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The assessment of prognostic markers is key to the improvement of therapeutic strategies for cancer patients. Some promising markers may fail to be applied in clinical practice, or some useless markers may be applied, because of misleading results ensuing from inadequate planning of the study and/or from an oversimplified statistical analysis. This commentary illustrates and discusses the main issues involved in planning an effective clinical study and the subsequent statistical analysis for the prognostic evaluation of a cancer marker. Another aim is to extend the most applied statistical models (ie, those using Kaplan-Meier and Cox) to enable the choice of the best-suited methods for study endpoints. Specifically, for tumor-centered endpoints like tumor recurrence, the issue of competing risks is highlighted. For markers measured on a continuous numerical scale, a loss of relevant prognostic information may occur by setting arbitrary cutoffs; thus, the methods to analyze the original scale are explained. Furthermore, because the P-value is not a sufficient criterion to assess the usefulness of a marker in clinical practice, measures for evaluating the ability of the marker to discriminate between “good” and “bad” prognoses are illustrated. Several tumor markers are considered both in human and veterinary medicine. Given the similarity between markers for human breast cancer and canine mammary cancer, an application of the statistical methods discussed within the article to a public dataset from human breast cancer patients is shown.

Lumateperone (ITI-007) is a tosylate salt with binding affinities to receptors implicated in the therapeutic actions of antipsychotic medications, including the serotonin 5HT2A receptors, dopamine D2 and D1 receptors and the serotonin transporter. It has a unique mechanism of action because it simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, implicated in serious mental illness. It can be considered a multi-target-directed ligand and a multifunctional modulator of serotoninergic system with possible precognitive, antipsychotic, antidepressant and anxiolytic properties. Lumateperone has been investigated as a novel agent for the treatment of schizophrenia, but it represents a new potential option for other psychiatric and neurological diseases, such as behavioural symptoms of dementia or Alzheimer’s disease, sleep disturbances, bipolar depression. Besides, it has demonstrated a favourable safety profile without significant extrapyramidal side effects, hyperprolactinemia or changes in cardiometabolic or endocrine factors versus placebo. Additional studies are warranted to confirm and examine the benefit of lumateperone and possible therapeutic targets. This paper is a comprehensive and thorough summary of the most important findings and potential future role of this particular compound in personalized treatments.

Background and purpose Recently, β-adrenoceptor blockade has emerged as a potential strategy to inhibit melanoma growth. However, it remains to be ascertained whether β-adrenoceptor stimulation by circulating catecholamines increases melanoma growth in mice. Experimental approach B16F10 melanoma-bearing mice were used to evaluate effects of adrenaline and specific adrenoceptor (AR) ligands on tumor volume. AR expression as well as effects of AR ligands on cell viability, production of mitochondrial reactive oxygen species (mROS) and proliferation activity in B16F10 cells were determined by biochemical analyses. Key results qPCR analyses revealed that B16F10 cells express both α- (α1B-, α2A- and α2B-AR) and β-ARs (β2 -AR). We found that treatment with the α- and β-AR agonist adrenaline or with the synthetic catecholamine isoprenaline, that selectively stimulates β-ARs, did not affect melanoma growth. Conversely, adrenaline reduced tumor growth in mice co-treated with propranolol, a β1β2-AR antagonist. Adrenaline had no effect in tumor-bearing β1β2-AR knockout mice, in which β1- and β2-ARs are lacking, but it reduced tumor growth when co-administered with propranolol suggesting that tumor β2-ARs negatively regulate adrenaline antitumor activity. Additionally, we found that α1-AR stimulation with cirazoline yielded a decrease in B16F10 melanoma size. These effects on melanoma growth were paralleled by reduced cell viability and proliferation activity as well as increased mROS production in α1-AR-stimulated B16F10 cells. Decreased viability, proliferation and mitochondrial function in B16F10 cells also occurred after α2-AR stimulation by α2-AR agonist ST-91. Conclusions and implications In B16F10 melanoma model, stimulation of α-AR subtypes yields in vivo and in vitro anticancer activity.

Background The Italian Lombardy region has been the epicenter of COVID-19 since February 2020. This study analyses the epidemiology of pediatric type 1 diabetes (T1D) onset during the first two pandemic waves and three previous years. Methods All the 13 pediatric diabetes centers in Lombardy prospectively evaluated charts of children at T1D onset (0–17 years), during year 2020. After calculating the annual incidence, the data were compared with those of the 3 previous years, using generalized linear models, adjusted for age and sex. Monthly T1D new onsets and diabetic ketoacidosis (DKA) were investigated yearly from 2017 to 2020. Data were extracted from outpatients charts of the pediatric diabetes centers and from the database of the national institute of statistics. Findings The estimated incidence proportion of T1D was 16/100·000 in 2020, compared to 14, 11 and 12 in 2019, 2018 and 2017, respectively. When adjusting for age and gender, the incidence was significantly lower in 2018 and 2017 compared to 2020 (adjusted incidence ratio: 0.73 and 0.77 respectively, with 95% CI: 0.63 to 0.84, and 0.67 to 0.83; p = 0·002 and p = 0·01), but no difference was found between the years 2020 and 2019. A reduction trend in the percentage of T1D diagnosis during the first wave (March-April) over the total year diagnoses was observed compared to previous years (11·7% in 2020, 17·7% in 2019, 14·1% in 2018 and 14·4% 2017). No difference was observed during the second wave (October-December) (32·8% in 2020, 33·8% in 2019, 34% in 2018, 30·7% in 2017). The proportion of DKA over the total T1D diagnoses during the second wave had higher trend than the first one (41·7% vs 33·3%), while severe DKA over the total DKA appeared higher during the first wave (60% vs 37·1%). Interpretation The study suggests an increase in the incidence of pediatric T1D in Lombardy throughout the past five years. Pandemic waves may have affected the clinical presentation at onset. Funding None.

Objectives: Second-generation antipsychotics (SGAs) increase appetite and weight, leading toward a metabolic syndrome. Risperidone and aripiprazole, the most widely used pediatric SGAs, have been studied predominantly in short-term clinical trials, where risperidone leads to a rapid weight increase and aripiprazole to a slower one, while long-term effects are not yet elucidated. Factors that may influence weight gain are likewise not clarified, although baseline weight, previous SGA exposure, pubertal status, and type of SGA have been suggested as moderators. We analyzed weight gain induced by risperidone and aripiprazole in a sample of pediatric outpatients enrolled into a 2-year observational study. Methods: We assessed at several time points their body mass index (BMI)-Z scores (age and sex-corrected and referred to national norms). We used hierarchical mixed-effects modeling to design BMI-Z trajectories and observed the effects of several variables on determining them. Results: The study group comprised of 127 patients, predominantly males (79%), of 12.6 years on average, treated with risperidone (81%) and aripiprazole (19%) for disruptive behavioral symptoms in patients with and without neurodevelopmental disorders. Overall, BMI-Z was 1.2 at first and 1.4 at last visit (no significant change). We could design four weight-change trajectories, determined by the factors: drug (risperidone/aripiprazole) and age status (children/adolescent). Additional factors not retained in the model but possibly explanatory include the previous duration of SGA treatment and a progressive patient-selection effect due to dropouts in this observational study. Risperidone treatment was associated with trends of BMI-Z increase in children and decrease in adolescents. Aripiprazole treatment was associated with significant BMI-Z increase, higher in children than in adolescents. Results are probably due to longer previous drug exposure in adolescents. Conclusions: Children were at risk of weight gain more than adolescents, for both risperidone and, of note, aripiprazole. Adolescents and patients with long previous drug exposure tend to reach stable BMI-Z, although in the range between excessive weight and obesity.

