the inability to exclude deaths in women with breast cancer diagnosed before invitation to screening, diluting any observable impact of screening, and the gradual implementation of screening in a country or region. CONCLUSIONS: Although analysing population breast cancer mortality rates over time can be a first step in examining changes following the introduction of screening, this method is of limited value for assessment of screening impact. Other methods and individual data are necessary to properly quantify the effect.

Single molecule ‘force spectroscopy’ techniques (e.g., atomic force microscopy) that measure the force required to unfold a protein and the associated length changes upon unfolding are increasingly utilized to investigate the kinetics and mechanism of protein unfolding. Although force spectroscopy techniques are capable of discerning subnanometer differences in molecular lengths, they are not able to provide a detailed structural view of the unfolding process. The interpretation of force measurements heavily relies on atomistic simulations. In this chapter, we review some of the major contributions of atomistic simulations to the interpretation of force spectroscopy measurements of single domain protein unfolding.

Hygienists are interested in hexavalent chromium due to its genotoxic and carcinogenic effect on humans. The use of products containing hexavalent chromium is decreasing in many industrial fields because of the substitution with less-toxic compounds. In the aeronautical industry, however, the chromate are added to primer paint as a corrosion inhibitor of aircrafts surfaces: so hexavalent chromium compounds are available in many primers with a composition ranging from 10% to 13%. The application of these primers by using electrostatic guns potentially exposes painting and coating workers at high concentrations of aerosols containing Cr(VI). The aim of the present study is the evaluation of professional exposure to hexavalent chromium during aircraft painting, by adopting both environmental personal sampling and biological monitoring. To valuate workers exposure levels the personal measurements results have been compared with the exposure limit values (TLV-TWA) and the urinary chromium contents with the biological exposure indices (IBE). Moreover the strategy of coupling environmental sampling with biological monitoring seems to be a useful instrument to measure the validity of the individual protection devices.

The determination of trans, trans muconic acid (t,t-MA) in human urine, a biomarker suggested by the American Conference of Governmental Industrial Hygienists for occupational benzene exposure, with a limit value of 500 microg/g creatinine, is usually performed by means of gas or liquid chromatographic methods. Almost all the HPLC methods make use of strong ionic exchange cartridges for sample cleaning, reverse phase separation and detection either by UV at lambda = 259 nm or; more recently, by electrospray tandem mass spectrometry: yet, not all of these methods have been validated for quantitative analysis considering also the matrix effect. This paper presents the quantitative analysis of t,t-MA in 94 end-shift urine samples from workers of an oil refinery performed by means of an HPLC/MS/MS analytical method that uses a commercially available deuterium labeled isotope as internal standard, that during the validation has highlited the problem of interferences due to urine ion suppression effect and to the interference from isobaric ions both for the analyte and the internal standared. The following mean values have been obtained: 47.37 microg/g creatinine for non smokers non occupationally exposed to benzene, 97.40 microg/g creatinine for non smokers exposed to benzene, 142.38 microg/g creatinine for smokers non occupationally exposed and 149.08 microg/g creatinine for smokers occupationally exposed to benzene. The results obtained demonstrate that using this analytical method for urinary t,t,MA it is possible to discriminate among groups with different levels of benzene exposure, due to all the possible benzenene sources: environmetal, occupational, due to smoking, and their possible combinations.

The Liverpool Statement 2005 was developed at the Fourth International Lung Cancer Molecular Biomarkers Workshop in Liverpool (October 27-29, 2005) and focused on the priorities for the European Union/United States (EU-US) Spiral Computed Tomography (CT) Collaborative Group. The application of spiral CT technology for early lung cancer screening has gained enormous momentum in the past 5 years. The EU-US Spiral CT Collaboration was initiated in 2001 in Liverpool, and subsequent meetings throughout Europe have resulted in the development of collaborative protocols and minimal data sets that provide a mechanism for the different trial groups to work together, with the ultimate aim to pool results. Considerable progress has been made with major national screening trials in the U.S. and Europe, which include IELCAP, NLST, and NELSON. The major objective of this international collaboration is the planned cross-analysis of the individual studies after they are reported. The EU-US researchers have agreed to a number of long-term objectives and to explore strategic areas for harmonization of complementary investigations.

