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Background and Objective: The use of herbal products globally is substantial, but varying definitions and regulatory frameworks have led to differences in their status as medicinal products and in approaches to monitoring their safety. This article explores the current landscape of herbal pharmacovigilance, drawing insights from interviews with global experts in the field, and offers recommendations for best practices to enhance the safety and benefit-to-harm balance of herbal products. Methods: This study comprised semi-structured interviews with members of the International Society of Pharmacovigilance-Herbal and Traditional Medicines Special Interest Group and the Nutrivigilance Information Exchange Network, recruited using purposive sampling. Data were stored and coded using NVIVO® and analysed thematically using a qualitative inductive approach. Results: Sixteen participants from 11 countries were interviewed, revealing diverse regulatory approaches and challenges in herbal pharmacovigilance. Key themes included legal status, awareness, identification and coding of herbal products, pre-/post-marketing product control, reporting of adverse drug reactions, causality assessment and signals of herbal products. This study yielded five general recommendations to further improve herbal pharmacovigilance worldwide. Conclusions: This study offers an overview of the global landscape of herbal pharmacovigilance, highlighting challenges in monitoring herbal products and presenting universal recommendations. These recommendations encompass increasing awareness, enhancing education and improving legislative frameworks. Given the growing use of herbal products, the implementation of strong pharmacovigilance practices is crucial to ensure consumer safety. [ABSTRACT FROM AUTHOR]

Background and Objective: Cases of appendicitis were identified in the pivotal randomized clinical trial on BNT162b2 mRNA vaccine and reported from coronavirus disease 2019 (COVID-19) vaccine pharmacovigilance systems. Three cohort studies and two self-controlled case series (SCCS) studies evaluating the association between mRNA vaccines and appendicitis reported discordant results. To address this uncertainty, the present study examines in a large population, with a SCCS design, the association between mRNA (BNT162b2 and mRNA-1273) and, for the first time, viral vector (ChAdOx1-S and Ad26.COV2-S) COVID-19 vaccines and acute appendicitis. Methods: The SCCS study design was used to evaluate the association between COVID-19 vaccination and subsequent onset of acute appendicitis. The study was based on record linkage of health archives through TheShinISS application, a statistical tool that locally processes data from regional health care databases according to ad hoc, study-tailored and common data model. The study population included all vaccinated subjects ≥ 12 years old between 27 December 2020 and 30 September 2021. The acute appendicitis was identified through discharge diagnoses of hospital admissions or emergency department visits. Incident cases were defined as those who experienced a first event of acute appendicitis in the study period, excluding subjects with a diagnosis of appendicitis in the previous 5 years. Exposure was defined as the first or second dose of BNT162b2, mRNA-1273 and ChAdOx1-S and the single dose of Ad26.COV2-S. The risk interval was defined as 42 days from the first or second vaccination dose and divided into pre-specified risk subperiods; the reference period was the observation time outside the risk interval. Relative incidences (RI) and 95% confidence intervals (95% CI) were estimated with the SCCS method 'modified for event-dependent exposures', through unbiased estimating equations. The seasonal component was considered as a time-dependent covariate. Results: In the 42-day risk interval 1285 incident cases of acute appendicitis occurred: 727 cases after the first dose and 558 cases after the second dose. In the main analysis, no increased risks of acute appendicitis were observed in subjects vaccinated with BNT162b, mRNA-1273, ChAdOx1-S and Ad26.COV2-S. The subgroup analyses by sex showed an increased risk in the 14–27 day risk interval, in males after the first dose of mRNA-1273 (RI of 1.71; 95% CI 1.08–2.70, p = 0.02) and in females after the single dose of Ad26.COV2-S (RI of 4.40; 95% CI 1.29–15.01, p = 0.02). Conclusions: There was no evidence of association of BNT162b, ChAdOx1-S, mRNA-1273 and Ad26.COV2-S with acute appendicitis in the general population. The results of the subgroup analyses by sex needs to be considered with caution. The multiplicity issue cannot be excluded being these hypotheses two of several hypotheses tested. In addition, relevant literature on the biological mechanism of the disease and evidence of similar effects with other vaccines or with the same vaccines are still lacking to provide strong support for a conclusion that there is an harmful effect in males and females with mRNA-1273 and Ad26.COV2-S. [ABSTRACT FROM AUTHOR]

A very recent survey explored how and why EU consumers are using food supplements. The aim of this manifesto is: to enhance the awareness on a safe use of food supplements; to promote the creation of a common European monitoring system; to inform citizens and health professionals about the potential risks associated with the consumption of these products; to stimulate the reporting of possible harm (adverse events). [Extracted from the article]