After mastectomy, immediate breast reconstruction is paramount. With the growing number of nipple-sparing mastectomies, the chances of successful one-stage reconstruction with implants are also increasing. Local safety is one of the main issues. This study investigated the factors that could lead to major or minor complications after expander-based versus direct-to-implant (DTI) reconstruction.The studied factors were age, body mass index (BMI), hypertension, smoking, diabetes, type of mastectomy (nipple-sparing/total), implant size, neoadjuvant/adjuvant chemotherapy, and radiotherapy. The study sample included 294 immediate reconstructions over 3 years. The primary outcome was the incidence of complications, major or minor depending on the necessity of revision surgery. For the DTI pocket, we applied a variant of the conventional submuscular technique.In DTI reconstructions (median follow-up 26 months), the complication rate was 17.2% (4.3% major and 12.8% minor) with no significant association with clinical variables. In expander-based reconstructions (median follow-up 19 months), the complication rate was 18.3% (12.5% major and 5.8% minor). Univariate analysis showed a significant association between overall complications and radiotherapy (P = 0.01) as well as between major complications and expander size (P 0.005), BMI (P 0.005), and radiotherapy (P 0.01); radiotherapy and BMI retained significance in multivariate analysis. Neoadjuvant/adjuvant chemotherapy did not affect the complication rate.There was evidence of an association between major complications and clinical variables in the expander-based cohort. Larger expander size was a predictor of failure, especially combined with radiation. Direct-to-implant reconstruction proved to be safe. We describe a reliable method of reconstruction and a safe range of implant sizes even beyond 500 g.

Warfarin-related nephropathy is an unexplained acute kidney injury, and may occur in patients with supratherapeutic INR, in the absence of overt bleeding. Similar findings have been observed in rats treated with dabigatran etexilate. We conducted a prospective study in dabigatran etexilate-treated patients to assess the incidence of dabigatran-related nephropathy and to investigate the possible correlation between dabigatran plasma concentration (DPC) and worsening renal function. One hundred and seven patients treated long term with dabigatran etexilate for non-valvular atrial fibrillation (NVAF) were followed up for 90 days. DPC, serum creatinine (SCr) and serum cystatin C were prospectively measured. Ninety five patients had complete follow-up data and were evaluable for primary endpoint. Eleven patients had supratherapeutic DPC, defined as DPC higher than 200 ng/ml at study enrolment, but at the end of follow-up no patient showed a persistent increase in SCr. No patients experienced acute kidney injury. Our study shows that no persistent renal detrimental effect is associated with dabigatran treatment. An increase in SCr during dabigatran treatment is reversible and it seems to be unrelated to dabigatran itself.

Interpersonal violence in the perinatal period is frequent and should be considered a prominent health issue due to the risk of escalation of violence and the significant impact on mothers’ parenting after childbirth. Domestic violence during pregnancy can be associated with fatal and non-fatal adverse health outcomes due to the direct trauma to a pregnant woman’s body and to the effect of stress on fetal growth and development. Emotional violence is a risk factor for prenatal and/or postpartum depression. Recent studies focusing on abusive situations during peripartum and possible preventive strategies were identified in PubMed/Medline, Scopus, Embase, and ScienceDirect. All of the available literature was retrospectively reviewed with a special attention to peer-reviewed publications from the last ten years. Results of the present narrative review suggest that perinatal health care professionals (general practitioners, gynecologists, obstetricians, psychologists, psychiatrists) should promptly detect interpersonal violence during and after pregnancy and provide health care for pregnant women. It seems pivotal to guarantee psychological care for abused women before, during, and after pregnancy in order to prevent the risk of depressive symptoms, other mental or physical sequelae, and mother-to-infant bonding failure. There is an urgent need for multifaceted interventions: programs should focus on several risk factors and should design tailored care pathways fitted to the specific needs of women and finalized to support them across the lifespan.

Experiencing various forms of violence in either childhood or adulthood has been associated with cardiovascular disease, both shortly after the event and during follow-up, particularly in women. The coronavirus disease 2019 pandemic has heightened the risk of domestic violence with serious sequelae for mental and cardiovascular health in women, possibly due to several contributing factors, ranging from lockdown, stay at home regulations, job losses, anxiety, and stress. Accordingly, it remains paramount to enforce proactive preventive strategies, at both the family and individual level, maintain a high level of attention to recognize all forms of violence or abuse, and guarantee a multidisciplinary team approach for victims of interpersonal or domestic violence in order to address physical, sexual, and emotional domains and offer a personalized care.

Introduction Cognitive decline and dementia recognize multiple risk factors and pathophysiological mechanisms, often involved simultaneously with complex interactions. Several studies have shown that both arterial hypertension and hypotension are associated with a greater risk of cognitive decline and dementia, but clinical evidence on this point is conflicting. Our aim was to conduct an umbrella review on cognitive function, dementia, and blood pressure, with particular attention to epidemiological, prognostic and therapeutic aspects. Evidence acquisition We conducted a dedicated literature search on PubMed for systematic reviews and meta-analyses that focused on arterial pressure, hypertension, hypotension and similar conditions, and cognitive function, cognitive decline and dementia. The internal validity of systematic reviews and meta-analyses was formally analysed using the OQAQ tool. The umbrella review was planned in accordance with current international recommendations and was described as specified by the PRISMA guidelines. Evidence synthesis 17 systematic reviews (including 13 meta-analyses) were included, for a total of 675 clinical studies and over 1 million patients. Hypertension results to be associated with a lower risk of Alzheimer's dementia, greater risk of vascular dementia and greater risk of cognitive decline. Orthostatic hypotension seems to be associated with greater risk of Alzheimer's dementia, vascular dementia and dementia of Parkinson's disease. Therapy with acetylcholinesterase inhibitors produces lower risk of cardiovascular events, greater risk of hypertension and greater risk of bradycardia, while the anti-hypertensive therapy leads to a lower risk of dementia of all types and lower risk of cognitive decline. Conclusions To date, the evidence on the relationship between blood pressure, cognitive decline and dementia provides somewhat heterogeneous data. Further studies are clearly needed, with explicit inclusion criteria as objective as possible, adequate follow-up and precise characterization of implemented cardiovascular and cognitive treatments.

On February 20, 2020 the first case of coronavirus disease (COVID-19) has been diagnosed in Italy. In a few weeks the Policlinico A. Gemelli Hospital in Rome has become a so called "COVID Hospital", so its structure has changed and consequently also the organization of the clinical activities of the Psychiatric Unit. In particular, outpatients' services (ambulatory and day hospital) have guaranteed the management of emergencies, the administration of oral and long acting drug therapies, the assistance of patients with severe mental illness by means of telephone checks.

Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recently recognized as a systemic disorder inducing a prothrombotic state. The molecular mechanisms underlying the hypercoagulable state seen in patients with COVID-19 is still incompletely understood, although it presumably involves the close link between inflammatory and hemostatic systems. The laboratory coagulation monitoring of severely ill COVID-19 patients is mandatory to identify those patients at increased thrombotic risk and to modulate thromboprophylaxis accordingly. In this review, we summarize the current understanding on the pathogenesis, epidemiology, clinical and laboratory features and management of coagulopathy associated with COVID-19.

To evaluate the association between the adherence to Mediterranean diet (MD) and disease impact, activity, and comorbidities in patients with rheumatoid arthritis (RA).Consecutive patients with RA were enrolled in this cross-sectional study. For each patient, Disease Activity Score on 28 joints (DAS28), Simple Disease Activity Index (SDAI), RA Impact of Disease (RAID), Health Assessment Questionnaire (HAQ), patient global assessment (PGA) and general health (GH) and a self-reported questionnaire called MD score were recorded.205 RA patients (median age 53 years, female 80.49 %) were enrolled. An association between MD score and HAQ (p-value = 0.033), PGA and GH (p-value 0.023 both) was observed. RAID total score had a statistically significant negative relationship with MD score (p-value = 0.016). A statistically significant negative association was found for pain (p-value = 0.025), functional disability (p-value0.001), sleep (p-value = 0.041), physical well-being (p-value = 0.027) and coping (p-value = 0.008). Multiple regression analysis to evaluate the relationship between significant RAID items and MD score did not show any statistical significance as all items are strongly related to each other. A negative trend, although not statistically significant was found for DAS28 and SDAI. The only comorbidity associated with MD score was arterial hypertension (OR = 0.94).In this Italian RA cohort, the adherence to MD was significantly associated with a better RAID, PGA and GH, but higher MD score was not significantly associated with lower disease activity. Our study suggests an overall potential beneficial effect of MD in RA patients.

Expression of the β-myosin heavy chain (β-MHC), a major component of the cardiac contractile apparatus, is tightly regulated as even modest increases can be detrimental to heart under stress. In healthy hearts, continuous inhibition of β-adrenergic tone upregulates β-MHC expression. However, it is unknown whether the duration of the β-adrenergic inhibition and β-MHC expression are related. Here, we evaluated the effects of intermittent β-blockade on cardiac β-MHC expression. To this end, the β-blocker propranolol, at the dose of 15mg/kg, was administered once a day in mice for 14 days. This dosing schedule caused daily drug-free periods of at least 6 h as evidenced by propranolol plasma concentrations and cardiac β-adrenergic responsiveness. Under these conditions, β-MHC expression decreased by about 75% compared to controls. This effect was abrogated in mice lacking β1- but not β2-adrenergic receptors (β-AR) indicating that β-MHC expression is regulated in a β1-AR-dependent manner. In β1-AR knockout mice, the baseline β-MHC expression was fourfold higher than in wild-type mice. Also, we evaluated the impact of intermittent β-blockade on β-MHC expression in mice with systolic dysfunction, in which an increased β-MHC expression occurs. At 3 weeks after myocardial infarction, mice showed systolic dysfunction and upregulation of β-MHC expression. Intermittent β-blockade decreased β-MHC expression while attenuating cardiac dysfunction. In vitro studies showed that propranolol does not affect β-MHC expression on its own but antagonizes catecholamine effects on β-MHC expression. In conclusion, a direct relationship occurs between the duration of the β-adrenergic inhibition and β-MHC expression through the β1-AR.

Background Climate and weather are known to affect multiple areas of human life, including mental health. In bipolar disorder (BD), seasonality represents an environmental trigger for mood switches, and climatic variables may contribute to recurrences. Several studies reported seasonal and climatic-related variations in the rate of suicide attempts. Suicide risk is relevant in BD, with approximately 25% of patients attempting suicide. Therefore, this study aimed to assess sensitivity to weather and climatic variations in BD subjects and its relationship with lifetime suicide attempts. Methods Three hundred fifty-two euthymic BD and 352 healthy control subjects, homogeneous with respect to socio-demographic characteristics, were enrolled. All participants were administered the METEO-Questionnaire (METEO-Q) to evaluate susceptibility to weather and climatic changes. We also investigated the potential relationship between sensitivity to climate and weather and lifetime suicide attempts in BD patients. Results METEO-Q scores and the number of subjects reaching the cut-off for meteorosensitivity/meteoropathy were significantly higher in BD patients. Within the clinical group, BD subjects with lifetime suicide attempts obtained higher METEO-Q scores, with no differences between BD-I and BD-II. The number of suicide attempts directly correlated with METEO-Q scores. The presence of suicide attempts was associated with the physical and psychological symptoms related to weather variations. Discussion Our findings support the relevance of sensitivity to weather and climate variations in a large sample of BD subjects and point out the association of this feature with lifetime suicide attempts.

The National Blood Centre (NBC) at the request of the Italian Scientific Society of Haemapheresis and Cell Manipulation (SIdEM) has funded and developed a software dedicated to the collection of data related to therapeutic apheresis procedures, known as the Italian Registry of Therapeutic Apheresis (IRTA). Although on a voluntary basis, participation in the registry was widespread. The data collected includes type and number of procedures, patients treated and their outcomes, and reported adverse events to the procedures. For the years 2019 and 2020, the therapeutic apheresis procedure was widely used in the field of haematology, transplantation and rheumatology and was mainly associated with mild adverse events, thus showing a high level of safety. In addition to allowing the competent institution to monitor an important activity in the transfusion medicine field, the Registry is a new starting point for collaboration between transfusion centres distributed throughout the national territory and could encourage the design of major clinical trials.

Early detection and prompt treatment of psychosis is of the utmost importance. The great variability in clinical onset, illness course, and response to pharmacological and psychosocial treatment is in great part gender-related. Our aim has been to review narratively the literature focusing on gender related differences in the psychoses, i.e., schizophrenia spectrum disorders. We searched the PubMed/Medline, Scopus, Embase, and ScienceDirect databases on 31 July 2021, focusing on recent research regarding sex differences in early psychosis. Although women, compared to men, tend to have better overall functioning at psychotic symptom onset, they often present with more mood symptoms, may undergo misdiagnosis and delay in treatment and are at a higher risk for antipsychotic drug-induced metabolic and endocrine-induced side effects. Furthermore, women with schizophrenia spectrum disorders have more than double the odds of having physical comorbidities than men. Tailored treatment plans delivered by healthcare services should consider gender differences in patients with a diagnosis of psychosis, with a particular attention to early phases of disease in the context of the staging model of psychosis onset.

Acute myocardial infarction (MI) is associated with an intense inflammatory response that is critical for cardiac repair but is also involved in the pathogenesis of adverse cardiac remodeling, i.e., the set of size, geometry, and structure changes that represent the structural substrate for the development of post-MI heart failure. Deciphering the pathophysiological mechanisms underlying cardiac repair after MI is, therefore, critical to favorably regulate cardiac wound repair and to prevent development of heart failure. Catecholamines and estrogen play an active role in regulating the inflammatory response in the infarcted area. For example, stress-induced catecholamines alter recruitment and trafficking of leukocytes to the heart. Additionally, estrogen affects rate of cardiac rupture during the acute phase of MI, as well as infarct size and survival in animal models of MI. In this review, we will summarize the role of β-adrenergic receptors and estrogen in cardiac repair after infarction in preclinical studies.

