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Pharmacy and pharmaceutical sciences embrace a series of different disciplines. Pharmacy practice has been defined as 'the scientific discipline that studies the different aspects of the practice of pharmacy and its impact on healthcare systems, medicine use, and patient care'. Thus, pharmacy practice studies embrace both clinical pharmacy and social pharmacy elements. Like any other scientific discipline, clinical and social pharmacy practice disseminates research findings using scientific journals. Clinical pharmacy and social pharmacy journal editors have a role in promoting the discipline by enhancing the quality of the articles published. As has occurred in other healthcare areas (ie, medicine and nursing), a group of clinical and social pharmacy practice journal editors gathered in Granada, Spain to discuss how journals could contribute to strengthening pharmacy practice as a discipline. The result of that meeting was compiled in these Granada Statements, which comprise 18 recommendations gathered into six topics: the appropriate use of terminology, impactful abstracts, the required peer reviews, journal scattering, more effective and wiser use of journal and article performance metrics, and authors' selection of the most appropriate pharmacy practice journal to submit their work., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. Re-use permitted under CC BY. Published by BMJ.)

Background and Objectives: Hospital pharmacists collaborate in clinical trials by managing the reception, conservation, distribution, return and destruction of the investigational medical products (IMP). However, errors can happen during the simultaneous management of multiple trials because each clinical trial stipulates its own method for managing the drug under study. In order to promote optimal management by hospital pharmacists, we developed a method for calculating a risk of error index for each experimental protocol, and wrote standard procedures for managing trials assigned low, moderate and high risk levels, to provide hospital pharmacists with a systematic tool for reducing human error in the management of IMPs for multiple clinical trials., Methods: Calculation of this risk of error index (ρ) entails four factors: the pharmacological risk of error (φ) inherent in the pharmacological characteristics and route of administration of the IMP (carcinogenic, mutagenic, cytotoxic nature of the drug, parental or non-parenteral administration), the technological risk of error (α) involved should drug compounding be required, the risk of error related to the number of patients enrolled (n p ) and the risk of error intrinsic to the protocol (π) when it involves placebos, randomisation or other factors. We developed the formula [Formula: see text] to define trials as low (ρ<50), moderate (51<ρ<150) and high risk (ρ>151) for hospital pharmacist error., Results: Calculations of this formula for 60 active trials indicated that seven (11.7%) of the protocols were low risk of hospital pharmacist error, 43 (71.7%) were moderate risk and 10 (16.6%) were high risk. For each of these categories (low, moderate and high risk) we have outlined standard procedures in order to minimise the occurrence of any errors., Conclusions: Following validation of our formula and standard procedures by the ISMETT Research Institute, we are promoting the use of the tool in other clinical centres as we believe it can help hospital pharmacists minimise the risk of error in managing experimental drugs for clinical trials., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Schistosomiasis is a neglected parasitic disease linked to water, posing a global public health concern with a significant burden in sub-Saharan Africa. It is transmitted by Schistosoma spp., causing both acute and chronic effects affecting the urogenital or the hepato-intestinal system. Through granuloma formation, chronic schistosomiasis weakens host immunity, heightening susceptibility to coinfections. Notably, female genital schistosomiasis (FGS), a disregarded gynecological condition, adversely affects girls' and women's reproductive health and increases vulnerability to HIV. This review explores the intricate interplay between schistosomiasis and HIV, considering their geographical overlap. We delve into the clinical features of this coinfection, underlying mutual influences on transmission, diagnostic challenges, and therapeutic approaches. Understanding the dynamics of FGS and HIV coinfection is pivotal for integrated healthcare strategies in regions with co-endemicity, aiming to mitigate the impact of the two infections on vulnerable populations.