Portmán Bay in Southern Spain is one of the most extreme cases in Europe of anthropogenic impact on the marine ecosystem by the disposal of mine tailings resulting from the processing of sulphide ores. First, the composition and extent of the surficial deposit were investigated from geochemical and metal analysis on high spatial density of sediment samples. Then, a disturbance experiment was conducted in the coastal area off Portmán Bay in order to investigate the potential impact of mining activities on marine ecosystems. Two research vessels were used for that experiment, one performing as a trawler resuspending bottom sediments while the other monitor the behaviour of turbid plumes thus generated and the evolution of their characteristics through time by using a range of acoustic and optical tools together with water and bottom sediment sampling for biogeochemical and metal analyses. The surficial part of the submarine extension of the mine tailings deposit is highly concentrated in As, Cd, Pb, Fe and Zn with peak concentrations adjacent to the present coastline, from where they decrease seawards before reaching average values for the Mediterranean Sea around 50-m water depth. The artificially triggered resuspension of the surface layer of the deposit led to the formation of resuspension plume about 100 m in width and up to 6 m in height. Resuspended plume was composed of fine particles which rapidly aggregated into flocs of 100 μm. While the biggest particles settled rapidly, the finest fraction remained in suspension during at least 3 h. Resuspended sediment and metal concentrations in particles remained at relatively high levels throughout the experiments following triggering. Fe, Pb, and As concentrations in resuspended particles showed a continuous increase while trawling before decreasing in parallel with the settling down of the resuspended sediments. Those metals have higher affinity with fine particles than with coarse ones, so that while the coarsest fraction from sediment plumes settled first, the finest fraction remained in suspension thus increasing the metals/sediments concentration ratio. On the other hand, Cd and Zn concentrations in suspended particles did not change significantly over time, which is thought to be caused by the fast dissolution of such metals in seawater. Beyond waste dumping itself, the observed increase in some metals in marine particulate material could have a significant impact on the adjacent coastal ecosystems due to their toxicity above certain thresholds. The consequences of the resuspension experiment here presented can be extrapolated to the impact of seafloor mining activities leading to the resuspension of metal-rich particle plumes into the water column. The experimental set-up presented here may be further explored for investigating metal behaviour during seafloor mining activities. [ABSTRACT FROM AUTHOR]

Introduction: The epidemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. There are several controversial hypotheses on the potentially harmful or beneficial effects of antihypertensive drugs acting on the renin–angiotensin–aldosterone system (RAAS) in coronavirus disease 2019 (COVID-19). Furthermore, there is accumulating evidence, based on several observational studies, that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) do not increase the risk of contracting SARS-CoV-2 infection. On the other hand, conflicting findings regarding the role of ACEIs/ARBs as prognosis modifiers in COVID-19 hospitalised patients have been reported. Objective: The aim of this large-scale, retrospective cohort study was to investigate whether prior exposure to ACEIs and/or ARBs was associated with all-cause mortality among over 40,000 hospitalised COVID-19 patients compared with calcium channel blockers (CCBs), a potential therapeutic alternative. Methods: This study was conducted using COVID-19 registries linked to claims databases from Lombardy, Veneto and Reggio Emilia (overall, 25% of Italian population). Overall, 42,926 patients hospitalised between 21 February and 21 April 2020 with a diagnosis of COVID-19 confirmed by real-time polymerase chain reaction tests were included in this study. All-cause mortality occurring in or out of hospital, as reported in the COVID-19 registry, was estimated. Using Cox models, adjusted hazard ratios (HRs) of all-cause mortality (along with 95% confidence intervals [CIs]) were estimated separately for ACEIs/ARBs and other antihypertensives versus CCBs and non-use. Results: Overall, 11,205 in- and out-of-hospital deaths occurred over a median of 24 days of follow-up after hospital admission due to COVID-19. Compared with CCBs, adjusted analyses showed no difference in the risk of death among ACEI (HR 0.97, 95% CI 0.89–1.06) or ARB (HR 0.98, 95% CI 0.89–1.06) users. When non-use of antihypertensives was considered as a comparator, a modest statistically significant increase in mortality risk was observed for any antihypertensive use. However, when restricting to drugs with antihypertensive indications only, these marginal increases disappeared. Sensitivity and subgroup analyses confirmed our main findings. Conclusions: ACEI/ARB use is not associated with either an increased or decreased risk of all-cause mortality, compared with CCB use, in the largest cohort of hospitalised COVID-19 patients exposed to these drugs studied to date. The use of these drugs therefore does not affect the prognosis of COVID-19. This finding strengthens recommendations of international regulatory agencies about not withdrawing/switching ACEI/ARB treatments to modify COVID-19 prognosis. [ABSTRACT FROM AUTHOR]

The Norwalk Harbor is the estuarine portion of the Norwalk River, which connects to Long Island Sound. Like many embayments, this macrotidal harbor experiences higher summer water temperatures than waters farther offshore, which contribute to water quality problems. The summer season is characterized by surface heating, strong tides (as in all seasons), weak winds, and low river discharge. To determine the relative importance of exchange with offshore waters in regulating the harbor temperature, a control volume approach is used to make a summer temperature budget for the harbor based on observations. Time series of harbor temperature, surface heat flux, and Norwalk River inflow are constrained with measurements of water temperatures, atmospheric conditions, and river discharge. The impact of offshore exchange is inferred as the residual after the real temperature change in the harbor, and all other sources of temperature change are constrained. The analysis indicates that, in the summer, the impact of offshore exchange is comparable to the impact of the surface heat flux and far greater than the impact of the river. Consequently, the harbor is much cooler during summer than it would be if it was not connected to Long Island Sound. The methods applied here are applicable to any relatively small, semi-enclosed body of water and do not require the use of models or velocity observations. It is likely that many other embayments have an appreciable degree of thermal buffering via exchange with offshore waters. [ABSTRACT FROM AUTHOR]

The article offers information on the Italian Drug Agency organized a workshop on the role of healthcare databases in supporting drug regulatory agencies in their pre- and post-marketing regulatory activities in April 2019. It mentions that the U.S. Food and Drug Administration (FDA) Sentinel System is a distributed data system. It also mentions that Canadian Network for Observational Drug Effect Studies uses a distributed database network.