One of the biomarkers suggested by the ACGIH to assess the professional exposure to benzene is the S-phenylmercapturic acid in the end-shift urine. The existence in the urine of N-acetyl-S(1,2-dihydro-2hydroxypHenyl)-L-Cysteine, a precursor of SPMA that can be turned into it by acid hydrolysis, is a possible cause of miscorrelation between environmental and biological monitoring. The amount of measured SPMA depends on the degree of hydrolysis and therefore it is a function both of the urine PH and of the storage conditions of the sample. 40 urine samples have been collected from workers exposed to benzene, both smokers and not smokers, and for each sample the percentage of SPMA measurable at pH 2 and without pH correction (free SPMA) has been calculated with respect to the SPMA measured after quantitative hydrolysis, with the objectives to determine if a correct assessment of the exposure requires the determination of total SPMA and which concentration value could correspond to the BEI of 25 microg/g of creatinine established by the ACGIH. An aliquot of the urine samples has been treated with 9M H2SO4, a second one is brought to pH 2 and a third one is analyzed as it is. All samples are analyzed by HPLC/MS/MS in negative ions/MRM mode, and quantitative analysis is performed using the internal standard method. The percentage found in samples treated at pH 2 is on average 45% of the total SPMA for smokers and 60% for non smokers, while the free SPMA varies from 1% to 66% due to the urine pH variability and to the lower concentrations detected. The determination of total SPMA allows the standardization of the preanalyticalfactors and the dosage with analytical methods less sensitive than HPLC/MS/MS.

To report the results of a three-year observational pilot study of lung cancer screening with low dose computed tomography (CT) and to present the study design of a randomised clinical trial named as ''Italung-CT''.Sixty (47 males and 13 females, mean age 64+/-4.5 years) heavy smokers (at least 20 packs-year) underwent three low-dose spiral CT screening tests one year apart on a single slice or multislice CT scanner. Indeterminate nodules were managed according to the recommendations of the Early Lung Cancer Action Project.and Indeterminate nodules were observed in 33 (55%) of the subjects (60% at the baseline screening test, 24% at the first annual test and 16% at the second annual test). The size of the largest indeterminate nodule was5 mm in diameter in 20 subjects, 10 of whom showed the nodule at the baseline test. Forty-five subjects (75%) completed the first annual test and 42 (70%) the second annual test. One (1.6%) prevalent lung cancer (adenosquamous carcinoma) and one (2.2%) incident lung cancer (small cell cancer at the first annual examination) were observed, as well as a pulmonary localisation of Hodgkin's lymphoma (at the second annual test). In addition, one subject underwent lung surgery for a chondromatous hamartoma.The results of the pilot study are substantially in line with those of other observational studies of greater sample size. This justifies optimism about the reliability of the results in the screened arm of the ''Italung CT'' trial which has just begun.

