Negative impact of hyperglycaemia on tocilizumab therapy in Covid-19 patients.

Tocilizumab (TCZ) is used for treating moderate-to-severe Covid-19 pneumonia by targeting interleukin-6 receptors (IL-6Rs) and reducing cytokine release. Yet, in spite of this therapy, patients with vs. patients without diabetes have an adverse disease course. In fact, glucose homoeostasis has influenced the outcomes of diabetes patients with infectious diseases. Of the 475 Covid-19-positive patients admitted to infectious disease departments (University of Bologna, University Vanvitelli of Napoli, San Sebastiano Caserta Hospital) in Italy since 1 March 2020, 31 (39.7%) hyperglycaemic and 47 (60.3%) normoglycaemic patients (blood glucose levels ≥140mg/dL) were retrospectively evaluated at admission and during their hospital stay. Of note, 20 (64%) hyperglycaemic and 11 (23.4%) normoglycaemic patients had diabetes (P<0.01). At admission, hyperglycaemic vs. normoglycaemic patients had fivefold higher IL-6 levels, which persisted even after TCZ administration (P<0.05). Intriguingly, in a risk-adjusted Cox regression analysis, TCZ in hyperglycaemic patients failed to attenuate risk of severe outcomes as it did in normoglycaemic patients (P<0.009). Also, in hyperglycaemic patients, higher IL-6 plasma levels reduced the effects of TCZ, while adding IL-6 levels to the Cox regression model led to loss of significance (P<0.07) of its effects. Moreover, there was evidence that optimal Covid-19 infection management with TCZ is not achieved during hyperglycaemia in both diabetic and non-diabetic patients. These data may be of interest to currently ongoing clinical trials of TCZ effects in Covid-19 patients and of optimal control of glycaemia in this patient subset.

Maternal anxiety, depression and sleep disorders before and during pregnancy, and preschool ADHD symptoms in the NINFEA birth cohort study.

AIMS.: Maternal mental disorders have been associated with the risk of attention-deficit/hyperactivity disorder (ADHD) in children. Within the context of a mother-child cohort, we examined whether maternal anxiety, depression and sleep disorders are associated with pre-school ADHD symptoms. METHODS.: The study included 3634 singletons from the Italian NINFEA (Nascita e INFanzia: gli Effetti dell'Ambiente') cohort. Maternal doctor-diagnosed anxiety, depression and sleep disorders before and during pregnancy were assessed from the questionnaires completed during pregnancy and 6 months after delivery. Mothers rated child ADHD symptoms at 4 years of age, according to the Diagnostic and Statistical Manual of Mental Disorders. Hyperactive-impulsive (ADHD-H), inattentive (ADHD-I) and total ADHD scores were analysed in the models adjusted for child's gender, first-born status, maternal age, education, alcohol consumption and smoking during pregnancy. RESULTS.: The total ADHD score at age 4 was associated with maternal lifetime anxiety (17.1% percentage difference in score compared with never; 95% CI 7.3-27.9%), sleep disorders (35.7%; 95% CI 10.7-66.5%) and depression (17.5%; 95% CI 3.2-33.8%). Similar positive associations were observed also for ADHD-H and ADHD-I traits, with slightly attenuated associations between maternal sleep disorders and child ADHD-I score, and maternal depression and both ADHD scores. All the estimates were enhanced when the disorders were active during pregnancy and attenuated for disorders active only during the pre-pregnancy period. CONCLUSIONS.: Maternal anxiety, depression and sleep disorders are associated with a relative increase in the number of ADHD-H, ADHD-I and total ADHD symptoms in preschoolers.

Sources of confounding in life course epidemiology.

In epidemiologic analytical studies, the primary goal is to obtain a valid and precise estimate of the effect of the exposure of interest on a given outcome in the population under study. A crucial source of violation of the internal validity of a study involves bias arising from confounding, which is always a challenge in observational research, including life course epidemiology. The increasingly popular approach of meta-analyzing individual participant data from several observational studies also brings up to discussion the problem of confounding when combining data from different populations. In this study, we review and discuss the most common sources of confounding in life course epidemiology: (i) confounding by indication, (ii) impact of baseline selection on confounding, (iii) time-varying confounding and (iv) mediator-outcome confounding. We also discuss the issue of addressing confounding in the context of an individual participant data meta-analysis.

Tenofovir disoproxil fumarate discontinuation for renal outcomes: any room for treatment personalization?