Purpose: Overweight and obesity represent worldwide a rising health problem. In this context, dietary supplements and herbal preparations are often used as self-medication for weight loss. The aim of this study was to describe the safety profile of dietary supplements for weight control by analyzing spontaneous reports of suspected adverse reactions (ARs) received by the Italian Phytovigilance System, from July 2010 to October 2017. Methods: The suspected ARs were collected using an ad hoc reporting form, registered in a database at the National Institute of Health and evaluated by a multidisciplinary group of experts. The causality assessment was performed using the WHO-UMC system or the CIOMS/RUCAM score. In case of serious adverse reactions, a feedback is provided to the reporter by e-mail. Results: Sixty-six spontaneous reports were collected. ARs involved cardiovascular system (26%), liver (14%), central nervous system (12%), skin (9%), gastrointestinal system (17%), thyroid (8%), kidney (4%), and other organs/systems (10%). In 64% of cases, the reaction was serious. Dechallenge was positive in 46 cases; three cases of positive rechallenge were reported. After the causality assessment, the association between the product intake and the adverse reaction was judged as possible in the majority of the cases (n = 43; 65%). Conclusions: The data collected confirmed the existence of safety concerns on herbal dietary supplements used for body weight control, mainly related to quality of products and their use as self-medication. In this scenario, spontaneous reports represent the only tools available to monitor safety of these products. [ABSTRACT FROM AUTHOR]

Aims: HNF1A is a gene coding for the transcription factor HNF1-α, mutated in some forms of MODY and type 2 diabetes mellitus characterized by a strong genetic component. The penetrance of HNF1A variants differs considerably; thus, to assess the genetic risk of diabetes in carrier subjects of a HNF1A mutant allele, a functional characterization of mutant forms is of paramount importance. Methods: The HNF1A gene was sequenced in two patients with partly discordant diabetic phenotype, carrying the p.Pro409His variant. To evaluate the pathogenicity of the variant, we measured the transactivation power of the corresponding P408H HNF1-α mutant mouse form on HNF1-α target promoters. Results: We found a lower but detectable activity of transactivation of the mutant form compared with the wild-type form and we excluded mechanisms of protein degradation or nuclear mislocalization. Conclusions: The HNF1A mutation p.Pro409His can be considered a mild variant that confers a moderate risk of type 2 diabetes mellitus in heterozygous carriers. [ABSTRACT FROM AUTHOR]

Herbal weight-loss supplements are sold as self-medication products, and are often used under the misconception that their natural origin guarantees their safety. Food supplements are not required to provide any benefit/risk profile evaluation before marketing; however, possible risks associated with use of herbal extracts in food supplements are becoming more and more documented in the literature. Some herbs are listed as the leading cause of herb-induced liver injury, with a severe or potentially lethal clinical course, and unpredictable herb-drug interactions. Garcinia cambogia (GC) extract and GC-containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we present four cases of acute liver failure in women taking GC extract for weight loss, and a literature review of clinical evidences about hepatic toxicity in patients taking dietary supplements containing GC extract. [ABSTRACT FROM AUTHOR]

Introduction: Food supplements containing red yeast rice (RYR) are proposed as an alternative in statin-intolerant patients, although they actually contain natural statin(s) and their safety in clinical practice is still incompletely characterized. We described and compared adverse events (AEs) associated with RYR products submitted to reporting systems maintained by the Food and Drug Administration (FDA), with a focus on liver and muscular events.Methods: We extracted RYR-related AEs from the FDA Adverse Event Reporting System (FAERS) [first quarter (Q1)-2004 to Q2-2016], a drug-based archive, and the Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) (Q1-2004 to Q1-2017). Disproportionality via reporting odds ratio (ROR) with 95% confidence interval (CI) calculation and case-by-case inspection were performed, with a focus on muscular and hepatic AEs.Results: One thousand three hundred AEs were extracted from FAERS (RYR mainly reported as a concomitant agent), whereas only 159 AEs were found in CAERS (RYR recorded mainly as a suspect agent). In FAERS, a large number of reports emerged for "general disorders and administration site conditions," whereas CAERS received also a high number of reports for "investigations" and "musculoskeletal and connective tissue disorders". Disproportionality analyses confirmed higher reporting of serious muscular and liver injuries: in FAERS, five cases of hepatic disorders (ROR = 13.71; 95% CI 5.44-34.57); in CAERS, 27 cases of rhabdomyolysis/myopathy (8.44; 5.44-13.10).Conclusions: Notwithstanding recognized limitations, these findings strengthen the importance of exploring multiple databases in safety assessment of RYR products, which should be monitored by clinicians for muscular and hepatic safety, and call for urgent review by policymakers to harmonize their regulatory status. [ABSTRACT FROM AUTHOR]