The unbinding of fluorescein from the single-chain Fv fragment of the 4D5Flu antibody is investigated by biased molecular dynamics with an implicit solvation model. To obtain statistically meaningful results, a large number of unbinding trajectories are calculated; they involve a total simulation time of more than 200 ns. Simulations are carried out with a time-dependent perturbation and in the presence of a constant force. The two techniques, which provide complementary information, induce unbinding by favoring an increase in the distance between the ligand and the antibody. This distance is an appropriate progress variable for the dissociation reaction and permits direct comparison of the unbinding forces in the simulations with data from atomic force microscopy (AFM). The time-dependent perturbation generates unfolding pathways that are close to equilibrium and can be used to reconstruct the mean force; i.e. the derivative of the potential of mean force, along the reaction coordinate. This is supported by an analysis of the overall unbinding profile and the magnitude of the mean force, which are similar to those of the unbinding force (i.e. the external force due to the time-dependent perturbation) averaged over several unbinding events. The multiple simulations show that unbinding proceeds along a rather well-defined pathway for a broad range of effective pulling speeds. Initially, there is a distortion of the protein localized in the C-terminal region followed by the fluorescein exit from the binding site. This occurs in steps that involve breaking of specific electrostatic and van der Waals interactions. It appears that the simulations do not explore the same barriers as those measured in the AFM experiments because of the much higher unfolding speed in the former. The dependence of the force on the logarithm of the loading rate is linear and the slope is higher than in the AFM, in agreement with experiment in other systems, where different slopes were observed for different regimes. Based on the unbinding events, mutations in the 4D5Flu antigen binding site are predicted to result in significant changes in the unbinding force.

Early diagnosis of neoplastic diseases enjoined large popularity in the last two decades. In many countries or European regions, population-based cancer screening programs for breast, cervical and colorectal cancer are going on. Diagnostic tests, like the PSA test for prostate cancer, are not yet validated in terms of their efficacy in reducing specific mortality, but their spontaneous diffusion is changing the pattern of the disease incidence. In this contribution, we discuss briefly the survival trends for some tumours (breast, cervix, colorectal, melanoma and prostate cancer) for which the occurrence rates are modified by screening and for some of them we evaluate the possible impact of early diagnosis on survival rates.

The study describes breast cancer mortality trends in Tuscany (period 1970-97), comparing Florence with the rest of Tuscany (Florence excluded), and, for Florence, incidence (period 1985-94) and survival (1985-86 versus 1991-92) trends, taking into account the diffusion of screening.Mortality and incidence rates, age-adjusted on the European population, and 95% confidence intervals (95% CI). Five-year relative survival rates and estimates of risk of dying provided by the Cox model.Mammographic screening, started at the beginning of the 1970s in some municipalities, largely involved the Florence area after 1990 (mammograms/years: from 8,000-9,000 to 28,000-29,000, respectively, before and after 1990). In the same period no population-based screenings were ongoing in the rest of Tuscany. A significant mortality drop was observed in Tuscany (-3.7%/year), starting at the beginning of the 1990s and observed for agesor = 74 (especially ages 40-49: -11.2%/year). The drop was similar in Florence and in the rest of Tuscany. In ages 50-69, incidence, increasing between 1985-87 and 1988-90 (+6.5%), rose sharply in 1991-94 (+17.0%); it was stable in other ages. Local disease increased more markedly in ages 50-69 (globally: +88.3%), but also in other ages (+20-30%). Regional and metastatic cancers decreased. A significantly better 5-year survival was observed among cases diagnosed in 1991-92, persisting after adjustment by extent of disease.Even if the causes of breast cancer mortality trends are not easy to clarify in an observational study. our data suggest that the drop in mortality observed in Tuscany at the beginning of the 1990s could be largely explained by both earlier detection, outside of an organized screening program, and by better treatments. The increase in incidence and the shift in stage distribution that occurred before the enlargement of the screening area and in age groups not involved in the program, supports the role of a 'spontaneous' widespread earlier detection. The better survival of the period 1991-92, only partly explained by the shift in stage at diagnosis, indirectly supports the role of improvement in therapy.