Tenofovir disoproxil fumarate (TDF) is a very effective antiviral drug that has been associated with tubular dysfunction. The aim of this study was to analyze the demographic, pharmacokinetic, and pharmacogenetic variables associated with TDF discontinuation for renal outcomes in stable HIV-positive patients using multivariable analyses. Three hundred and four patients were included (73% male, with median age and eCrCl of 45.3 years and 90.9 mL/min, respectively). After a median follow-up of 28.3 months, 27 patients discontinued TDF for renal adverse events [persistent urinary abnormalities (n = 21) or eCrCl < 60 mL/min (n = 6)] providing an incidence of 3.77 events per 100 patient-year. The probability of TDF discontinuation was higher with several features (male gender, older age, not Caucasians ancestry, absence of intravenous drug abuse, protease inhibitors, previous indinavir, HCV-positivity, lower CD4 cell count, detectable HIV-RNA, lower eCrCl, spot-urine proteinuria) and higher tenofovir concentrations but not genetic variants. Tenofovir plasma concentrations were prognostic of TDF discontinuation for renal adverse events suggesting that dose-adjustment may be warranted for long-term safety.

Imaging tests in staging and surveillance of non-metastatic breast cancer: changes in routine clinical practice and cost implications.

BACKGROUND: Although guidelines do not recommend computerised tomography (CT), positron emission tomography (PET) or magnetic resonance imaging (MRI) for the staging or follow-up of asymptomatic patients with non-metastatic breast cancer, they are often requested in routine clinical practice. The aim of this study was to determine the staging and follow-up patterns, and relative costs in a large population of breast cancer patients living and treated in a Southern Italian region. METHODS: We analysed the clinical computerised information recorded by 567 primary-care physicians assisting about 650 000 inhabitants in the Campania region. Patients with non-metastatic breast cancer were identified and divided into calendar years from 2001 to 2010. The number of diagnostic tests prescribed per 100 patients (N/Pts) and the mean cost per patient was determined 3 months before diagnosis and up to 1 year after diagnosis. Costs are expressed in constant 2011 euros. RESULTS: We identified 4680 newly diagnosed cases of asymptomatic non-metastatic breast cancer. N/Pts increased significantly (P<0.0001) from 2001 to 2010. The mean number of prescribed mammograms, bone scans, abdominal ultrasound and chest X-rays ('routine tests'), and costs was unchanged. However, the number of CT, PET scans and MRI ('new tests')prescriptions almost quadrupled and the mean cost per patient related to these procedures significantly increased from [euro ]357 in 2001 to [euro ]830 in 2010 (P<0.0001). CONCLUSIONS: New test prescriptions and relative costs significantly and steadily increased throughout the study period. At present there is no evidence that the delivery of new tests to asymptomatic patients improves breast cancer outcome. Well-designed clinical trials are urgently needed to shed light on the impact of these tests on clinical outcome and overall survival.

School-based anti-smoking intervention for physiotherapy students: a three-year non-randomized trial.

INTRODUCTION: The aim of the study was to assess the efficacy of a school-based intervention for reducing tobacco consumption among physiotherapy students. MATERIALS AND METHODS: This controlled trial involved two groups of physiotherapy students: a treatment group (A) and a control group (B). Treatment consisted of a seminar on smoking-related diseases (3 hours) and training (at least 10 months) in a respiratory diseases or thoracic surgery unit. The control group (B) did not undergo any treatment. The main outcome was the prevalence of smokers. Follow-up lasted 3 years. RESULTS: Groups A and B comprised 78 and 72 students, respectively. The two groups did not differ in terms of gender distribution, mean age, prevalence of smokers and nicotine dependence. In group A, the prevalence of smoking declined from 36% to 33% between T0 and T1 (3 years), the relative risk (RR) at T1 being 0.93 (95% CI: 0.6-1.44). In group B, the prevalence increased from 28% to 35% between T0 and T1, with a RR at T1 of 1.26 (0.76- 2.11). The prevalence reduction "attributable" to the intervention in group A 7.7%, while a 27.8% increase in prevalence "attributable" to the absence of intervention was found in group B. However, the differences were not statistically significant. CONCLUSIONS: School-based interventions seem to be effective in reducing the prevalence of smoking among healthcare students. Further studies on larger samples and with standardized methodology are required in order to confirm these preliminary findings.

The independent role of prenatal and postnatal exposure to active and passive smoking on the development of early wheeze in children.