Objective: The standard treatment for epilepsy is based on the appropriate use of antiseizure medications (ASMs) to prevent the recurrence of seizures. For the newer ASMs, however, little information on their safety profile is available. This work sought to fill this gap by creating a database for ASM use in a paediatric hospital and the adverse drug reactions (ADRs) reported., Methods: This observational single-centre study was conducted from January 2018 to December 2020 and recorded the type of ASM treatment for paediatric epileptic patients cared for at the Neuropsychiatry Unit of the Salesi Paediatric Hospital in Ancona, Italy, as well as any ADRs., Results: In all, 519 patients were admitted to the ward with a diagnosis of epilepsy, 362 (69.7%) of whom were prescribed ASMs. Valproic acid was the most frequently prescribed drug (29.96%), followed by levetiracetam (13.97%) and carbamazepine (9.16%). We recorded 24 ADRs in 20 patients, half of which (n=12) occurred with polytherapy. Among the ADRs associated with monotherapy, 25% (n=6) were induced by carbamazepine; 12.5% (n=3) were associated with either valproic acid, clonazepam or lamotrigine; 8.3% (n=2) were associated with perampanel, clobazam or levetiracetam; while one patient experienced ADR due to vigabatrin, one due to ethosuximide and one due to cannabidiol. The median patient age was 7.5 years and most ADRs were not serious., Conclusion: During the 3-year observation period, 6% of epileptic patients on ASMs showed one or more ADRs. Carbamazepine was responsible for about a quarter of these reactions, two of which were serious. Half of the ADRs occurred with polytherapy, which often included valproic acid and stiripentol. It is to be hoped that such active pharmacovigilance through the collaboration of hospital pharmacists and physicians will serve to improve the management of treatment., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Pharmacy and pharmaceutical sciences embrace a series of different disciplines. Pharmacy practice has been defined as "the scientific discipline that studies the different aspects of the practice of pharmacy and its impact on health care systems, medicine use, and patient care". Thus, pharmacy practice studies embrace both clinical pharmacy and social pharmacy elements. Like any other scientific discipline, clinical and social pharmacy practice disseminates research findings using scientific journals. Clinical pharmacy and social pharmacy journal editors have a role in promoting the discipline by enhancing the quality of the articles published. As has occurred in other health care areas (i.e., medicine and nursing), a group of clinical and social pharmacy practice journal editors gathered in Granada, Spain to discuss how journals could contribute to strengthening pharmacy practice as a discipline. The result of that meeting was compiled in these Granada Statements, which comprise 18 recommendations gathered into six topics: the appropriate use of terminology, impactful abstracts, the required peer reviews, journal scattering, more effective and wiser use of journal and article performance metrics, and authors' selection of the most appropriate pharmacy practice journal to submit their work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: as a legacy of the large asbestos consumption until the definitive ban in 1992, Italy had to tackle a real epidemic of asbestos related diseases. The Italian National Registry of Malignant Mesotheliomas (ReNaM) is a permanent surveillance system of mesothelioma incidence, with a regional structure. Aims, assignments and territorial network of ReNaM are described, as well as data collection, recording and coding procedures., Objectives: to describe the Italian epidemiological surveillance system of mesothelioma incidence, to provide updated data about occurrence of malignant mesothelioma in Italy, and to discuss goals, attainments, and expectations of registering occupational cancer., Design: analysis of data by malignant mesothelioma incident cases surveillance system., Setting and Participants: Italy, network of regional surveillance system, all Italian regions., Main Outcome Measures: a Regional Operating Centre (COR) is currently established in all the Italian regions, actively searching incident malignant mesothelioma cases from health care institutions. Occupational history, lifestyle habits, and residential history are obtained using a standardized questionnaire, administered to the subject or to the next of kin by a trained interviewer. The extent of dataset, epidemiological parameters, and occupations involved are reported updated at 31.12.2016, and standardized incidence rates are calculated., Results: at December 2016, ReNaM has collected 27,356 malignant mesothelioma cases, referring to the period of incidence between 1993 and 2015. The modalities of exposure to asbestos have been investigated for 21,387 (78%) and an occupational exposure has been defined for around 70% of defined cases (14,818)., Conclusions: the Italian experience shows that epidemiological systematic surveillance of asbestos related diseases incidence has a key importance for assessing and monitoring the public health impact of occupational and/or environmental hazards, programming preventive interventions, including remediation plans and information campaigns, and supporting the efficiency of insurance and welfare system. Monitoring the incidence of malignant mesothelioma through a specialized cancer registry is essential to follow-up the health effects of changing modalities and extent of occupational exposures over years and of environmental contamination. Such consolidated surveillance system is recommended also for occupational cancers with low aetiological fraction.

The phenomenon of "vaccine hesitancy" has only been studied for a few years, and this attitude is becoming a serious threat that can frustrate the efforts of recent years that have led to the achievement of relevant scientific advances to human health. The paper analyzes the possible causes, the scope of the phenomenon and its consequences, trying to identify the most effective actions to resolve this trend.

Competing Interests: Competing interests: None declared.

Background: A key to the effective management of malaria is prompt and accurate diagnosis, and the use of malaria rapid diagnostic tests (mRDTs) is becoming relevant in the absence of reliable microscopy. This study explored the phenomenon of using the wrong buffer vial (often a kit from another brand or buffer from HIV rapid test kits), dextrose, saline or distilled water among health care providers who used RDTs for malaria diagnosis in resource poor settings in Enugu South East, Nigeria., Materials and Methods: Laboratory personnel (medical laboratory scientists, technicians, assistants, nurses, community health extension workers (CHEW), community health officers (CHO) and doctors) were interviewed using structured questionnaires and results were checked using the SOP checklist. The selection criterion was a prior experience with using RDTs, and any facility that did not use RDTs was excluded., Results: Of the 80 study participants that completed their questionnaires, 56.3% reported that malaria diagnosis was positive using non-buffer RDTs detection while others reported negative results. Among the various professionals who used RDTs, 76.2% reported to have run out of RDT buffer stock at least once. Of the study participants that ran out of RDT buffer solution, 73% declared to have used non-RDT alternatives (physiological saline, 0.9% NaCl), distilled water, HIV buffer or ordinary water). Only 30% had received formal training on the proper usage and application of RDTs while 70% had never received any formal training on RDTs but learnt the technique of using RDT on the job., Conclusions: This study demonstrated that at least three quarters of health care workers in a resource poor setting had run out of buffer when using malaria RDTs and that the majority of them had used buffer substitutes, which are known to generate inaccurate tests results. This has the consequence of misdiagnosis, thus potentially damaging the credibility of malaria control., Competing Interests: Competing Interests: No competing interests declared., (Copyright © 2014: Ogboi et al.)