BACKGROUND Platelet gel from cord blood (CBPG) is a recently developed blood component for topical use. We report a case of life-threatening mucositis after high-dose chemotherapy with fotemustine and cytarabine that was successfully treated with CBPG. CASE REPORT A patient with non-Hodgkin lymphoma who was undergoing autologous hematopoietic stem cell transplantation developed severe oral and esophageal mucositis with severe bacterial sepsis and cytomegalovirus infection, causing prolonged neutropenia. CBPG was topically administered daily to the oral cavity. The CBPG was partially reabsorbed and partially swallowed. RESULTS After 8 consecutive days of administration, the patient's oral mucosa markedly improved, showing restitutio ad integrum, and the patient's clinical status progressively improved. No side effects were seen after CBPG application. CONCLUSION This case supports the need to conduct controlled studies comparing the efficacy of autologous and allogeneic platelet gel from adult and umbilical cord blood for the topical treatment of severe oral mucositis occurring after high-dose chemotherapy.

Human pegivirus (HPgV, formerly called GB virus C/hepatitis G virus) is a poorly understood RNA virus of the Flaviviridae family. The HPgV infection is common worldwide and the virus is likely transmitted by blood products. At this time, no causal association between HPgV and human diseases has been identified. While waiting for new findings to better understand the Pegivirus genus, the aim of our narrative review is to discuss the currently available information on HPgV focusing on its prevalence in blood donors and its potential threat to transfusion safety.

This review takes into consideration the main mechanisms involved in cellular remodeling following an ischemic injury, with special focus on the possible role played by non-genomic estrogen effects. Sex differences have also been considered. In fact, cardiac ischemic events induce damage to different cellular components of the heart, such as cardiomyocytes, vascular cells, endothelial cells, and cardiac fibroblasts. The ability of the cardiovascular system to counteract an ischemic insult is orchestrated by these cell types and is carried out thanks to a number of complex molecular pathways, including genomic (slow) or non-genomic (fast) effects of estrogen. These pathways are probably responsible for differences observed between the two sexes. Literature suggests that male and female hearts, and, more in general, cardiovascular system cells, show significant differences in many parameters under both physiological and pathological conditions. In particular, many experimental studies dealing with sex differences in the cardiovascular system suggest a higher ability of females to respond to environmental insults in comparison with males. For instance, as cells from females are more effective in counteracting the ischemia/reperfusion injury if compared with males, a role for estrogen in this sex disparity has been hypothesized. However, the possible involvement of estrogen-dependent non-genomic effects on the cardiovascular system is still under debate. Further experimental studies, including sex-specific studies, are needed in order to shed further light on this matter.

Background Mediterranean diet (MD) is considered a well-balance and potentially anti-inflammatory diet characterized by high consumption of olive oil, unrefined cereals, fresh or dried fruit and vegetables, fish, dairy, meat and with a moderate amount of red wine. Currently, there is conflicting data for the benefits of MD in RA, and no enough evidence to support a role of MD in the prevention and treatment of rheumatoid arthritis (RA) [1]. Objectives The aim of our study was to evaluate the association between MD adherence and disease activity, general health (GH) and comorbidities in patients with RA. Methods Consecutive patients with RA (ACR/EULAR Criteria 2010) were enrolled in this cross-sectional study. For each patient, Disease Activity Score on 28 joints (DAS28), Simple Disease Activity Index (SDAI), patient GH and a self-reported questionnaire called MD score [2] were recorded. The association between MD score and the above mentioned variables was assessed through univariate regression models (MD score as response variable and the variables of interest as independent variables). Results from each model were reported in terms of: 1) test of association (Likelihood Ratio test, with a Chi-square distribution); 2) for categorical independent variables, estimated differences of mean MD score between groups, with respective 95% CI; 3) for numerical independent variables, estimate of correlation coefficient and regression slope coefficient, with respective 95% CI. All analyses were performed using the R software. Results 205 patients (197 Italian) were enrolled: median age at visit 53 (q1-q3: 44-59) years, age at onset 38 (q1-q3: 28-47), disease duration 12 (q1-q3: 7-19), female 80.49%, rheumatoid factor and/or anti–citrullinated protein antibody positivity 58.54%, radiographic damage 41.79%. Comorbidities were also assessed: gastrointestinal 19% (gastro-esophageal reflux disease; inflammatory bowel disease; gastritis; esophagitis), chronic renal failure 1%, arterial hypertension 21.95%, diabetes mellitus 3.9%, coronary artery disease 1.95%. A significant positive correlation was found between MD score and GH, as shown in the table below: this suggests a low/moderate tendency of having better GH with higher MD score. Although not statistically significant, a negative correlation was found with DAS28 and SDAI, suggesting an association between higher MD score with lower disease activity. Among comorbidities, a significant difference of mean MD score values between subjects with and without arterial hypertension was also found (mean difference -2.0 CI: -3.7, -0.2; p=0.029). Conclusion In this Italian RA cohort, the adherence to MD was significantly associated with a better GH, but higher MD score was not significantly associated with lower disease activity. Arterial hypertension was the only comorbidity associated with lower MD score, probably due to the fact that the prevalence of the other comorbidities was low. Our study suggests an overall beneficial effect of MD in RA patients. Further studies are needed to better understand the impact of lifestyle modification (e.g. diet) in achieving RA disease control. References [1] Forsyth C, et al. Rheum Intern 2018 [2] Demosthenes B, et al. Nutr metab cardiovasc dis 2006 Disclosure of Interests None declared

Schizophrenia is a major mental disorder characterized by hallucinations, delirium, behavioral disorders, and a variable range of chronic persistent symptoms. The mainstay in the pharmacologic treatment of schizophrenia is represented by antipsychotic agents. Nevertheless, an increasing body of evidence suggests that supplementation with omega-3 fatty acids may improve the course and symptoms of schizophrenia. Omega-3 fatty acids are necessary for the human organism to develop and function optimally, in maintaining normal physiological conditions, and, consequently, in human health. Therefore, its intake is very important through all stages of life. The current paper discusses the growing body of research examining the relationship between schizophrenia and omega-3 fatty acids that supports the efficacy of polyunsaturated fatty acids as a supplemental treatment.