Molecular dynamics simulations are used to probe the properties of non-native states of the protein human alpha-lactalbumin (human alpha-LA) with a detailed atomistic model in an implicit aqueous solvent environment. To sample the conformational space, a biasing force is introduced that increases the radius of gyration relative to the native state and generates a large number of low-energy conformers that differ in terms of their root-mean-square deviation, for a given radius of gyration. The resulting structures are relaxed by unbiased simulations and used as models of the molten globule and partly denatured states of human alpha-LA, based on measured radii of gyration obtained from nuclear magnetic resonance experiments. The ensembles of structures agree in their overall properties with experimental data available for the human alpha-LA molten globule and its more denatured states. In particular, the simulation results show that the native-like fold of the alpha-domain is preserved in the molten globule. Further, a considerable proportion of the antiparallel beta-strand in the beta-domain are present. This indicates that the lack of hydrogen exchange protection found experimentally for the beta-domain is due to rearrangement of the beta-sheet involving transient populations of non-native beta-structures. The simulations also provide details concerning the ensemble of structures that contribute as the molten globule unfolds and shows, in accord with experimental data, that unfolding is not cooperative; i.e. the various structural elements do not unfold simultaneously.

This study describes the characteristics of a representative sample of terminally ill cancer patients at admission to Italian palliative care programs, the rate and reasons for discontinuation of care, and survival after enrollment. All Italian palliative care units (PCUs) specifically committed to palliative care were asked to consecutively register all new patients (n = 3901) between January and June, 1995. Fifty-eight of the 62 PCUs contacted by the Steering Committee completed the study. A random sample of 589 evaluable patients was prospectively selected from the 2667 eligible patients. Patients were mostly referred by a general practitioner (31.2%) or a specialist (42.1%). Most patients (84.7%) were followed until death. Seventy-seven discontinued care because of hospital admission (6.6%), change of residence (3.9%), refusal (1.7%), or improvement (0.8%). Median survival was 37.9 days; 14.3% of the patients died within 7 days, and 15.3% lived longer than 180 days. A statistically significant association between survival and gender, cancer type, setting of the first visit, and type of unit was observed. In Italy, as in other countries with different health systems, referral of cancer patients to palliative care tends to occur late in the course of the disease. This study suggests that the process of enrollment and the duration of patients' survival in palliative care, when studied in large unselected populations, can provide important information relevant to the care of terminally ill patients.

The study analyzes the relationship between the incidence trends of breast carcinoma in situ (CIS) and the spread of mammography screening in the Italian area of Florence (about 608,000 female residents).In this area, since the seventies, a mammographic screening by personal invitation was performed by the Center for Cancer Prevention (CSPO) in some rural municipalities. After 1990, the municipality of Florence and other municipalities were involved in the screening.The study included all cases of female breast carcinomas in situ reported to the population-based Tuscany Cancer Registry between 1985 and 1995. On the basis of information from the CSPO files, the cases were categorized into: "screen-detected", "self-referrals", and "other" (CSPO cases diagnosed in symptomatic women or at periodic check up after breast cancer plus hospital cases).Overall, 332 women with breast carcinoma in situ (CIS) were registered between 1985 and 1995. The CIS incidence rate increased from 2.39/100,000 women in 1985-87 to 6.22/100,000 in 1994-95. The largest increase was observed for the ductal carcinoma in situ (2.9 times) and in women aged 50-69 years (3.8 times). In this age group, cases diagnosed at the screening by personal invitation accounted for 69% of the rise in CIS incidence. The proportion of mastectomy lowered from 41% before 1990 to 25% after 1990.In the Florence area the CIS incidence trend, showing a marked increase beginning in 1991, was mainly explained by the spread of the mammographic screening by personal invitation. The period during which mammographic screening became widespread coincided with a change in the treatment policy of breast cancer, with a high proportion of breast conserving surgery also for CIS. Therefore, the rise in CIS incidence rates correlated with the widespread use of mammographic screening did not substantially increase the number of women treated by mastectomy.