There is recognition that biomedical research into the causes of mental disorders and their treatment needs to adopt new approaches to research. Novel biomedical techniques have advanced our understanding of how the brain develops and is shaped by behaviour and environment. This has led to the advent of stratified medicine, which translates advances in basic research by targeting aetiological mechanisms underlying mental disorder. The resulting increase in diagnostic precision and targeted treatments may provide a window of opportunity to address the large public health burden, and individual suffering associated with mental disorders. While mental health and mental disorders have significant representation in the "health, demographic change and wellbeing" challenge identified in Horizon 2020, the framework programme for research and innovation of the European Commission (2014-2020), and in national funding agencies, clear advice on a potential strategy for mental health research investment is needed. The development of such a strategy is supported by the EC-funded "Roadmap for Mental Health Research" (ROAMER) which will provide recommendations for a European mental health research strategy integrating the areas of biomedicine, psychology, public health well being, research integration and structuring, and stakeholder participation. Leading experts on biomedical research on mental disorders have provided an assessment of the state of the art in core psychopathological domains, including arousal and stress regulation, affect, cognition social processes, comorbidity and pharmacotherapy. They have identified major advances and promising methods and pointed out gaps to be addressed in order to achieve the promise of a stratified medicine for mental disorders., (© 2013 Published by Elsevier B.V. and ECNP.)

Background: Although, Nigeria had conducted various national surveys followed by central and state level trainings for survey administrators, prior pre-survey trainings have not been systematically evaluated to assess their impact on knowledge gain and final outcome of the survey. A central training of trainers' session was organized for master trainers on the conduct of the 2012 National AIDS and Reproductive Health Survey., Objectives: To evaluate the impact of training on the quality of conduct of a national research survey in the 36 states and the Federal Capital Territory in Nigeria., Method: A total of 185 participants consisting of State AIDS Program Coordinators, Reproductive Health Coordinators, State Laboratory Scientists, Lead Supervisors and Counselor Testers were invited from the 36 states in Nigeria and the FCT for the central training of trainers in Abuja. The training lasted 5 days and the trainees were grouped into two on the basis of behavioral epidemiology and laboratory components. Training tools such as the developed protocol, training power point slides, practical sessions such as role plays, and usage of HIV rapid test kits were utilized during the training. The facilitators were drawn from Federal Ministry of Health (FMoH), universities and research Institutions as well as Non-Governmental Organizations (NGOs). The facilitators prepared and administered 25 structured questions for the behavioral group and 28 questions for the laboratory group at the beginning of the training to assess the participants' knowledge of HIV and the survey. The same questions answered by Trainees responded to the same questions prior to the commencement and at the end of the trainings. Scores were aggregated to 100 for each test. We conducted paired t-test to determine statistically significant differences between pre-test and post-test results at 0.05 significance level and ANOVA to determine if there were differences in knowledge level among different groups., Result: The overall mean pre-test and post-test scores were 64.0% and 77.4% respectively indicating a 13.4% knowledge gain above what it was at the beginning of the training. The mean pre-test score and post-test score for the Southern states (SN) were 64.7% and 80.3% while that of the Northern states (NN) were 63.5% and 75.3% representing a knowledge gain of 15.6% and 11.8% respectively. There was statistical significant difference in the post-test scores between the two regions (p=0.001) and in knowledge gained after the training (p=0.017)., Conclusions and Public Health Implications: Comparison between the pre test and post test scores at the 5-day training showed a significant gain in knowledge of participants. The survey training contributed positively to the preparation and building of knowledge needed for the conduct of 2012 NARHS-plus.