So far, only three small outdated studies have investigated hepatitis C virus (HCV) incidence and risk factors among illicit drug users (DUs) in Italy. Thus, during 2007-2010, we conducted a prospective cohort study among DUs attending 17 Italian rehabilitation centers serving urban areas. Two hundred eighty-four HCV-uninfected DUs were prospectively followed by interview and anti-HCV antibody and RNA testing every 6 months. Incidence was calculated using the person-years method. Infection predictors were assessed by time-dependent Cox analysis. Participants were mostly male (83.4%), under opioid substitution therapy (OST) (78.9%), non-injecting DUs (67.9%), and with a mean age of 30.8. Ninety-one of 224 DUs initially under OST interrupted treatment during the follow-up. Overall HCV incidence was 5.83/100 person-years at risk (PYAR) [95% confidence intervals (CI), 3.63-9.38]. The incidence did not significantly differ according the participants' sociodemographic characteristics or the degree of urbanization of the towns involved in the study. The incidence was higher for DUs under than for those not under OST (6.23 vs 4.50/100 PYAR; p = 0.681). Incidence was also higher for those with than for those without OST interruption (7.17 vs 5.04/100 PYAR; p = 0.55). However, all these differences were non-significant. At last follow-up visit, a significant decrease in frequency of sharing equipment for preparation/using drugs (by injection or not) was observed by analyzing either the whole cohort or DUs under OST only. Anti-HCV seroconversion resulted independently associated with sharing drug preparation/use equipment, backloading, having a HCV-positive sexual partner, or household and (marginally) intravenous injection. In this study, HCV incidence was non-negligible and OST seemed to lack effectiveness in reducing it. In Italy, implementation of combined harm reduction interventions and antiviral treatment of chronically infected DUs would be needed. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenic purpura (ITP) is an immunomediated disease characterized by a decrease in platelet count and, in its more severe forms, by bleeding symptoms. Many drugs have been implicated in the pathogenesis of drug-induced thrombocytopenia in adults; only limited data on drug-related ITP in children have been published. Our study was set up to evaluate the consistency of the association between drug and vaccine use and ITP in children. This study is part of an Italian multicentre study on adverse drug reactions in children, coordinated by the Italian National Institute of Health, which was started in November 1999 and is ongoing. The study was conducted by enrolling all children aged more than 1 month who were hospitalized through the paediatric emergency department for the following conditions: thrombocytopenia (platelet count <100 x 103/L); acute neurological disorders; non-infectious mucocutaneous diseases and vasculitis; and endoscopically confirmed gastroduodenal lesions and/or clinically defined haematemesis and melaena. Children with chronic pathologies or concomitant diagnoses of cancer or immunodeficiency were not included in our study. During hospital admission, a physician interviewed parents using a structured questionnaire. The main aim of the interview was to collect information on drug exposure in a time period of 3 weeks and vaccine exposure in a period of 6 weeks preceding hospitalization. Using a case-control study design, exposure of children with thrombocytopenia (cases) to drugs and vaccines was compared with similar exposure of children with gastroduodenal lesions and neurological disorders (controls); this allowed us to estimate the odds ratios (ORs) of the occurrence of thrombocytopenia associated with the use of drugs or vaccines. Up to December 2007, the study population included 387 cases of thrombocytopenia and 1924 controls. Despite the low platelet count, ITP was generally a mild disease, without serious bleeding in the majority of cases and associated with a short length of hospital stay. After adjusting for concurrent use of other drugs, use of the antibacterials was associated with a more than 2-fold increase in the risk of developing ITP (OR 2.4; 95% CI 1.8, 3.1). Mucolytics and NSAIDs were associated with an OR of 1.9; 95% CI 1.2, 2.9 and 1.5; 95% CI 1.0, 2.1 respectively, while paracetamol (acetaminophen) was associated with an OR of 1.5; 95% CI 1.2, 2.0. MMR vaccination was associated with an increased risk of developing ITP (OR 2.4; 95% CI 1.2, 4.7). The results of this study provide evidence for an association between ITP and exposure to selected antibacterials, NSAIDs, paracetamol, mucolytics and MMR vaccination. [ABSTRACT FROM AUTHOR]

Natural health products are promoted to the public as equally or more effective and less toxic than conventional drugs. However, some 'natural' medicines are known to have adverse effects. From April 2002 to August 2007, 18 suspected adverse reactions associated with propolis-containing products were reported to the national surveillance system of natural health products, coordinated by the Italian National Health Institute. Sixteen reports concerned allergic reactions (with dermatological or respiratory symptoms), while two concerned the digestive tract. Some of the reactions were serious: six patients were admitted to hospital or visited an emergency department and in two of these a life-threatening event was reported. In seven patients (four of whom were children), an allergic predisposition was indicated. Propolis, a resinous substance collected by honeybees from the buds of living plants, has been used for several purposes (dermatitis, laryngitis, oral ulcers) because of its wide range of suggested activities (antibacterial, antiviral, antifungal, anti-inflammatory, antioxidant and chemopreventive actions). However, propolis is also a potent sensitizer and should not be used in patients with an allergic predisposition, in particular an allergy to pollen. In Italy, products containing bee derivatives (bee pollen, royal jelly or propolis) are available to the public as food supplements. No label warning of possible adverse reactions is found on the packaging, although it is well known that atopic and asthmatic individuals may be at an increased risk of allergic reactions after using these products. The public and healthcare practitioners should be aware of the risk of allergic reactions to products derived from bees and a warning should be added to the packaging of these products. [ABSTRACT FROM AUTHOR]