Peak bone mass is an important determinant of future bone mass and of the risk of osteoporosis and subsequent fractures. Although some information concerning bone mineral density (BMD) in adults affected with systemic lupus erythematosus (SLE) is available, few data on children and adolescents have been reported. Many variables, such as duration and activity of the disease, reduced sun exposure, and steroid therapy have been suggested as risk factors in the pathogenesis of osteoporosis in SLE. In this study, we longitudinally evaluated, by dual energy X-ray absorptiometry (DEXA), the BMD of 20 young patients affected with juvenile SLE (JSLE), in order to establish the degree of osteoporosis and the influence of steroid treatment, among other clinical variables. At baseline, the mean BMD in JSLE patients was 0.978 g/cm2 and in controls 1.038 g/cm2 (P = 0.31). At 1 year (time 2), this value became 0.947 g/cm2 in JSLE children; the mean individual difference was 0.28 g/cm2 (3.4%). Only in those patients aged 19-25 years BMD was significantly lower than in controls, both at baseline and at time 2. Considering the steroid treatment, no significant difference between the two groups was found either at baseline or at time 2; however, the mean yearly BMD loss in the steroid patients was 0.031 g/cm2 (3.5%) vs. 0.005 g/cm2 (0.5%) in those who had not taken steroids. A significantly inverse correlation between BMD and the cumulative dosage of corticosteroids has been detected. BMD produced a significantly inverse correlation to the cumulative dosage of corticosteroids; no significant correlation has been found between BMD and disease activity or duration.

A multicenter study involving six palliative care units in Italy was carried out on 159 terminal cancer patients seen at home or in hospital. The physician or the nurse completed independently from the patient the Therapy Impact Questionnaire (TIQ), a questionnaire devised for quality-of-life evaluation in terminal cancer patients. The patient's assessment was used as the valid reference measurement to compare with the health-care workers' evaluation to assess the validity of the latter. The results showed that percentages of agreement were higher for physical than for psychological and cognitive symptoms, and that there was a greater agreement on the absence rather than on the presence of a problem. None of the characteristics of the patient nor of the proxy showed any statistically significant relationship with the two disagreement indexes. The results suggest that caution is needed in the use of health-care workers as alternative sources of information regarding patients' quality of life.

The aim of our case-control study was to estimate the effect on mortality from colorectal cancer (CRC) of a population-based screening with a faecal occult blood test started in 1982 in a rural area of the district of Florence. We examined the relationship between mortality and the interval since the most recent screening. The cases in the study were 206 individuals who had died from CRC after the age of 41 years. Five controls were selected randomly from the list of individuals alive at the time of diagnosis of the corresponding case and were matched by sex, age and place and length of residence. After adjustment for potentially confounding factors, the odds ratio (OR) for death from CRC for screened persons vs. those not screened was 0.60 [95% confidence interval (CI), 0.4-0.9]. The OR was lowest in the first 3 years after the most recent test (OR = 0.54; 95% CI, 0.3-0.9) and increased towards unity subsequently. Our results suggest that screening for CRC by biennial faecal occult blood testing can reduce mortality from the disease.

A cost-effectiveness analysis has been conducted in order to evaluate effects and costs of a nationwide mammographic breast cancer screening programme compared with no screening in a 30 years period. The analysis includes seven different phases of breast cancer, from the screening programme itself to the treatment of terminal illness. The estimates use italian published data and field studies. The calculations were performed with the Miscan computer simulation package: a programme providing for the screening of women aged 50-69 at two years intervals might be expected to result in a 1,650 deaths prevented and 14,500 years of life gained each year. The overall net costs of the programme were assessed at between 2,893 and 3,212 thousand million lire, the cost per life saved between 59.8 and 66.4 million lire and the cost per life-year gained between 6.6 and 7.3 million lire (between 10.7 and 11.5 million lire with a 5% discount rate, an estimate lower than that of German programme). The analysis produces important information for the Italian policy debate over mammography and it also contributes to the development of economic evaluation in our country.