Onchocerciasis is a disease of public health and socio-economic importance in Ethiopia. The aim of this study was to assess parasitological and clinico-epidemiological features of onchocerciasis in the Anfilo District, West Wellega, prior to implementation of Community Directed Treatment with Ivermectin (CDTI) to generate epidemiological and parasitological data for use in control program of the disease and subsequent evaluation of CDTI. A cross-sectional study was conducted in Anfilo District of West Wellega zone during a period of 1 month: from mid-August to mid-September 2006. Data on socio-demographic characteristics were collected using a standardized questionnaire prepared for this purpose. All persons were examined clinically for skin signs and symptoms of onchocerciasis. Two skin snips, one from each side of the gluteal fold were taken using blood lancet and sterilized razor blade and examined for microfilaria. All data were categorized, coded, entered in a data base and analyzed using SPSS version 15.0. for windows. A total of 1114 individuals ≥15 years were examined for microfilariae (mf) of Onchocerca volvulus and onchocercal skin disease (OSD). The prevalence of onchocercal (mf) carrier was 74.8% (833/1114). In both genders, the prevalence of onchocerciasis showed direct correlations with the age of individuals (R (2) = 0.79, P < 0.05). The infection rate varied with the occupation of the study subjects, with preponderance among farmers. Among the subjects with onchocerciasis, the mf density ranged from 1.0 to 711.0 per mg of skin snip with a mean density (SD) and median values of 32.1 (61.5) and 10.4 respectively. The overall community microfilariae load (CMFL), the most sensitive parasitological indicator of onchocerciasis was 19.6. The pervasiveness of OSD among the study subjects was 26.4%. OSD was more frequent in males (32.4%) than their female counterparts (20.8%, P < 0.05). The overall prevalence of onchocercal nodule carrier, the symptom opted for determining the community-wide prevalence of onchocerciasis was 12.1%. Leopard skin, the proxy of longstanding infection of onchocerciasis in the community, was also relatively high (19.1%). The abundance of mf in skin would definitely lead to high transmission potential in the Anfilo District. The situation in the Anfilo District should call for continued CDTI, owing to success of similar recommendations for such programmes in other parts of the country and elsewhere.

Background: Data was obtained from all study subjects and blood and fecal specimen were collected from all subjects who apparently volunteer to take part in the study., Objective: To determine prevalence of hookworm infection and its association with anemia. METHODS.: A cross-sectional study was conducted from February to April 2007 in Diga District, East Wollega Zone. Hematocrit test was done on all blood samples. All stool specimens were processed with a Kato-thick method and examined for parasites and the density of parasites was determined as eggs per gram of stool (epg). Frequencies and proportions were used for the descriptive analysis of the data and Pearson Chi-square test was used to assess the associations between the demographic characteristics of the study subjects and the findings of the test samples., Results: The overall prevalence of intestinal parasites was 64.9% Hookworm was the predominant (49.7%) intestinal parasite identified among the study participants. The density of hookworm egg ranged from 48 epg to 11,520 epg with mean and median values of 685 and 288 epg respectively. The observed result for hematocrit ranged from 12% to 50% with mean (SD) and median values of 34.6% (4.7) and 36% respectively. The prevalence of anemia is 65.5% among study participants. Among those subjects with hookworm, 83.9% were anemic. On the contrary only 41 (22.5%) study subjects who appeared negative for hookworm on stool examination were anemic., Conclusion: The prevalence of hookworm is higher and it is associated with anemia in East Wollega zone. Therefore intervention strategies should consider the concomitance of hookworm and anemia in the implementations of appropriate prevention and control strategies.

Objectives: A number of studies suggest that postprandial hyperglycemia produces oxidative stress, leading to complications associated with diabetes. However, hyperglycemia-induced oxidative stress may affect groups of people other than diabetics, such as smokers and athletes with specific diet plans. Based on previous reports that seated breathing meditation reduces hyperglycemia, the present study was designed to determine the effects of diaphragmatic breathing on postprandial plasma glycemia, insulin, oxidative stress, and antioxidant levels in athletes with normal glucose metabolism., Design: Data collected before and after consumption of a 900-calorie breakfast composed of 80% carbohydrates, 10% proteins, and 10% lipids were analyzed. Ten (10) minutes after the meal, 8 subjects spent 40 minutes performing diaphragmatic breathing in a quiet place. The other 8 subjects, representing the control group, spent the same time sitting in an equivalent quiet place reading a magazine., Subjects: Data from 16 amateur male cyclists age 30.12±4.9 years (±SD) were analyzed. Their mean height and weight were 177.81±5.3 cm and 71.40±5.2 kg, respectively. All subjects underwent a physical examination and were determined to be in good health., Outcome Measures: Blood samples were collected immediately before the meal as well as 1 hour and 2 hours after the meal, and plasma levels of glucose, insulin, reactive oxygen metabolites, and biologic antioxidant potential were determined. Heart rate was also recorded., Results: Results show that in normal subjects, acute hyperglycemia induces free-radical production while reducing the antioxidant levels (p<0.05). Diaphragmatic breathing reduces heart rates (p<0.01), increases insulin (p<0.05), reduces glycemia (p<0.01), and reduces free-radical production as indicated by the higher antioxidants levels (p<0.05)., Conclusions: Diaphragmatic breathing, likely through the activation of the parasympathetic nervous system, increases insulin, reduces glycemia, and reduces reactive oxygen species production.