On March 11th, 2011 the Mw 9.0 2011 Tōhoku-Oki earthquake resulted in a tsunami which caused major devastation in coastal areas. Along the Japanese NE coast, tsunami waves reached maximum run-ups of 40 m, and travelled kilometers inland. Whereas devastation was clearly visible on land, underwater impact is much more difficult to assess. Here, we report unexpected results obtained during a research cruise targeting the seafloor off Shimokita (NE Japan), shortly (five months) after the disaster. The geography of the studied area is characterized by smooth coastline and a gradually descending shelf slope. Although high-energy tsunami waves caused major sediment reworking in shallow-water environments, investigated shelf ecosystems were characterized by surprisingly high benthic diversity and showed no evidence of mass mortality. Conversely, just beyond the shelf break, the benthic ecosystem was dominated by a low-diversity, opportunistic fauna indicating ongoing colonization of massive sand-bed deposits. [ABSTRACT FROM AUTHOR]

In order to calculate budgets of particulate matter and sediment-bound contaminants leaving the continental shelf of the Gulf of Lion (GoL), settling particles were collected in March 2011 during a major storm, using sediment traps. The collecting devices were deployed in the Cap de Creus submarine canyon, which represents the main export route. Particulate matter samples were analyzed to obtain mass fluxes and contents in organic carbon, Al, Cr, Co, Ni, Cu, Zn, Cd, Pb and La, Nd and Sm. The natural or anthropogenic origin of trace metals was assessed using enrichment factors (EFs). Results are that Zn, Cu and Pb appeared to be of anthropogenic origin, whereas Ni, Co and Cr appeared to be strictly natural. The anthropogenic contribution of all elements (except Cd) was refined by acid-leaching (HCl 1 N) techniques, confirming that Zn, Cu and Pb are the elements that are the most enriched. However, although those elements are highly labile (59-77 %), they do not reflect severe enrichment (EFs <4). Most particles originate from the Rhone River. This has been confirmed by two different tracing procedures using rare earth elements ratios and concentrations of acid-leaching residual trace metals. Our results hence indicate that even in this western extremity of the GoL, storm events mainly export Rhone-derived particles via the Cap de Creus submarine canyons to the deep-sea environments. This export of material is significant as it represents about a third of the annual PTM input from the Rhone River. [ABSTRACT FROM AUTHOR]

The serum- and glucocorticoid-regulated kinase (Sgk1) is essential for hormonal regulation of epithelial sodium channel-mediated sodium transport and is involved in the transduction of growth factor-dependent cell survival and proliferation signals. Growing evidence now points to Sgk1 as a key element in the development and/or progression of human cancer. To gain insight into the mechanisms through which Sgk1 regulates cell proliferation, we adopted a proteomic approach to identify up- or downregulated proteins after Sgk1-specific RNA silencing. Among several proteins, the abundance of which was found to be up- or downregulated upon Sgk1 silencing, we focused our attention of RAN-binding protein 1 (RANBP1), a major effector of the GTPase RAN. We report that Sgk1-dependent regulation of RANBP1 has functional consequences on both mitotic microtubule activity and taxol sensitivity of cancer cells. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs are widely used to treat behavioural and psychological disturbances associated with Alzheimer's disease (AD), although only modest evidence from randomized controlled trials supports their efficacy, and increasing evidence from post-marketing surveillance shows serious adverse events associated with their use, including increased mortality. The AdCare study, a non-profit, randomized, placebo-controlled, double-blind, multicentre, pragmatic trial coordinated by the Italian National Institute of Health, aimed to evaluate the long-term safety and efficacy profiles of three atypical antipsychotic drugs (risperidone, olanzapine and quetiapine) and one conventional antipsychotic drug (haloperidol) in treating psychosis, aggression and agitation in outpatients with AD. The study was planned to be carried out in 19 clinical centres and to enrol 1000 outpatients. According to Italian law, in the case where a patient is considered unable to give informed consent, a legal representative designated by the court has to provide it. Because of difficulties in the informed consent procedure, the study had to be prematurely interrupted. From February 2009 to April 2010, 83 patients gave informed consent to participate in the trial. Fifty-six patients (68%) were included with consent given by a legal representative, while 27 patients (32%) were considered to provide personal informed consent on the basis of the results from a specifically built procedure. Patients and caregivers were offered the opportunity to participate in the trial before the occurrence of behavioural disturbances, in order to provide them with enough time to consider their participation in the study. Twenty-three patients experienced behavioural, clinically relevant symptoms and were randomized to the study drug; all randomized patients except one had consent for inclusion in the study given by legal representatives. After trial interruption, all patients taking an active drug continued treatment with the same molecule in clinical practice. Randomized controlled trials are acknowledged as the gold standard source of evidence on drug safety and efficacy. The AdCare study showed that an excessively rigid regulation can become a major obstacle while carrying out therapeutic research with incapacitated persons. [ABSTRACT FROM AUTHOR]