Aims : Bipolar disorders (BDs) and eating disorders (EDs) are both common and severe mental illness and present wide areas of symptomatological overlap. The present study aims to focus on the most significant aspects of this comorbidity. Methods This review summarizes epidemiology, aethiopathology, prognostic impact, assessment, treatment of comorbidity between BDs and EDs, and comorbidity between bipolar or eating disorders and other psychiatric disorders. We have reviewed articles published in PubMed/Medline, Scopus, Embase, ScienceDirect from 2005 to 2020 concerning comorbidity between eating and bipolar disorders, and systematic reviews or metanalysis on comorbidities between EDs or BDs and other psychiatric disorders. Results Studies that specifically evaluate the prevalence of EDs in patients with bipolar disorder are more than the studies that investigate the opposite. In BDs, binge eating disorder (BED) represents the most common eating disorder with a prevalence ranging from 8,8% to 28,8%, whereas BN has a prevalence ranging from 4,8% to 10%, and AN from 1% to 7,4%. Instead, in ED patients, prevalence of bipolar disorders ranges from 11,5% to 68.1%. The relationship between EDs and BDs has not been yet investigated enough and consequently has not been totally understood. The presence of EDs has been considered as a marker of clinical severity in patients with bipolar disorders, whereas the presence of bipolar disorder in patients with EDs seems not to have a considerable effect on the age at onset of ED symptoms and on their severity. Comorbidities between EDs or BDs and other psychiatric disorders were also examined. Discussion Given the strong co-occurrence of eating and bipolar disorder, the treatment for one of these should consider that the other one may co-exist, and therefore should focus on both of them. In patients suffering from one of these disorders, the early screening for the other one should be made. As for pharmacological treatment, it is mandatory to consider that pharmacological treatment effective for one of the two disorders could worsen symptoms of the other, for instance many psychotropic medications could cause weight gain. Further studies are needed to reach an early diagnosis through the development of screening tools, and to deepen aspects of this comorbidity that remain still unknown with particular regard to pharmacological treatment and to biopsychological aspects that might be useful in determining the aetiopathology.

Background:Mediterranean diet (MD) is a well-balanced, nutritionally adequate and potentially anti-inflammatory diet that encompasses all food groups. Presently, there are conflicting data about the benefits of MD in rheumatoid arthritis (RA). Not enough evidence support a role of MD in the prevention and treatment of RA, and a modest impact of MD on laboratory parameters has been described. Greater effect on subjective aspects of the disease such as joint pain, morning stiffness, and fatigue was reported.Objectives:To investigate whether the adherence to MD affects RA perception as measured by Rheumatoid Arthritis Impact of Disease (RAID) score.Methods:Consecutive patients Results:205 RA patients were enrolled: median age at visit 53 (q1-q3: 44-59) years, female 80.5 %. The median MD and RAID score were 35 (q1-q3: 32-39) and 2.42 (q1-q3: 0.63-4.51) respectively.RAID total score had a statistically significant negative relationship with MD score (regression coefficient -0.08; p-value=0.016). Concerning the single RAID items, a statistically significant negative association was found for pain (regression coefficient -0.08; p-value=0.025), functional disability (regression coefficient -0.13; p-valueMultiple regression analysis to evaluate the relationship between significant RAID items and MD score did not show any statistical significance as all items are strongly related to each other.Conclusion:To our knowledge, this is the first study addressing the relationship between the adherence to MD and the perception of RA impact. A better MD adherence was associated with lower self-reported composite total RAID score as well as lower pain, functional disability, sleep, physical well-being and coping. The effect of MD adherence on overall RAID is relevant but, at the same time, a prominent effect of one single item on the others could not be documented. This study confirmed the importance of non-pharmacological interventions, such as diet, in RA management.References:[1] Gossec L, et al. Ann Rheum Dis 2011;70(6):935-42.[2] Panagiotakos DB, et al. Nutr Metab Cardiovasc Dis 2006;16(8):559-68.Disclosure of Interests:Francesca Ingegnoli: None declared, Isabella Scotti: None declared, Tommaso Schioppo: None declared, Tania Ubiali: None declared, Giuseppe Marano: None declared, Patrizia Boracchi: None declared, Orazio De Lucia: None declared, Antonella Murgo: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB

Cardiac dysfunction is often observed in patients with cancer also representing a serious problem limiting chemotherapeutic intervention and even patient survival. In view of the recently established role of the immune system in the control of cancer growth, the present work has been undertaken to investigate the effects of a panel of the most important inflammatory cytokines on the integrity and function of mitochondria, as well as of the cytoskeleton, two key elements in the functioning of cardiomyocytes. Either mitochondria features or actomyosin cytoskeleton organization of in vitro‐cultured cardiomyocytes treated with different inflammatory cytokines were analyzed. In addition, to investigate the interplay between tumor growth and cardiac function in an in vivo system, immunocompetent female mice were inoculated with cancer cells and treated with the chemotherapeutic drug doxorubicin at a dosing schedule able to suppress tumor growth without inducing cardiac alterations. Analyses carried out in cardiomyocytes treated with the inflammatory cytokines, such as tumor necrosis factor α (TNF‐α), interferon γ (IFN‐γ), interleukin 6 (IL‐6), IL‐8, and IL‐1β revealed severe phenotypic changes, for example, of contractile cytoskeletal elements, mitochondrial membrane potential, mitochondrial reactive oxygen species production and mitochondria network organization. Accordingly, in immunocompetent mice, the tumor growth was accompanied by increased levels of the inflammatory cytokines TNF‐α, IFN‐γ, IL‐6, and IL‐8, either in serum or in the heart tissue, together with a significant reduction of ventricular systolic function. The alterations of mitochondria and of microfilament system of cardiomyocytes, due to the systemic inflammation associated with cancer growth, could be responsible for remote cardiac injury and impairment of systolic function observed in vivo.

Background: Aim of the study was the validation of the Bipolar Disorder Rating Scale (BDRS) in an Italian population. Secondary aim was the evaluation of differences between unipolar and bipolar depression and between bipolar I and II depressed patients.Method: 125 Bipolar Disorder and 60 Major Depressive Disorder patients were administered an Italian translation of the BDRS (I-BDRS), Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS) and Temperament and Character Inventory-Revised (TCI-R).Results: I-BDRS showed considerable validity and reliability. Factor analysis found 3 subscales, two linked to depressive symptoms and one to mixed symptoms. Measures concerning depression (MADRS and HAM-D) were positively related to the I-BDRS's subscales, but mostly to the two subscales measuring depression. In mixed symptoms, the mean of the bipolar group was significantly higher than the unipolar group suggesting that the BDRS was able to distinguish between unipolar and bipolar depressed patients.Conclusion: I-BDRS is a valid scale for the measurement of depression in BD patients, with a notable internal consistency (Cronbach's α 0.82), a significant consistency between items/total (Cronbach's α from 0.80 to 0.82) and positive correlation with other scales (MADRS r = 0.67, p < 0.001; HDRS r = 0.81, p < 0.001; YMRS r = 0.46 p < 0.0001). The mixed state sub-scale shows usefulness in differentiating bipolar from unipolar patients. I-BDRS could be a sensitive tool, both in pure depression and in mixed states, and could be used in the everyday screening and treatment of Bipolar Disorder.