Aim: We determined the combined effects of cold and exercise on oxidative stress during submaximal exercise., Methods: Sixteen amateur male cyclists pedaled at a constant speed corresponding to 85% of maximal HR as determined in normal conditions. Eight athletes pedaled indoors at 23 °C while 8 athletes pedaled outdoors at a temperature of 4-6 °C. We then evaluated the levels of reactive oxygen metabolites and plasma levels of antioxidants after exercise., Results: Performing a physical task in cold conditions increased the free radical production, as demonstrated by the augmented levels of reactive oxygen metabolites and the concomitant decrease of plasma levels of antioxidants in outdoors cyclists as compared to indoors cyclists. The overall ANOVA and the post-hoc comparisons revealed a significant exercise and temperature effect. The mean level of reactive oxygen metabolites in athletes who exercised indoors was significantly lower than that of the outdoor athletes. Moreover, the outdoors group presented plasma levels of antioxidants significantly lower than those of the indoors group., Conclusion: Since several sports are performed outdoors during the winter season, the increased risk of oxidative stress in cold conditions must be considered in these disciplines. Cyclists, football and rugby players, and runners are all affected by the elevation in oxygen radicals induced by cold and should take appropriate precautions, such as specific antioxidant integration.

The aim of this study was to evaluate the effect of Lactobacillus rhamnosus IMC 501 and Lactobacillus paracasei IMC 502 on oxidative stress in athletes during a four-week period of intense physical activity. Two groups of twelve subjects each were selected for this analysis. The first group consumed a daily dose of a mixture of the two probiotic strains (1:1 L. rhamnosus IMC 501 and L. paracasei IMC 502; ~10(9) cells/day) for 4 weeks. The second group (control) did not consume any supplements during the 4 weeks. Blood samples collected immediately before and after the supplementation were analyzed, and plasma levels of reactive oxygen metabolites and biological antioxidant potential were determined. Faeces were also collected and analyzed before and at the end of the probiotic supplementation. Antioxidative activity and oxidative stress resistance of the two strains were determined in vitro. Results demonstrated that intense physical activity induced oxidative stress and that probiotic supplementation increased plasma antioxidant levels, thus neutralizing reactive oxygen species. The two strains, L. rhamnosus IMC 501(®) and L. paracasei IMC 502(®), exert strong antioxidant activity. Athletes and all those exposed to oxidative stress may benefit from the ability of these probiotics to increase antioxidant levels and neutralize the effects of reactive oxygen species.

Our previous study found that when injected with Nociceptin/Orphanin FQ (N/OFQ) into the brain, male Dark Agouti (DA) rats, which are resistant to metabolic syndrome, have greater hyperphagia than male Wistar Ottawa Karlsburg W (WOKW) animals, which are prone to this disease. We attributed this difference to the fact that these two strains have different cocaine-amphetamine regulated transcript peptide (Cart) gene sequences and expression. In order to address this hypothesis, the present work focused on sex differences and analyzed not only male but also female N/OFQ-induced (0.25 and 0.5 nmol/rat) food intake in terms of their Cart and N/OFQ receptor gene expression in the hypothalamic area. In N/OFQ-naive WOKW females, cart gene expression is extremely elevated compared to N/OFQ-naive WOKW males. When male and female WOKW littermates are stimulated with N/OFQ, the food intake of females is significantly lower than that of the males. Granted, the N/OFQ feeding behavior experiments were not performed on the animals measured for Cart gene expression, but nonetheless, the responses observed in littermates point to an interesting avenue for further inquiry.

Background: Alcohol withdrawal refers to a cluster of symptoms that may occur from suddenly ceasing the use of alcohol after chronic or prolonged ingestion. These symptoms make alcohol abstinence difficult and increase the risk of relapse in recovering alcoholics. In previous studies, we demonstrated that treatment with Nociceptin/orphanin FQ (N/OFQ) significantly reduces alcohol consumption and attenuates alcohol-seeking behavior induced by environmental conditioning factors or by stress in rats. In this study, we evaluated whether activation of brain NOP receptors may also attenuate alcohol withdrawal signs in rats., Methods: For this purpose, animals were subjected to a 6-day chronic alcohol intoxication (by intragastric administration), and at 8, 10, and 12 hours following cessation of alcohol exposure, they were treated intracerebroventricularly (ICV) with N/OFQ (0.0, 1.0, and 3.0 μg/rat). Somatic withdrawal signs were scored after ICV treatment. In a subsequent experiment, to evaluate N/OFQ effects on alcohol withdrawal-induced anxiety, another group of rats was subjected to ethanol intoxication and after 1 week was tested for anxiety behavior in the elevated plus maze (EPM). In the last experiment, an additional group of rats was tested for anxiety elicited by acute ethanol intoxication (hangover anxiety). For this purpose, animals received an acute dose (3.0 g/kg) of 20% alcohol and 12 hour later were tested in the EPM following ICV N/OFQ (0.0, 1.0, and 2.0 μg/rat)., Results: Results showed that N/OFQ significantly reduced the expression of somatic withdrawal signs and reversed anxiety-like behaviors associated with both chronic and acute alcohol intoxication. N/OFQ did not affect anxiety scores in nondependent animals., Conclusions: These findings suggest that the N/OFQ-NOP receptor system may represent a promising target for the development of new treatments to ameliorate alcohol withdrawal symptoms., (Copyright © 2011 by the Research Society on Alcoholism.)