Evaluation of the quality of life of oncological patients is now perceived as a major element of cancer treatment, and various instruments for measuring it have been proposed. However, whatever instrument is used must be capable of reflecting the different ways in which different contexts and cultures respond to cancer. We administered the Italian version of the Rotterdam Symptom Checklist (RSCL) to 60 patients with advanced disease attending five oncological centres in Romagna (central Italy). The RSCL was found to be able to measure both psychological and physical well-being and to detect a difference between patients on low/medium and those on high-burden chemotherapy. The Italian version of the RSCL is an adequate scale that is capable of capturing patient perceptions and could be used for monitoring the quality of life of Italian patients participating in clinical trials.

The Italian national health services is under criticism. Although recent legislative changes are intended to introduce managed competition, there is no clear epidemiological view of the health care needs and priorities. Several inconsistencies and inequalities (particularly between the northern and the southern regions) are obvious, both in the health status of the population and in the provision of health care. Problems that should be addressed by future governments are: the uneven distribution of medical technology; the persistence of large inequalities, documented by outcomes such as rheumatic fever, between northern and southern regions; the large variability in clinical practices; the lack of an explicit policy as far as the diffusion of advanced technology is concerned; the ensuing "hidden" rationing; and the peculiar relationship between public and private health structures. Both the current ideological shift towards a market economy for health care and the traditional lack of epidemiological input in health care planning could threaten a rational approach to these problems.

Magnetic resonance imaging (MRI) of the hand in patients with psoriatic arthritis (PA) was evaluated and compared with MRI of the hand in patients with rheumatoid arthritis (RA). Both MRI and X-ray examinations of the hands were performed in 28 PA patients and 18 RA patients. The MRI showed a PA pattern characterized by a more pronounced soft tissue swelling as compared with RA patients. Diffuse and pronounced periarticular oedema that spread to the subcutis was evident in 24 (85.7 %) PA patients. Subchondral changes were characteristic of PA patients, and were observed in 12 of 28 PA patients (42.8 %). In these cases, conventional X-ray examination failed to show any bone change. These two changes were not seen in RA patients. Our preliminary results indicate that MRI might play a role in differential diagnosis between PA and RA especially in the early phase of the disease in which conventional radiological examination is negative.

This paper investigated differential direct costs determined by the difference between implementation of mammographic screening program for breast cancer detection in the city of Florence (PFD) and the "absence" of the PFD. The involved resources have been identified, quantified and evaluated. The results of the I round (1991/92) of the PFD involve the following different phases: invitations, mass screening, diagnostic assessment. Differential net costs aumonted to 780 million for total cost, and to 53,000 per screened woman. The PFD invited 27,325 women per year; at the I round, the PFD registered an attendance rate of 53.9% and a recall rate of 4.3%, with a total cost of about one thousand million and a cost per screened woman of about L. 64,000. Instead, economic results of alternative "absence" of screening registered a total cost of 170 million and a cost per screened woman of about L. 100,000. Costs for detected cancer amount about to 8.2 million for PFD and 5.7 million for "absence" of the Program. Sensitivity analysis has been performed texting the fundamental parameters of the PFD: attendance rate, recall rate and life time average of the investiments. The sensitivity analysis, performed on the PFD, registered a variation of total cost from 859 million to 1,216 million and a variation of the total cost per woman screened from L. 43,500 to L. 80,000. Sensitivity analysis results highlighted the fundamental role played by women's attendance and by the percentage of women recalled for diagnostic assessment.

Several experimental and non experimental studies have shown that mammography every 2-3 years can reduce mortality for breast cancer in women over 50 of about the 30%. On this basis, in the last few years several programmes, population-based, have been organised at Regional and National level in Europe. In this paper the main process indicators useful to assess early the impact of a screening programme are discussed. The proposal of a system for the programme evaluation is mainly based on the experience of the Two County Study, in Sweden, the most important randomised clinical trial in this field.