Aim: To describe and evaluate spontaneous reports of suspected adverse reactions (ARs) associated with herbal laxatives received by the Italian Medicines Agency and the Italian National Institute of Health between April 2002 and January 2011. Methods: Spontaneous reports of suspected ARs were individually analyzed by a multidisciplinary group of experts, and a causality assessment was performed. Results: Twenty-six reactions were reported during the study period. Of these, eight were associated with herbal medicinal products and 18 were related to herbal food supplements. Almost 80% of the reports on ARs involved women. The ARs, classified by System Organ Class, were associated with gastrointestinal, skin and subcutaneous tissue, and hepatobiliary disorders. Fifty percent of the reactions were serious, with the patients requiring hospitalization; of these, one was life-threatening. Most of the herbal remedies associated with the reported ARs contained liquorice, dandelion, and/or plants containing anthraquinones. Possible causes of the ARs were long-term use, idiosyncratic reactions or hypersensitivity, and interaction with other treatments. All of these factors and the presence of a large number of components in the same product increased the unpredictability of the final effect. Conclusions: The total number of 26 ARs recorded in 8 years is limited; however, the an under-reporting effect cannot be excluded. Moreover, taking into account the seriousness of the reported ARs, the low number of reports does not represent a guarantee of safety. To reduce the risk of an adverse outcome, herbal laxatives should be used only over the short term. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to describe suspected adverse reactions (ARs) associated with herbal products used for weight control in Italy. Methods: Spontaneous reports of suspected ARs associated with herbal products used for weight control were collected by the Italian National Institute of Health (April 2002 to June 2010), and the causality assessment was performed. Results: Forty-six of the suspected ARs were associated with herbal products used for weight control. Women were involved in 85% of the reports. The reactions affected mainly the cardiovascular system, the skin, the digestive system, the central nervous system, and the liver. A large proportion of ARs were serious. In more than half of the suspected ARs, the use of other therapies (herbs and/or drugs) was reported, while concomitant conditions were present in 22% of the reports. Conclusions: The use of herbal dietary supplements for weight loss is associated with several ARs. Considering the risk/benefit ratio, consumers should pay attention when using these products. [ABSTRACT FROM AUTHOR]

Serum and glucocorticoid regulated kinase 1 (Sgk1) is a serine–threonine kinase that is activated by serum, steroids, insulin, vasopressin, and interleukin 2 at the transcriptional and post-translational levels. Sgk1 is also important in transduction of growth factors and steroid-dependent survival signals and may have a role in the development of resistance to cancer chemotherapy. In the present paper, we demonstrate that Sgk1 activates MDM2-dependent p53 ubiquitylation. The results were obtained in RKO cells and other cell lines by Sgk1-specific RNA silencing and were corroborated in an original mouse model as well as in transiently and in stably transfected HeLa cells expressing wild-type or dominant negative Sgk1 mutant. Sgk1 contributes to cell survival, cell-cycle progression, and epithelial de-differentiation. We also show that the effects of Sgk1 on the clonogenic potential of different cancer cells depend on the expression of wild-type p53. Since transcription of Sgk1 is activated by p53, we propose a finely tuned feedback model where Sgk1 down-regulates the expression of p53 by enhancing its mono- and polyubiquitylation. [ABSTRACT FROM AUTHOR]

To review the current literature on suspected green tea-related hepatic reactions and to describe two new cases reported within the framework of the Italian surveillance system of natural health products. A literature search of publication between 1999 and October 2008 retrieved 34 cases of hepatitis. Histological examination of the liver revealed inflammatory reactions, cholestasis, occasional steatosis, and necrosis. A positive dechallenge was reported in 29 cases. There was one reported death. A positive rechallenge occurred in seven cases (20%). In the two new cases, the causality assessment was judged as “possible” according to the RUCAM score. Our analysis of the published case reports suggests a causal association between green tea and liver damage. The hepatotoxicity is probably due to (-)-epigallocatechin gallate or its metabolites which, under particular conditions related to the patient’s metabolism, can induce oxidative stress in the liver. In a few cases, toxicity related to concomitant medications could also be involved. [ABSTRACT FROM AUTHOR]

The interleukin-2 is a cytokine that is essential for lymphocytic survival and function. Ectopic expression of the IL-2 receptor in epithelial tissues has been reported previously, although the functional significance of this expression is still being investigated. We provided novel structural and functional information on the expression of the IL-2 receptor in kidney cancer cells and in other normal and neoplastic human epithelial tissues. In A-498 kidney cancer cells, we showed that IL-2 binding to its own receptor triggers a signal transduction pathway leading to the inhibition of proliferation and apoptosis. We found that the inhibition of proliferation is associated with Erk1/2 dephosphorylation, whereas the survival signals appear to be mediated by Sgk1 activation. This investigation focuses on the IL-2 induced regulation of Sgk1 and describes a role of the IL-2 receptor and Sgk1 in the regulation of epithelial tumor cell death and survival. [ABSTRACT FROM AUTHOR]

The therapeutic and commercial success of phosphodiesterase 5 inhibitors such as Viagra, Levitra and Cialis has sparked renewed interest in the phosphodiesterases as drug discovery targets. Virtually all the phosphodiesterases are expressed in the CNS, making this gene family a particularly attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders. Significantly, all neurons express multiple phosphodiesterases, which differ in cyclic nucleotide specificity, affinity, regulatory control and subcellular compartmentalization. Therefore, phosphodiesterase inhibition represents a mechanism through which it could be possible to precisely modulate neuronal activity. In this article, we review the current state of the art in the burgeoning field of phosphodiesterase pharmacology in the CNS. [ABSTRACT FROM AUTHOR]

Primary meningeal lymphoma is a rare occurrence. We present a case of an immunocompetent patient operated on for a fronto-parietal lesion similar to a meningioma, which the histological examination diagnosed as a mucosa-associated lymphoid tissue (MALT)-type lymphoma. She received no further post-operative treatment and after 36 months showed no evidence of disease. In a review of the literature, we identified 14 similar cases of MALT lymphoma pre-operatively diagnosed as meningioma. Recognition of this rare meningeal location of a lymphoma involving the central nervous system is useful for a proper diagnosis and adequate treatment. [ABSTRACT FROM AUTHOR]