This study investigated the effect of Rhodiola rosea L. extract on acquisition and expression of morphine tolerance and dependence in mice. Therefore animals were injected with repeated administration of morphine (10 mg/kg, subcutaneous) twice daily for five or six days, in order to make them tolerant or dependent. Rhodiola rosea L. extract (0, 10, 15 and 20 mg/kg) was administered by the intragastric route 60 min prior to each morphine injection (for acquisition) or prior the last injection of morphine or naloxone on test day (for tolerance or dependence expression, respectively). Morphine tolerance was evaluated by testing its analgesic effect in the tail flick test at the 1st and 5th days. Morphine dependence was evaluated by counting the number of withdrawal signs (jumping, rearing, forepaw tremor, teeth chatter) after naloxone injection (5 mg/kg; intraperitoneal) on the test day (day 6). Results showed that Rhodiola rosea L. extract significantly reduced the expression of morphine tolerance, while it was ineffective in modulating its acquisition. Conversely, Rhodiola rosea L. extract significantly and dose-dependently attenuated both development and expression of morphine dependence after chronic or acute administration. These data suggest that Rhodiola rosea L. may have human therapeutic potential for treatment of opioid addiction.

The aim of the present study was to investigate the effects of a Rhodiola rosea L. extract on the prevention of the development of nicotine dependence and for the reduction of abstinence suffering following nicotine cessation in mice. Dependence was induced in mice by subcutaneous injections of nicotine (2 mg/kg, 4 times/day) for eight days. Spontaneous abstinence syndrome was evaluated 20 h after the last nicotine administration, by analysis of withdrawal signs, as affective (anxiety-like behaviour) and physical (somatic signs and locomotor activity). Rhodiola rosea L. extract was administered orally during nicotine treatment (10, 15 and 20 mg/kg) or during nicotine withdrawal (20 mg/kg). Results show that both affective and somatic signs (head shaking, paw tremors, body tremors, ptosis, jumping, piloerection and chewing) induced by nicotine withdrawal are abolished by administration of Rhodiola rosea L. extract in a dose-dependent fashion, during both nicotine exposure and nicotine cessation. In conclusion, our data encourage additional studies to define the use of R. rosea L. as a therapeutic approach in the treatment of smoking cessation.

Diaphragmatic breathing is relaxing and therapeutic, reduces stress, and is a fundamental procedure of Pranayama Yoga, Zen, transcendental meditation and other meditation practices. Analysis of oxidative stress levels in people who meditate indicated that meditation correlates with lower oxidative stress levels, lower cortisol levels and higher melatonin levels. It is known that cortisol inhibits enzymes responsible for the antioxidant activity of cells and that melatonin is a strong antioxidant; therefore, in this study, we investigated the effects of diaphragmatic breathing on exercise-induced oxidative stress and the putative role of cortisol and melatonin hormones in this stress pathway. We monitored 16 athletes during an exhaustive training session. After the exercise, athletes were divided in two equivalent groups of eight subjects. Subjects of the studied group spent 1 h relaxing performing diaphragmatic breathing and concentrating on their breath in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin. The consequence is a lower level of oxidative stress, which suggests that an appropriate diaphragmatic breathing could protect athletes from long-term adverse effects of free radicals.