Maternal smoking during pregnancy increases childhood asthma risk, but health effects in children of nonsmoking mothers passively exposed to tobacco smoke during pregnancy are unclear. We examined the association of maternal passive smoking during pregnancy and wheeze in children aged ≤2 years.Individual data of 27 993 mother-child pairs from 15 European birth cohorts were combined in pooled analyses taking into consideration potential confounders.Children with maternal exposure to passive smoking during pregnancy and no other smoking exposure were more likely to develop wheeze up to the age of 2 years (OR 1.11, 95% CI 1.03-1.20) compared with unexposed children. Risk of wheeze was further increased by children's postnatal passive smoke exposure in addition to their mothers' passive exposure during pregnancy (OR 1.29, 95% CI 1.19-1.40) and highest in children with both sources of passive exposure and mothers who smoked actively during pregnancy (OR 1.73, 95% CI 1.59-1.88). Risk of wheeze associated with tobacco smoke exposure was higher in children with an allergic versus nonallergic family history.Maternal passive smoking exposure during pregnancy is an independent risk factor for wheeze in children up to the age of 2 years. Pregnant females should avoid active and passive exposure to tobacco smoke for the benefit of their children's health.

Relationships between total and regional adiposity and epicardial fat in obese women: how can dual-energy X-ray absorptiometry be associated with echocardiographic epicardial fat measurements?

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Obesity is an increasingly prevalent metabolic disorder and it is associated with a large number of comorbidities, including cardiovascular diseases. Adipose tissue is an active endocrine organ and its ectopic depots and distribution have different metabolic meanings on risks for health; as a matter of fact, epicardial fat seems to play a specific role in cardiovascular diseases. The use of dual-energy X-ray absorptiometry (DXA) to evaluate and follow-up patients affected by obesity is becoming a very important point in the management of the disease. WHAT THIS STUDY ADDS: An investigation of the association between epicardial fat and regional adiposity by DXA in female obese patients. The total amount of central (trunk) fat mass is more strongly correlated than android visceral fat mass to epicardial thickness in obese women. In the interpretation of whole-body DXA data, physician should consider trunk fat mass for good and independent predictivity on epicardial fat depots. Our aim was to analyse in a population of obese women the relationship between the amount of epicardial fat as measured by transthoracic echocardiography (US) and the parameters of regional adiposity by dual-energy X-ray absorptiometry (DXA), with particular reference to a new software for visceral fat assessment and to a new 'heart-suited' regions of interests (ROIs). Sixty patients who satisfied technical inclusion criteria underwent whole-body DXA scan and US on the same day. Total and android fat mass (FM) and FM percentage (FM%) were considered as well as visceral fat (VAT) subcompartment in the android region; moreover, six new ROIs were designed on whole-body DXA images for the investigation of adiposity parameters at heart level. US provided epicardial fat thickness (EPI-thickness) and area (EPI-area), as measured following previously validated methods. Body mass index (BMI), gynoid and lower limbs (FM and FM%) were found not statistically correlated with EPI-thickness. The highest correlation was achieved by trunk FM (and FM%, with r = 0.544 and 0.480 respectively, P < 0.001), followed by ROI-1 FM (ROI-1 was drawn following thoroughly the cardiac profile), and android FM. Multivariate analysis including age, weight, BMI, trunk FM and the new ROIs (added one by one), retained in the final model trunk FM. Correlations of DXA with EPI-area were superimposable. In obese women, VAT or other new-designed ROIs are not better correlated than traditional ROIs (i.e. trunk) with epicardial fat amount.

Pathophysiological mechanisms linking depression and atherosclerosis: an overview.

It is well recognized that depression is independently associated with cardiovascular events. However, uncertainties remain on the pathophysiological pathways underlying the association between depression and coronary heart disease. In addition to the traditional cardiovascular risk factors, autonomic nervous system (ANS), low grade of inflammation, platelet and hypothalamic-pituitary-adrenal axis function and genetic factors may adversely impact the endothelium of the arterial wall. We provide an overview of the pathophysiological mechanisms and indices which seem to have a role in promoting and accelerating atherosclerosis and its complications due to plaque rupture and thrombosis. Given that the relationship between depression and atherosclerosis cannot be fully explained by single mechanisms, which seem at least partially interrelated, the depression-related dysfunctions in the ANS and hypothalamic-pituitary-adrenal axis seem to play a major role, promoting chronic inflammation, endothelial dysfunction and platelet activation and aggregation, which in turn are key steps in the development of atherosclerosis and its complications.