A case of calcifying pseudo-tumor of the thoracic spine, a rare lesion with tumor-like behavior and a probable inflammatory-reactive origin, is described. The clinical-pathological and neuro-radiological aspects of this lesion are discussed in relation to surgical treatment. In accordance with the other cases reported in the literature, the case observed confirmed the benign behavior of the lesion and the effectiveness of surgical treatment for achieving complete resolution of clinical symptoms without any recurrences, even when removal is only subtotal. [ABSTRACT FROM AUTHOR]

In 1998–99 and 1999–2000 six trials were conducted to evaluate the effect of fungicides on Fusarium head blight in the field, on infected kernels and deoxynivalenol (DON) concentration in grain. A single application of prochloraz, tebuconazole, epoxiconazole or bromuconazole, applied to durum wheat varieties at the manufacturer's recommended dose at the beginning of anthesis stage, provided good control of the disease when infective pressure in the field was low to medium, and when the main pathogens were F. graminearum and F. culmorum. Kresoxim-methyl showed a low efficacy at controlling the disease. Tebuconazole, prochloraz and bromuconazole were effective at controlling F. graminearum and F. culmorum, while kresoxim-methyl was not effective in reducing Fusarium infected kernels. DON concentration in grain of cultivars inoculated with F. graminearum and F. culmorum was high, averaging 4.2 mg kg−1 (untreated control). Tebuconazole, prochloraz and bromuconazole reduced DON concentration by 43%, while epoxiconazole was ineffective. DON concentration in kernels of naturally infected cultivars was 1.95 mg kg−1, a concentration which exceeds the 1 mg kg−1 maximum level of contamination allowed in the United States. Furthermore prochloraz, bromuconazole and tebuconazole applications, in the naturally inoculated trials, reduced DON concentration from 73% to 96%, while epoxiconazole showed the lowest effectiveness. Moreover, a positive linear correlation between Fusarium infected grains and the DON concentration was observed. [ABSTRACT FROM AUTHOR]

Objective. To investigate the prevalence of use of unconventional therapies in Italy, the main health problems associated with and the motivations for use of these therapies. Methods. Questions about the use of unconventional therapies were inserted in a nation-wide survey conducted by face-to-face interviews with all members of sampled families by the National Institute of Statistics during four quarters of the years 1999–2000. Data presented here are based on the results of the first two quarters of the survey (September and December 1999) during which a representative sample of 30,000 Italian families (70,898 individuals) was interviewed. Results. Almost 9 million people (15.6% of the Italian population) used at least one unconventional therapy during the period 1997–1999. Homeopathy was the most frequently used (8.2% of the population), followed by manual treatments (7%), herbal medicine (4.8%) and acupuncture (2.9%). Homeopathy was also quite commonly used by children (7.7% of Italian children). The main reason for use was concern about potential toxicity of "conventional medicine". The health problem most frequently treated with all kinds of unconventional therapies was pain. Conclusions. Use of unconventional therapies has almost doubled since 1991. However, with 15.6% of the Italian population (9 million people) using at least one therapy, Italy ranks among the "light" users compared with other European countries. Homeopathy is the most frequently used therapy. The typical user is, as in other western countries, a highly educated woman aged 35–44 years and resident in the richest part of the country (north-eastern Italy). [ABSTRACT FROM AUTHOR]

OBJECTIVES: The aim of this study was to evaluate whether the transmission of hepatitis C virus (HCV) between spouses occurs through sexual contact or through other types of exposure. METHODS: We consecutively enrolled 311 chronic HCV carriers and their spouses. The spouses underwent HCV blood testing. Exposure to parenteral risk factors was compared between couples of which both partners were HCV positive and couples with one positive partner. In couples with both partners positive, qualitative detection of serum HCV RNA and genotyping were performed. RESULTS: The prevalence among spouses was 10.3% (32/ 311). The mean age was higher for HCV-positive spouses (57.7 vs 49.6 yr for HCV-negative spouses; p< 0.01). The prevalence among spouses increased with the duration of marriage, whereas no difference was found in relation to the clinical status of the index case. The 32 HCV-positive spouses reported parenteral exposure (blood transfusion, drug use, and use of multiple-use glass syringes inside or outside the family) more often than the 279 HCV-negative spouses (84.4% vs26.2%; odds ratio [OR], adjusted for age by multiple logistic regression analysis, 12,4; 95% CI = 4.5-34.0). The percentage of couples sharing glass syringes was significantly higher among those with both partners infected (65.6% vs 12.9%; OR = 12.9; 95% CI = 5.4-31.4). Qualitative serum HCV RNA was determined in 22 couples with both partners infected; in 13 of them, both partners were HCV RNA positive, whereas in the remaining nine, only one partner was positive. In eight of the 13 couples with both partners HCV RNA positive, the same genotype was found for both partners. CONCLUSIONS: The findings that the same genotype was detected for both partners in relatively few couples, and that a history of parenteral exposure was an independent predictor of HCV positivity, suggest that the risk of sexual trans-mission is low. The sharing of glass syringes may have played an important role in transmission between spouses. [ABSTRACT FROM AUTHOR]