The aim of this study was to investigate the expression and function of the transient receptor potential vanilloid 2 (TRPV2) in human glioma cells. By Real-Time-PCR and western blot analysis, we found that TRPV2 messenger RNA (mRNA) and protein were expressed in benign astrocyte tissues, and its expression progressively declined in high-grade glioma tissues as histological grade increased (n = 49 cases), and in U87MG cells and in MZC, FCL and FSL primary glioma cells. To investigate the function of TRPV2 in glioma, small RNA interfering was used to silence TRPV2 expression in U87MG cells. As evaluated by RT-Profiler PCR array, siTRPV2-U87MG transfected cells displayed a marked downregulation of Fas and procaspase-8 mRNA expression, associated with upregulation of cyclin E1, cyclin-dependent kinase 2, E2F1 transcriptor factor 1, V-raf-1 murine leukemia viral oncogene homolog 1 and Bcl-2-associated X protein (Bcl-X(L)) mRNA expression. TRPV2 silencing increased U87MG cell proliferation as shown by the increased percentage of cells incorporating 5-bromo-2-deoxyuridine expressing beta(III)-tubulin and rescued glioma cells to Fas-induced apoptosis. These events were dependent on extracellular signal-regulated kinase (ERK) activation: indeed inhibition of ERK activation in siTRPV2-U87MG transfected cells by treatment with PD98059, a specific mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor, reduced Bcl-X(L) protein levels, promoted Fas expression, and restored Akt/protein kinase B pathway activation leading to reduced U87MG cell survival and proliferation, and increased sensitivity to Fas-induced apoptosis. In addition, transfection of TRPV2 in MZC glioma cells, by inducing Fas overexpression, resulted in a reduced viability and an increased spontaneous and Fas-induced apoptosis. Overall, our findings indicate that TRPV2 negatively controls glioma cell survival and proliferation, as well as resistance to Fas-induced apoptotic cell death in an ERK-dependent manner.

Background: The purpose of this study was to re-examine intragastric ethanol intubation as a dependence induction method that effectively induces physical dependence upon ethanol over a short time period, is devoid of intrinsic stress artifacts, inexpensive, and easy to implement., Methods: Male Wistar rats were subjected to ethanol dependence induction via intragastric ethanol intubation. Ethanol solution (final concentration 20%, made up in a dietary liquid vehicle consisting of powdered milk, sucrose, and water) was intubated 4 times per day, at 4-hour intervals, for 6 consecutive days (for a total of 10 g/kg/day). The utility of this procedure was evaluated for inducing physical dependence, determined by daily and final withdrawal ratings. Anxiety-like behavior associated with ethanol dependence history was examined using the elevated plus-maze (EPM) test, conducted 5 days after ethanol withdrawal. To evaluate whether potential stress-like effects of intragastric intubation per se produce lasting effects on behavior, experimentally naive rats were compared with vehicle-intubated rats for anxiety-like behavior on the EPM., Results: Blood alcohol levels reached stable levels between 200 and 250 mg%, measured 1 hour after the second and third ethanol intubation on days 2, 4, and 6. Ethanol-treated rats developed significant somatic withdrawal signs, recorded daily between 10 and 12 hours after the last ethanol administration. At 5 days postwithdrawal, ethanol-treated rats showed significant anxiety-like behavior, measured by decreased open arm time and open arm entries on the EPM, compared with vehicle controls. Additionally, ethanol postdependent rats showed decreased open arm time compared with experimentally naive rats. EPM performance did not differ between vehicle-intubated and naive rats. No withdrawal seizures were observed and mortality rate was near zero., Conclusions: These findings suggest that intragastric ethanol administration produces a behavioral profile consistent with ethanol dependence (i.e., significant withdrawal signs after termination of ethanol exposure and elevated anxiety-like behavior persisting beyond completion of physical withdrawal), and that the intubation procedure itself does not produce lasting nonspecific anxiety-like effects. Thus, under the conditions employed here, this procedure provides an effective tool for inducing and evaluating the consequences of ethanol dependence in animal models of ethanol reward and motivation.

Background: Alcoholism is a chronic disease characterized by frequent intoxications followed by withdrawal episodes and relapse to alcohol use. Neuroplastic changes associated with these intoxication and withdrawal cycles are thought to play a key role in disease progression. Recently, it has been shown that neuropeptide S (NPS), a newly deorphanized neuropeptide receptor system, facilitates relapse to alcohol seeking in laboratory animals. Given that a history of ethanol intoxication may increase vulnerability to alcohol addiction, we sought to determine whether NPS receptor (NPSR) gene expression is altered during withdrawal., Methods: Rats were subjected to 1 week of intoxication by oral alcohol administration. NPSR gene expression was analyzed by in situ hybridization in rats 12 hours and 7 days after the last alcohol administration. To investigate the functional significance of NPSR system adaptation following protracted withdrawal 7 days after intoxication, we tested the anxiolytic-like properties of NPS in nondependent and postdependent rats using the shock probe defensive burying test (DB)., Results: At both time points, increased NPSR gene expression was observed in several brain areas, including the endopiriform nucleus, the motor cortex, and the medial amygdaloid nucleus. Moderate increases in gene expression were also found in the lateral hypothalamus, paraventricular nucleus, basolateral and central amygdala. Differences from control animals were more pronounced after 7 days of abstinence. The upregulation of the NPSR system at this time point was confirmed by functional data indicating that intracerebroventricular (ICV) NPS administration (0.0, 0.3, and 0.1 nmol/rat) elicits more pronounced anxiolytic effects in postdependent animals than in controls subjected to the electric shock probe DB test., Conclusions: Neuropeptide S receptor mRNA expression is increased in different brain areas of postdependent rats; as shown in the DB test, this expression change is functionally relevant.