Summary Background The regenerative effectiveness of lipoaspirate procedures relies on the presence of mesenchymal stem cells, but the stromal microenvironment and hormonal secretions of the adipose tissue may be involved in cancer growth. Only few oncological outcome studies of fat grafting at the surgical site of malignant neoplasms of mesenchymal origin are available; none of these studies examined a series of sarcoma cases. Objectives We analyzed outcome in terms of local or distant spread and overall survival to investigate the oncological safety of fat grafting in patients with sarcoma. Patients and methods Sixty consecutive patients who had undergone 143 fat grafting procedures after surgical resection of bone and soft tissue sarcomas of the head, trunk, and limbs with clear resection margins were enrolled from 2004 to 2015 in our tertiary care center. A multidisciplinary sarcoma team administered adjuvant therapies. Patients were recurrence free at fat grafting. Results The overall median follow-up was 7.5 years. At follow-up after fat grafting (2.4 years), one patient had distant metastasis and two had local relapse. Kaplan–Meier analysis showed disease-free survival rate of 95.4% (CI: 89.1–100.0) at 24 months. The risk of local recurrence (LR) within 24 months was 4.6% (CI: 0.0–20.9). The probability of not having LR after fat grafting was ≥ 89.1%. Conclusion We found no evidence of an increased cancer risk after fat grafting procedures in patients with sarcoma, but a stimulatory role of fat cannot be excluded for bone sarcomas based on the cases reported here, and further studies are therefore needed.

The present study describes a new mixed program of psychoeducational and psychological interventions for bipolar patients, applicable during everyday practice. Thirty-two bipolar patients recruited at a psychiatric day-hospital service have been admitted to a program consisting of 30 meetings and 2 follow-ups at 6 and 12 months. The psychoeducational support determined a general improvement of all included patients. At baseline, patients with residual depression had higher Hamilton Depression Rating Scale (HDRS) scores than euthymic patients (mean score ± SD: 21.25 ± 3.92 vs. 7.00 ± 2.95, respectively). After psychoeducation sessions, the HDRS scores of euthymic patients remained stable (mean ± SD: 7.00 ± 3.74), whereas the HDRS scores of depressed patients demonstrated a statistically significant improvement (mean ± SD: 14.00 ± 6.72, t = 2.721, p = 0.03). Results of the Connor-Davidson Resilience scale and specifically constructed questionnaire Questionario per la Valutazione della Conoscenza e dell'Apprendimento per il Disturbo Bipolare showed a statistically significant improvement in resilience and insight in all recruited patients. Psychoeducational intervention as adjunctive treatment to pharmacotherapy seems to be very effective in bipolar patients, not only for those in the euthymic phase, but this model could also be extended to patients with an ongoing mild or moderate depressive episode.

Background & Objective: Cariprazine is a piprazine derivative approved by the FDA in 2015 for the treatment of schizophrenia and bipolar manic or mixed episodes in adults. High affinity for D3 dopamine receptors and observed actions on 5HT1A, 5HT2A and alpha 1B receptors differentiate it pharmacologically from other antipsychotics. This review is a comprehensive and thorough summary of the most important findings on cariprazine use in bipolar mania and depression. Pharmacokinetics, pharmacogenetics, tolerability and safety adverse effects are discussed in this paper. Results & Conclusion: Moreover, the results from pivotal clinical trials are presented. Cariprazine represents an additional option for clinicians to treat patients with bipolar disorder. It shows a unique pharmacological profile and has demonstrated in randomized clinical trials efficacy and general tolerability compared to placebo in bipolar mania and seem to be a promising therapeutic option for bipolar depression.

Human T-cell leukemia viruses (HTLV-1 and HTLV-2) are associated with a variety of human diseases, including some severe ones. Transfusion transmission of HTLV through cellular blood components is undeniable. HTLV screening of blood donations became mandatory in different countries to improve the safety of blood supplies. In Japan and Europe, most HTLV-infected donors are HTLV-1 positive, whereas in the United States a higher prevalence of HTLV-2 is reported. Many industrialized countries have also introduced universal leukoreduction of blood components, and pathogen inactivation technologies might be another effective preventive strategy, especially if and when generalized to all blood cellular products. Considering all measures available to minimize HTLV blood transmission, the question is what would be the most suitable and cost-effective strategy to ensure a high level of blood safety regarding these viruses, considering that there is no solution that can be deemed optimal for all countries.

Abstract. Background: The objective of this prospective multicentre cohort study was to characterise the use of pharmacological and non-pharmacological treatment for cardiovascular disease (CVD) risk factors and intermittent claudication (IC) symptoms in clinical practice patients with peripheral artery disease (PAD), and to determine the care gap with international guidelines and evidence-based therapy. Patients and methods: From 2011 through 2013, participating centres enrolled consecutive patients with PAD of atherosclerotic origin demonstrated by ultrasound, ankle brachial index (ABI) 0.9 and symptoms of IC. A seven item grid was built for the assessment of care gap (percentage of patients eligible for a treatment who did not receive it). Results: All patients (232) presented at least one CVC risk factor, 90.2% at least two, and 91.5% had either established CAD or cerebrovascular disease or at least two CVD risk factors. Care gap was lower than 25% for any method to stop smoking, lipid lowering agents, antiplatelet and/or anticoagulation therapy and any kind of exercise program; between 25% and 50% for ACE-inhibitors/angiotensin II antagonist therapy; between 50% and 75% for beta-blocker therapy; and higher than 75% for supervised exercise program and use of cilostazol. Patients with and without CAD/cerebrovascular disease were differently treated with clopidogrel (27.3% and 4.8%, p≤0.001), any antiplatelet/anticoagulant therapy (98.7% and 83.3%, p≤0.001) and beta-blockers (46.8% and 16.0%, p≤0.001). Conclusions: Many gaps with evidence-based recommendations are still present in the pattern of the use of pharmacological and non-pharmacological treatment for CVD risk factors and IC symptoms in clinical practice PAD patients.

Solvent/detergent-treated plasma was licensed >30 years ago. It has several specific characteristics, the most important being the standardized content of clotting factors, the lack of antibodies implicated in transfusion-related acute lung injury pathogenesis and the very high level of safety against transfusion-related viral infections. Since 1992, many clinical studies have confirmed its safety and efficacy in a wide range of congenital and acquired bleeding disorders. After a brief analysis of the pharmaceutical characteristics of solvent/detergent plasma, this review will focus on the clinical experience with this virus-inactivated plasma.

In addition to their major role in transfusion medicine, there is increasing evidence that ABO blood group antigens (complex carbohydrate molecules widely expressed on the surface of red blood cells and several other cell types) are implicated in the development of a wide array of pathologic conditions. In particular, intense research has been dedicated over the last 50 years to the study of the association between non-O blood type and the risk of developing cardiovascular disorders. Several pathways have been hypothesized to explain this relationship, the most reasonable implying the influence of the ABO blood group on circulating plasma levels of von Willebrand factor, factor VIII, and several inflammatory cytokines. This narrative review summarizes the current knowledge on the role of ABO antigens in both venous and arterial thromboses, focusing on their association with clinical scoring systems evaluating thrombotic risk.