The clinical usefulness of Magnetic Resonance Imaging (MRI) of the knee in the depiction of meniscal, ligament and tendon lesions is well known. In contrast, the role MRI plays in the diagnosis of chondromalacia remains debated, the gold standard being arthroscopy. A new technique, i.e., MR arthrography (MRA), has been recently proposed which consists of the intraarticular injection of a paramagnetic contrast agent (Gd-DTPA) during MRI. Thirty-one patients with clinically suspected chondromalacia of the knee were examined with MRA. The exams were performed with a 1T superconductive magnet and a dedicated coil. All the patients were examined before (baseline scans) and after paramagnetic contrast agent injection. MRA results were compared with arthrographic findings. Baseline MRI had 25% sensitivity, 77.9% specificity and 83% diagnostic confidence in the diagnosis of chondromalacia; these figures increased to 93%, 97.6% and 91.5% after contrast agent injection. This preliminary experience confirms MRA to be a useful tool in the diagnosis of chondral knee conditions.

Nicotinamide has been recently introduced, in addition to intensive insulin therapy for patients with recent-onset insulin-dependent diabetes mellitus (IDDM) to protect beta cells from end-stage destruction. However, available data are conflicting. A double blind trial in 56 newly-diagnosed IDDM patients receiving nicotinamide for 12 months at a dose of 25 mg/kg body weight or placebo was designed in order to determine whether this treatment could improve the integrated parameters of metabolic control (insulin dose, glycated haemoglobin and C-peptide secretion) in the year after diagnosis. In addition to nicotinamide or placebo, patients received three to four insulin injections daily to optimize blood glucose levels. Patients treated with nicotinamide or placebo received similar doses of insulin during follow-up and 1 year after diagnosis with comparable glycated haemoglobin levels (6.7±1.8 % nicotinamide vs 7.1±0.6 % placebo). Basal and glucagon stimulated C-peptide secretion detectable at diagnosis were similarly preserved in the course of 12 months follow-up both in nicotinamide and placebo treated patients. No adverse effects were observed in patients receiving nicotinamide. When age at diagnosis was taken into account, nicotinamide treated older patients ( > 15 years of age) showed significantly higher stimulated C-peptide secretion than placebo treated patients (p < 0.02). These results suggest that nicotinamide can preserve and improve stimulated beta-cell function only in patients diagnosed after puberty. We conclude that in these patients nicotinamide can be added to insulin at the time of disease diagnosis to maintain and possibly improve residual beta-cell function. However, further studies on patients diagnosed after puberty are needed to confirm whether nicotinamide can be considered an additional tool to insulin in early-onset IDDM.

Turbo Spin-Echo (Turbo SE) pulse sequences represent a new type of fast sequences characterized by a dramatic reduction in acquisition time with similar intrinsic contrast to that of conventional Spin-Echo (SE) pulse sequences. For a preliminary clinical comparison of turbo SE and SE sequences, a consecutive series of 25 patients with focal liver lesions was investigated by means of MRI at 1.0 T. The patients were selected on the basis of US or CT positive liver scans for focal lesions. All patients underwent MRI following the same protocol: axial T1-weighted (T1W) gradient echo (GE) sequences (TR/TE = 110/6 ms) with the "breath-hold" technique, T2-weighted (T2W) SE sequences (TR/TE = 1730/90 ms; FL = 60, M = 128 x 256, 2 AC, TA = 7 min 26 sec) and turbo SE sequences (TR/TE = 5100/112 ms, M = 240 x 256, 2 AC, TA = 2 min 48 sec). Slice thickness was 10 mm with a 1-mm gap in all cases. Qualitative (number, size and definition of the lesions) and quantitative (contrast-to-noise ratio (CNR) and relative CNR) variables were considered. SE and turbo SE sequences demonstrated the same number of lesions; the smallest lesion (3 mm) was identified by turbo SE sequences. Turbo SE sequences better depicted lesion margins than SE sequences. In all cystic conditions, CNR was higher in turbo SE than in SE sequences, while it was lower in all the extant conditions. This preliminary experience proves turbo SE pulse sequences to be a valuable tool in liver MRI, which calls for further clinical trials.