Effects of selective serotonin reuptake inhibitor therapy on endothelial function and inflammatory markers in patients with coronary heart disease.

We investigated the effect of sertraline on inflammation and endothelial function in patients with coronary heart disease (CHD) and symptoms of depression. One hundred patients with CHD and depression were randomized in a double-blind fashion to receive sertraline or a placebo. We measured symptoms of depression (Beck Depression Inventory (BDI) score), levels of inflammatory markers (C-reactive protein (CRP) and interleukin-6 (IL-6)), and flow-dependent endothelium-mediated dilation (FMD) before and after 20 weeks of treatment. Sertraline treatment significantly reduced the BDI score as compared with both baseline and placebo. Levels of CRP and IL-6 also decreased after 20 weeks of sertraline treatment, whereas they did not significantly change in the placebo group. There was a significant improvement in FMD in patients on sertraline treatment, whereas there was no change in FMD in the placebo group. Sertraline improves endothelial function and reduces inflammatory markers in patients with CHD and symptoms of depression.

[Renal transplantation in the North Italy Transplant program (NITp): Organ allocation and results]. / Il trapianto renale nel Nord Italia Transplant program (NITp): assegnazione degli organi e risultati.

Renal transplantation is an effective therapeutic tool for patients with end-stage renal diseases (ESRDs). Data reported in this article summarize the results obtained from 30 years' activity in the North Italy Transplant program (NITp), the first transplant organization in Italy that implemented a donor procurement and organ transplantation network. In the NITp kidney allocation is governed by a computerized algorithm, NITK3, put in place in 1997, aimed at ensuring equity, transparency and traceability during the stages of the allocation decision-making process. The NITp working group has recognized the NITK3 criteria and they are periodically reviewed following the results of the analysis of patients' transplantation odds. The results obtained with the use of the NITK3 algorithm have been very satisfactory: after 6 yrs, a significantly higher percentage of patients at immunological risk (sensitized or waiting for re-transplant), of patients waiting for >3 yrs and of patients with 0-1 HLA A,B,DR mismatches have been transplanted. Moreover, a higher percentage of kidneys were used locally (in a hospital within the procurement area), and this is known to stimulate donor procurement. Finally, we performed a preliminary statistical analysis of transplants carried out from 1998-2002 in 5/16 centers of the NITp area, demonstrating the quality of the NITp program in terms of patient and graft survival, and that donor and recipient age are the variables significantly impacting on transplant results.

Markers of inflammation and multiple complex stenoses (pancoronary plaque vulnerability) in patients with non-ST segment elevation acute coronary syndromes.

OBJECTIVE: To assess the relation between markers of inflammation and the presence of multiple vulnerable plaques in patients with non-ST segment elevation acute coronary syndromes. DESIGN: Prospective cohort study of 55 patients with non-ST segment elevation acute coronary syndromes and angiographically documented coronary disease. Blood samples were obtained at study entry for the assessment of high sensitivity C reactive protein (CRP), neopterin, and neutrophil count. Coronary stenoses were assessed by quantitative computerised angiography and classified as "complex" (irregular borders, ulceration, or filling defects) or "smooth" (absence of complex features). Extent of disease was also assessed by a validated angiographic score. RESULTS: Neutrophil count (r = 0.36, p = 0.007), CRP concentration (r = 0.33, p = 0.02), and neopterin concentration (r = 0.45, p < 0.001) correlated with the number of complex stenoses. Patients with multiple (three or more) complex stenoses, but not patients with multiple smooth lesions, had a higher neutrophil count (5.9 (1.4) x 10(9)/l v 4.8 (1.4) x 10(9)/l, p = 0.02), CRP concentration (log transformed) (1.08 (0.63) v 0.6 (0.6), p = 0.03), and neopterin concentration (log transformed) (0.94 (0.18) v 0.79 (0.15), p = 0.002). Multiple regression analysis showed that neopterin concentration (B = 4.8, 95% confidence interval (CI) 1.9 to 7.7, p = 0.002) and extent of coronary artery disease (B = 0.6, 95% CI 0.03 to 1.2, p = 0.04) were independently associated with the number of complex stenoses. CONCLUSIONS: Acute inflammatory markers such as high neutrophil count, CRP concentration, and neopterin concentration correlate with the presence of multiple angiographically complex coronary stenoses. Neopterin concentration was a stronger predictor of multiple complex plaques than were neutrophil count and CRP concentration. These findings suggest that a relation exists between inflammation and pancoronary plaque vulnerability.