Subjects undergoing major orthopedic surgery and acutely ill hospitalized medical patients represent a population at medium-high risk for venous thromboembolism (VTE). They are treated with low molecular weight heparin (LMWH) and direct oral anticoagulants [DOACs] for VTE prevention. We conducted a meta-analysis of phase III randomized clinical trials evaluating LMWH enoxaparin versus DOACs for prophylaxis of VTE by combining studies including patients undergoing elective total hip and knee replacement surgery, and acutely ill hospitalized medical subjects. Studies were searched using PubMed, MEDLINE, and EMBASE databases until December 2016. Differences in clinical outcomes for efficacy and safety endpoints between treatment groups were expressed as risk differences with 95% confidence intervals (95% CI), using random effects regression models. Fourteen RCTs were considered (60,467 subjects). Overall mortality, symptomatic deep venous thrombosis, non-fatal pulmonary embolism (PE) major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) are not different between treatment regimens. Treatment with LMWH enoxaparin is associated with a lower risk of fatal PE plus VTE-related death compared therapy with DOACs (RD = 0.040%, 95% CI 0.001-0.080%, p = 0.0434). Subgroup analysis shows an incidence of MB (RD = 0.181%, 95% CI 0.029-0.332%, p = 0.0033) and CRNMB (RD = 0.546%, 95% CI 0.009-1.082%, p = 0.0462) in patients treated with 40 mg OD enoxaparin compared to DOACs. In major orthopedic surgery and acutely ill hospitalized medical patients, DOACs do not offer clear advantages in terms of clinical efficacy compared to enoxaparin. The advantage of the latter in terms of major and CRNMB, when used at a dose of 40 mg, is statistically significant, but small in terms of clinical relevance.

The worldwide burden of snakebite is high and venomous snakes are found in many regions of the world and are a threat to public health. In Italy, for instance, viper bites are an infrequent but not negligible event. Although people who have been bitten by a snake rarely wish to donate blood within a "short" time, it is however important to evaluate their eligibility to donate blood or blood components as their donation could be a problem for donor management, especially if a specific policy is not in place. The aim of this manuscript is to summarise the worldwide existing donor deferral policy for snakebites and to provide some indications in order to facilitate decision-making and to guarantee maximum safety for the donors as well as for the recipients.

ST-elevation and non-ST-elevation myocardial infarction (STEMI, NSTEMI) are considered two distinct pathophysiologic entities. We evaluated cardiac troponin I (cTnI) release in STEMI and NSTEMI using a "contemporary" (CV10 to 20% at the 99th percentile concentration) cTnI assay for patients undergoing early percutaneous coronary intervention (PCI).856 patients with suspected acute coronary syndrome consecutively admitted to the Emergency Department of the Maggiore Hospital of Novara (225 STEMI and 135 NSTEMI) were selected according to: 1) early (≤ 4 h from admission) and successful PCI; and 2) cTnI measurements at ED presentation and within 24h. The influence of the MI type on cTnI concentrations at baseline and after PCI as well as the velocity of cTnI [cTnI V=absolute increase (after log conversion of cTnI measurements)/delay between the two measurements] was studied by multiple regression analysis, adjusting for patient parameters.A statistically significant interaction between MI type and time from symptoms was reported on cTnI concentrations (p0.0001): STEMI and NSTEMI differed for cTnI releases at admission and after revascularization. Higher cTnI V in STEMI was detectable in patients admitted within 6h from symptoms. Baseline cTnI concentrations were lower in patients with a history of coronary artery disease (CAD) and increased with aging (p0.0001). In the elderly (75 years), the cTnI V was significantly increased.STEMI and NSTEMI patients have different patterns and dynamics of cTnI release influenced by the interaction with time from symptoms, by aging and history of CAD.

Dittoni S, Mazza M, Losurdo A, Testani E, Di Giacopo R, Marano G,Di Nicola M, Farina B, Mariotti P, Mazza S, Della Marca G.Psychological functioning measures in patients with primary insomniaand sleep state misperception.Acta Neurol Scand 2013: DOI: 10.1111/ane.12078.© 2013 John Wiley & Sons A/SObjective – Sleep state misperception (SSM) is a term used in theInternational Classification of Sleep Disorders to indicate people whomistakenly perceive their sleep as wakefulness. SSM is a form ofprimary insomnia. The aim of this study was to record psychologicalfunctioning measures (anxiety, depression, ability to feel pleasure,obsessive–compulsive traits) in a population of patients with primaryinsomnia and to evaluate the relationship between these measures andthe patients’ perception of their sleep. Materials and Methods –Seventy-six consecutive patients with primary insomnia were enrolled:34 men and 42 women, mean age 53.9 13.1. Sleep study includedthe following: Pittsburgh Sleep Quality Index, Epworth SleepinessScale, Berlin’s Questionnaire and home-based polysomnography.Psychometric evaluation included the following: Self-AdministeredAnxiety Scale, Beck’s Depression Inventory, Maudsley’s ObsessiveCompulsive Inventory, Snaith–Hamilton Pleasure Scale, EatingAttitude Test. Results – All patients with insomnia had psychometricscores higher than the general population, but very few patients, inboth groups, had anxiety or depression scores consistent with severemood or anxiety disorders. Comparisons between subjective andobjective scores confirmed that most sleep parameters wereunderestimated. Patients with SSM had lower anxiety scores ascompared to patients without SSM. Conclusions – The study did notsucceed in identifying any predictor of sleep misperception.We speculate that a group of patients, rather than being extremelyworried by their insomnia, may have a sort of agnosia of their sleep.

This study aimed to test the effectiveness of an individualized, integrated, day-care treatment programme for the acute phase of "difficult-to-treat depression" (DTD) in a sample of bipolar and unipolar subjects with a complex co-morbidity pattern.A total of 291 patients meeting criteria for DTD were consecutively recruited. All participants underwent a 12-week day-care intervention including individual psychological support and group psycho-education. Subjects were assessed for depressive symptom severity by the 21-item Hamilton Depression Rating Scale (HDRS) at the baseline (T0) and after 4 (T1) and 12 (T2) weeks of treatment. A repeated measures general linear model was performed to test for interactive effects among variables.An overall significant improvement was detected in the majority of cases (F = 138.6, p0.0001). Responders reported lower rates of personality disorders and higher baseline depressive severity. An interaction between bipolarity and co-morbidity was associated with a poorer outcome (F = 5.9, p = 0.0034). Family involvement was the only significant predictor for symptom improvement (F = 7.9, adjusted p = 0.0025).Our intervention proved to be effective in the treatment of complex and severe forms of depression. Our results on the role of family support require further investigation to better define suitable targets for tailored therapeutic approaches.

Psychotropic drugs can produce cardiovascular side effects associated with a degree of cardiotoxicity. The coexistence of a heart disease complicates the management of mental illness, can contribute to a reduced quality of life and a worse illness course. The co-occurrence of psychiatric disorders in cardiac patients might affect the clinical outcome and morbidity. Moreover, the complex underlying mechanism that links these two conditions remains unclear. This paper discusses the known cardiovascular complications of psychotropic drugs and analyzes the important implications of antidepressive treatment in patients with previous cardiac history.

Alzheimer's disease (AD) is a degenerative disorder characterized by a decreased regional cerebral blood flow (CBF). It is most likely that a reduction in CBF could displace a pathway leading to AD genesis, in so far neuron death explains a sustained reduction in the supply of oxygen, glucose, and nutrients. Nevertheless, the concept of secondary CBF deficiency cannot explain the critical stages of early memory loss while, on the other hand, the picture of progressive ischemia due to primary CBF decline sheds light on the course of AD in a most persuasive manner. The concept of primary CBF deficiency is even more strengthened by the lack of correlation between degree of dementia and amount of CBF. Vascular abnormalities, frequently observed to co-occur with AD, might play a critical role in the initiation and aggravation of AD pathology given that the elimination of amyloid-β (Aβ) through a vascular route is an important brain Aβ clearance mechanism and its failure leads to formation of vascular amyloidosis and dense-core plaques. The goal of this review is to provide scientists comprehensive knowledge of the state-of the art influence vascular damage and reduced perfusion have on the final development of AD and to hopefully stimulate more research in this area of neuroscience.