To evaluate risk factors associated with intrafamiliar transmission of hepatitis C virus (HCV), 113 hepatitis C virus index subjects with chronic HCV infection and their 267 family contacts were studied from January 1994 to October 1995. Overall, 16 family contacts (6%) were positive for anti-HCV by ELISA II generation. The prevalence was 11.3% in spouses and 2.9% in other relatives (odds ratios: 4.2; 95% CI: 1.4–12.6). Spouses who had been married to the index cases longer than 20 years had a 7.5–fold risk (95% CI: 1.0–336.3) of HCV seropositivity as compared to those married less than 20 years. In univariate analysis HCV seropositivity was associated with surgical intervention, use of glass syringes and hospitalization. The results of multivariate logistic analysis showed that any parenteral exposure (odds ratios: 3.8; 95% CI: 1.2–12.8) and sexual contact with an anti-HCV index case (odds ratios: 3.0; 95% CI: 1.0–9.4) were both independent predictors of HCV seropositivity among household contacts of HCV positive index cases. These findings indicate that sexual contact and any parenteral exposure both play an independent role in the spread of HCV infection in the family setting. [ABSTRACT FROM AUTHOR]

Objective: To analyse the contribution of adverse drug events (ADEs) to the overall number of referrals or visits at an emergency department, to determine the proportion of more severe episodes requiring hospital admission and to characterize the different causes of drug-related visits or admissions. Methods: A 1-year prospective collection of data on visits performed at an emergency department. All visits, observed during 1 week every month, were analyzed in order to identify suspected ADEs. The effects of age and sex on the frequency of ADE-related visits and admissions were evaluated. All patients hospitalized because of an ADE were followed up in order to collect information about progress and outcome of the events, which were also assessed in terms of avoidability. Results: Among the 5497 patients who visited the Emergency Department over 1 year, 235 (4.3%) experienced an ADE, 45 of these (19.1%) were subsequently hospitalized, among whom there were five deaths. Dose-related therapeutic failures were the main causes of drug-related admissions (55.6%), whereas adverse drug reactions caused the most frequent drug-related visits to the Emergency Department (63.8%). Although the frequency of drug-drug interactions leading to a visit to the Emergency Department was small (3.8%), this type of event was more severe, because most of these patients were hospitalized. No age/sex effect was observed in the proportion of ADE-related hospital admissions. Twenty-five (1.4% of the total admissions) of the 45 ADE-related admissions were evaluated as preventable, contributing by more than 61% of the overall length of hospital stay. Conclusion: The high proportion of drug therapeutic failures leading to an admission highlights the need for public education, particularly to prevent non-compliance. [ABSTRACT FROM AUTHOR]

Objective: To compare the risk of hospitalization for gastroduodenal ulcer associated with the use of ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs). Methods: A cohort and a nested case-control study were carried out. All residents in the region of Umbria (Italy), aged 35–84 years, who had been given at least one NSAID prescription in 1993 and 1994 were identified. Exposure to drugs was ascertained through a drug prescription database. We estimated rate ratios of hospitalization for gastroduodenal ulcer with or without complications in the current, recent or past period according to exposure to different NSAIDs. Results: Rate ratio estimates, adjusted for age and sex, were 2.8 for any current NSAID and 1.4 for any recent NSAID. The highest rate ratios of lesions of any severity for current NSAID use were observed for piroxicam (RR: 4.6) and ketorolac (RR: 3.4). For gastrointestinal haemorrhage or perforation the highest rate ratios were those for ketorolac (RR: 5.9) and piroxicam (RR: 4.8). Rate ratio estimates did not change after adjustment for concomitant use of gastrotoxic drugs, use of gastroprotective agents not associated with NSAIDs and prior use of NSAIDs. Conclusion: Our study demonstrates the need to adhere to the restrictions relating to the indications and duration of use of ketorolac. At present piroxicam represents a greater public health concern since it is confirmed to be among the most gastrotoxic NSAIDs and is one of the most commonly prescribed NSAIDs in Italy. [ABSTRACT FROM AUTHOR]

Extrapyramidal adverse effects (EPAs) due to neuroleptic treatment are routinely treated with anticholinergic antiparkinsonian drugs (APDs). We studied the use of these drugs in the general population exposed to neuroleptic drugs to improve our knowledge of the epidemiology of EPAs. We selected all the neuroleptic and antiparkinsonian drug prescriptions delivered in the province of Rome (ca. 3 750 000 inhabitants) from 1986 to 1989. During the study period, 10.6% of neuroleptic-treated subjects were concurrently prescribed anticholinergic antiparkinsonian drugs. The influence of different factors on APD prescriptions was evaluated through a logistic regression model. The highest probability of receiving APDs was associated with trifluperidol treatment (odds ratio=5.0, using chlorpromazine as baseline); among the commonly prescribed neuroleptics, sulpiride, levosulpiride and tiapride chlorydrate had the lowest probability of coprescription with APDs (odds ratios less than 0.1). The probability of being prescribed anticholinergic antiparkinsonian drugs decreased with age and increased with the amount of neuroleptics prescribed. This study surveys a very large sample using a population-based approach, whereas the same topics have previously only been studied in limited inpatient populations. [ABSTRACT FROM AUTHOR]

Comments on the study 'Health Conditions and Health Service Utilisation,' by E. Ernst on the use of complementary alternative medicine in children in Italy. Frequency of use among children in the age group 2-10 years; Reasons why unconventional medicine eas chosen for children.