Autosomal malignant osteopetrosis. From diagnosis to therapy.

Osteopetrosis is a heterogeneous family of rare human genetic disorders due to markedly decreased bone resorption. It is one among disorders causing osteosclerosis of the trabecular bone and/or hyperostosis of the cortical bone. Four types of human osteopetrosis have been clearly defined, but patients with atypical symptoms are frequent, suggesting that there are additional forms. The most severe expression of this condition in its malignant form is inherited as an autosomal recessive disorder and it is usually fatal before school age. It presents with failure to thrive, severe hepatosplenomegaly, pancytopenia and nerve compression leading to blindness and deafness during infancy. The case of a 2-month-old female child with severe hepatosplenomegaly, failure to thrive, nystagmus, pancytopenia, gengival hyperplasia, optic atrophy, absent evoked visual potential and increased bone density within the total skeleton, is reported. Diagnosis of autosomal recessive malignant osteopetrosis was established by transiliac bone biopsy. She underwent bone marrow transplantation, but died soon afterwards. This rare and mortal disorder of bone formation requires early diagnosis and immediate pharmacological treatment, consisting in administration of vitamin D, in order to enhance bone resorption and of prednisone to improve hematological indexes and, if possible, bone marrow transplantation in order to ameliorate quality of life and survival.

Bone loss determined by quantitative ultrasonometry correlates inversely with disease activity in patients with endogenous glucocorticoid excess due to adrenal mass.

OBJECTIVE: Glucocorticoid excess is widely recognized as one of the most important causes of bone loss. The mechanism of glucocorticoid-induced osteoporosis is presumably multifactorial, and consists of the loss of organic and non-organic compounds. Efforts have been made to develop simple physical methods for the assessment of bone tissue for the screening of subjects at high risk of osteoporosis, without the use of radioactive sources or ionizing radiation. Quantitative ultrasonometry (QUS) has been suggested as a useful method for monitoring patients undergoing glucocorticoid therapy, which is the most common cause of glucocorticoid excess. QUS appears to detect more structural bone changes than the traditional methods and allows assessment of bone density and elasticity, both characteristics influenced by organic and non-organic bone compounds. However, the use of QUS has not yet been extensively investigated in subjects with endogenous cortisol excess. The aim of this study was to evaluate the usefulness and predictive power of QUS in assessing bone loss in subjects with differing degrees of endogenous cortisol excess due to adrenal mass. DESIGN: Thirty-four patients (20 women and 14 men) aged between 21 and 59 years were evaluated; fifteen (9 women and 6 men; median age, 42 years) were affected by overt Cushing's syndrome (CS) and nineteen (11 women and 8 men; median age, 44 years) by subclinical CS, defined as lacking clinical signs of hormone excess despite the presence of at least two abnormalities in hypothalamic-pituitary-adrenal axis function, as assessed by routine endocrine tests. All women included were eumenorrhoic. METHODS: QUS measurement of amplitude-dependent speed of sound was performed on the 2nd to 5th proximal phalanges of the non-dominant hand using a DBM Sonic 1200R bone profiler (Igea S.r.l, Italy). The results were compared with bone density assessed on lumbar vertebrae (L1-L4) and femoral neck sites by dual-energy X-ray absorptiometry (DEXA). RESULTS: A strongly significant bone loss was detected by finger QUS measurement when the patients were considered either all together or as two subgroups (P<0.001, all). The bone density decrease in the fingers was similar to that found at the lumbar spine and femoral neck by the DEXA technique. Lumbar and finger Z-scores correlated inversely with 24 h urinary free cortisol (UFF) excretion (P<0.01, both). Finger Z-scores also correlated inversely with the estimated duration of subclinical CS (P<0.05). Concerning disease activity, only UFF was confirmed by multivariate analysis to be an independent factor influencing bone loss (P<0.05). A positive correlation between the results of the two techniques was found in controls (P<0.05) but not in patients. The lack of correlation between the two techniques in patients can probably be attributed to the different parameters of bone alteration measured by the techniques. CONCLUSIONS: The detection of bone loss in subclinical CS similar to that in overt CS suggests that all subjects with endogenous cortisol excess should be evaluated for bone mass. QUS measurement appears to be a reliable, radiation-free, simple and fast tool for the identification of bone alteration in subjects with endogenous cortisol excess.

Acute myocardial infarction caused by amphetamines: a case report and review of the literature.