This review explores the epidemiological evidence for the relationship between depression and cardiovascular disease from a mechanistic standpoint. It is important to examine the biological, behavioral and social mechanisms to improve outcomes for depressed cardiac patients. A number of plausible biobehavioral mechanisms linking depression and cardiovascular disease have been identified. Tricyclic antidepressants have various effects on the cardiovascular system, while selective serotonin reuptake inhibitors are not associated with adverse cardiac effects and should, therefore, be the preferred choice for the treatment of most patients with comorbid depression and cardiovascular disease.

Background Whether radiotherapy (RT) is beneficial in elderly (⩾70years) patients undergoing conservative surgery for early breast cancer has long been controversial. Recent randomised trials show that most elderly patients do not benefit from RT. We started a prospective non-randomised trial to address this issue in 1987 and now present results for the 627 consecutive pT1/2cN0 patients recruited, and treated by conservative surgery (quadrantectomy) and tamoxifen, and assigned non-randomly to RT or no RT. Methods We used multivariate competing risks models to estimate 15-crude cumulative incidence (CCI) of ipsilateral breast tumour recurrence (IBTR), distant metastasis and breast cancer mortality. The models incorporated a propensity score as a measure of probability of receiving RT based on baseline characteristics, to account for the lack of randomisation. Results For pT1 patients, 15-year CCIs of IBTR, distant metastasis and breast cancer death were indistinguishable in the RT and no RT groups. For pT2 patients, 15-year CCI of IBTR was much higher in those not given RT (14.6% versus 0.8%, p =0.004), although breast cancer mortality and distant metastasis did not differ significantly between RT and no RT. Conclusions Consistent with the findings of recent randomised trials, our long-term data indicate that most elderly, ER-positive patients with pT1 cN0 breast cancer treated by quadrantectomy do not benefit from RT. The 14.6% CCI of IBTR in our pT2 patients is an additional finding not presented in the trials and suggests that RT should be administered to elderly patients with pT2 disease.

Cardiac hypertrophy is a homeostatic response to elevated afterload. Na+/H+ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na+/H+ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about +50%) and normal chamber size and function, whereas cariporide-treated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition.British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631

Keywords: itching, nodules, pregabalin, prurigoSUMMARYWhat is known and objective: Prurigo nodularis (PN) is achronic skin condition that is difficult to treat. Pregabalin isone of the possible treatments for PN but its safety and effi-cacy are not well defined. We aimed to assess the efficacy ofpregabalin in patients with PN.Methods: Thirty patients (10 men, 20 women; mean age51.6 ± 9.39 years) were treated with pregabalin (75 mg/day) for3 months. Efficacy was classified as (i) successful (disappear-ance of the pruritus and reduction of nodules); (ii) slightimprovement/reduction of the nodules, that is, number and/orflattening, no disappearance of itching; or (iii) unsuccessful.Results: Twenty-three patients (76%) responded successfullyafter 3 months of treatment. There was a statistically signifi-cant difference between visual analogue scale scores beforeand after 1 month treatment period (8AE15 ± 2AE04 and 1AE5±1AE12,respectively; P

Aims To assess different aspects of the definition of valvular/non-valvular atrial fibrillation (AF) used in clinical practice by physicians who usually treat this condition. Methods and results We prospectively conducted a web-based survey including cardiologists and internists who attended continuing medical education courses on cardiovascular medicine. A questionnaire was drawn up, containing 17 questions clustered into five main topics: (A) known rheumatic aetiology; (B) site/type of valve involvement; (C) prosthetic heart valve; (D) haemodynamic relevance; (E) miscellaneous. The overall response rate was 22.4% (21.1% for cardiologists and 24% for internists). Coexistence of both medical history of rheumatic disease and clinical signs of valvular involvement were considered as essential prerequisites for the diagnosis of rheumatic AF by half of the respondents, and one-third assumed that lone aortic valve disease was sufficient for AF to be defined as valvular. A similar proportion of respondents considered that in the presence of mitral regurgitation, AF had to be defined as valvular. The majority of responding physicians considered the degree of valvular defect of lesser importance for the definition of valvular or non-valvular origin of AF. Conclusion We found important heterogeneity and uncertainties in the answers given by physicians who usually treat patients with AF, as evidence of the lack of precise and unique definitions of the origin of AF (valvular/non-valvular). It is urgent to issue clear widely accepted definitions of the origin of AF, which should improve clinical practice and research.

Aims The behavioural-addiction perspective suggests that Internet addiction (IA) and pathological gambling (PG) could share similar characteristics with substance dependence. Despite the similarities between IA and PG, it is not clear whether these disorders share different or similar psychopathological conditions. The aim of the present study was to test whether IA patients presented different psychological symptoms, temperamental traits, coping strategies and relational patterns compared with PG patients. The hypothesis was that IA patients will show greater interpersonal disengagement than PG patients. Methods Two clinical groups (31 IA patients and 11 PG patients) and a control group (38 healthy subjects) matched with the clinical groups for gender and age were enrolled. The clinical groups were gathered in a psychiatric service for IA and PG in a hospital. Anxiety, depression, coping strategies, attachment, temperament, and global assessment of functioning were measured. MANOVAs, ANOVAs and post-hoc comparisons were carried out in order to test the hypothesis. Results Despite IA and PG showing similar differences with the control group on the levels of depression, anxiety and global functioning, the two clinical groups showed different temperamental, coping and social patterns. Specifically IA patients compared with the PG patients showed a greater mental and behavioural disengagement associated with an important interpersonal impairment. The two clinical groups shared an impulsive coping strategy and socio-emotional impairments. Conclusions Despite IA and PG patients presenting similar clinical symptoms, IA condition was characterised by a more relevant mental, behavioural, and social disengagement compared to PG condition.

The contribution of endothelin to the genesis of neointimal development in collared rabbit carotid arteries, a widely accepted model of atherosclerosis, was investigated. Three sets of rabbits were studied. In the first group, a non-occlusive, biologically inert silastic collar was positioned around the right carotid artery of the rabbit. In another group, the application of the collar was accompanied by endothelial denudation via a Fogarty arterial balloon catheter, while the third group of animals underwent only endothelial denudation. After two weeks, intimal hyperplasia of a similar degree was observed in all groups. The administration of the nonselective ET A ET B receptor antagonist Bosentan, significantly reduced both the neointimal area and the intima/media area ratio in all groups. However, the beneficial effects of Bosentan were less pronounced in balloon injured vessels than in collared ones. The results of the present study indicate that i) endothelin has a key role in the development of intimal hyperplasia following arterial collaring, ii) the contribution of endothelin to intimal hyperplasia is greater in collared arteries that in balloon injured ones, and iii) the nonselective ET A ET B receptor antagonists are potential tools for the prevention of intimal hyperplasia.