Cardiotoxicity manifesting as myocardial ischemia is not generally recognized as a side effect of amphetamine use or abuse. However, at least 9 cases have been reported since 1987. In this report a case of acute myocardial infarction due to oral amphetamine therapy is presented. The patient was treated with thrombolytic therapy but there were no signs of reperfusion. His coronary cine-angiograms were normal. The literature regarding amphetamine use or abuse is also reviewed, and the possible mechanisms of this pathology are analyzed.

Split liver is an effective tool to transplant paediatric patients.

Transplantation activity is dependent upon organ procurement; although great efforts are made to enlarge the cadaver donors' pool, it still remains far too small to meet the recipients' need. Waiting time is a particular problem for paediatric patients, and mortality on the waiting list for liver transplantation is very high. The number of paediatric donors is far too small to satisfy the request. To enlarge the liver pool, the split-liver procedure was introduced in several Transplant Centers. In November 1997, the North Italy Transplant program (NITp) Working Group for Liver Transplantation decided to start an official Split-liver Program. A protocol was therefore defined and criteria for donor's and recipient's eligibility were established to minimize the risk. The Working Group also standardized the technical procedure and defined collaboration between centers. Out of 410 cadaver liver donors used in the NITp, from 1 November 1997 until 31 May 1999, 49 patients (37 males and 12 females) were chosen for the split-liver procedure. Mean age was 29.9 +/- 17.5 years. Mean ICU stay of the donors was considerably short (2.5 +/- 2.1 days), and the other conditions foreseen for donor eligibility were met. In all cases (except two) an "in situ" technique was performed. Forty-nine adult recipients and 43 children were transplanted by the split-liver technique in our Transplant Centers. One right lobe and five left liver lobes were sent to Transplant Centers outside the NITp. Adult recipient age ranged from 18 to 60 years (mean 46.4 +/- 11.7 years), and the paediatric one from 2 to 144 months (mean 24.8). Mean patient follow-up was 8.3 +/- 5.5 months. In the paediatric group, the graft was successful in 34 cases (79%), five patients (10.2%) died and four (9.3%) were re-transplanted. In the adult group, graft survival was 67.3%, 11 (22%) patients died and 5 (10%) were re-transplanted. On 1 November 1997, 30 paediatric patients were on the liver waiting list. In the preceding 19 months, 52 patients were newly enrolled, and 36 transplants were performed. The mean waiting time of paediatric patients was 259 days (range 1-919 says). From 1 November 1997 to 31 May 1999, 61 paediatric patients were newly enrolled. In this period 70 patients were transplanted. The mean waiting time was 185 days (1-1010 days). At present, the liver waiting list includes eight paediatric patients. Split-liver transplantation is a successful procedure, effective in reducing waiting time for paediatric patients. It should be established if this may be a tool to enlarge the organ pool also for adult liver transplantation.

BRCA1 and BRCA2 mutations in central and southern Italian patients.

Protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) assay were used to scan the BRCA1 and BRCA2 genes in 136 unrelated Italian breast/ovarian cancer patients. In the sample tested, BRCA1 and BRCA2 equally contributed to site-specific breast cancer patients who reported one to two breast cancer-affected first-/ second-degree relative(s) or who were diagnosed before age 40 years in the absence of a family history of breast/ovarian cancer. BRCA1 and BRCA2 mutations were mostly found in patients with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years and BRCA2 for tumours diagnosed after age 50 years. The BRCA1 and BRCA2 mutation spectrum was consistent with a lack of significant founder effects in the sample of patients studied.

Winter mortality in Emilia-Romagna, Italy.

In this epidemiological study we have studied during 1997 in Emilia-Romagna (population about four million) Italy, mortality from ischaemic heart disease, hypertension, cerebrovascular and respiratory disease in 50-89 year-olds. The data were collected from "Ufficio Risorse Informative" and "servizio Meteorologico" of the Emilia-Romagna region. The results show high indices of deaths in the elderly, the highest being those of the 80-89 year-olds, during the winter with a maximum in January. There were some differences between males and females with regard to cold-related mortality of the different diseases. Comparing mortality rates of persons living in the North (Piacenza) and in the South (Rimini) of Emilia-Romagna, a consistent lower mortality was found in the people of Rimini. These results confirm the close relationship between advanced age, cold and excess mortality in Emilia-Romagna. The results suggest that at least two factors may be involved in explaining excess winter mortality: the sympathetic system changes in the elderly and the effects of cold on some haemostatic factors.