Deltamethrin is a pesticide largely used. Acute toxicity of this compound was extensively investigated, whereas less information is available on the effects of subchronic and/or chronic exposure to deltamethrin or on the effects of its dermal absorption. Sparse data are also available on deltamethrin neurotoxicity. This study has assessed in the rat the effects of dermal application of deltamethrin (30 mg/kg/day in cyclohexane for 4 weeks to the skin of the back of the neck) on microanatomy of cerebrocortical areas (frontal cortex and hippocampus) and on cholinergic and dopaminergic neurotransmission markers. Treatment with deltamethrin caused nerve cell loss and the appearance of signs of neuronal sufferance primarily in layer III of frontal cortex as well as in the dentate gyrus and to a lesser extent in the CA1 and CA3 subfields of hippocampus. Deltamethrin induced also astrogliosis. Cholinergic neurotransmission markers investigated in frontal cortex, hippocampus and striatum were acetylcholine (ACh), the synthesizing and catabolic enzymes choline acetyltransferase and acetylcholinesterase and the high affinity ACh uptake system labeled with [(3)H]hemicholinium-3. These markers were unaffected by deltamethrin administration. Dopamine and the dopamine plasma membrane transporter labeled with [(3)H]GBR 12935 were unaffected by treatment with deltamethrin in frontal cortex and decreased significantly in hippocampus and striatum. These findings indicate that dermal exposure to the pyrethroid insecticide deltamethrin using an administration module mimicking a possible long-lasting occupational skin contact is accompanied by cerebrocortical injury and loss of hippocampal and striatal dopamine and dopamine transporter. The sensitivity of dopaminergic system in our experimental model suggests that dermal exposure to deltamethrin could represent a risk factor for Parkinson's disease.

This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the regulation of different alcohol-related behaviors in animals and in humans. Dr. Donald Gehlert described the development of a new corticotrophin-releasing factor receptor 1 antagonist and showed its efficacy in reducing alcohol consumption and stress-induced relapse in different animal models of alcohol abuse. Dr. Andrey Ryabinin reviewed recent findings in his laboratory, indicating a role of the urocortin 1 receptor system in the regulation of alcohol intake. Dr. Annika Thorsell showed data supporting the significance of the neuropeptide Y receptor system in the modulation of behaviors associated with a history of ethanol intoxication. Dr. Roberto Ciccocioppo focused his presentation on the nociceptin/orphanin FQ (N/OFQ) receptors as treatment targets for alcoholism. Finally, Dr. Markus Heilig showed recent preclinical and clinical evidence suggesting that neurokinin 1 antagonism may represent a promising new treatment for alcoholism. Collectively, these investigators highlighted the significance of neuropeptidergic neurotransmission in the regulation of neurobiological mechanisms of alcohol addiction. Data also revealed the importance of these systems as treatment targets for the development of new medication for alcoholism.

The present study was undertaken to develop an animal model exploiting food cue-induced increased motivation to obtain food under operant self-administration conditions. To demonstrate the predictive validity of the model, rimonabant, fluoxetine, sibutramine and topiramate, administered 1 hour before the experiment, were tested. For 5 days, female Wistar rats were trained to self-administer standard 45 mg food pellets in one daily session (30 minutes) under FR1 (fixed ratio 1) schedule of reinforcement. Rats were then trained to an FR3 schedule and finally divided into two groups. The first group (control) was subjected to a standard 30 minutes FR3 food self-administration session. The second group was exposed to five presentations of levers and light for 10 seconds each (every 3 minutes in 15 minutes total). At the completion of this pre-session phase, a normal 30-minute session (as in the control group) started. Results showed that pre-exposure to environmental stimuli associated to food deliveries increased response for food when the session started. Corticosterone and adrenocorticotropic hormone plasma levels, measured after the 15-minute pre-exposure, were also significantly increased. No changes were observed for the other measured hormones (growth hormone, prolactin, thyroid-stimulating hormone, luteinizing hormone, insulin, amylin, gastric inhibitor polypeptide, ghrelin, leptin, peptide YY and pancreatic polypeptide). Rimonabant, sibutramine and fluoxetine significantly reduced food intake in both animals pre-exposed and in those not pre-exposed to food-associated cues. Topiramate selectively reduced feeding only in pre-exposed rats. The present study describes the development of a new animal model to investigate cue-induced increased motivation to obtain food. This model shows face and predictive validity, thus, supporting its usefulness in the investigation of new potential treatments of binge-related eating disorders. In addition, the present findings confirm that topiramate may represent an important pharmacotherapeutic approach to binge-related eating.

Aim: Ultimate is a sport played by hundreds of thousands of people in more than 42 countries; however, it is still mainly known as a recreational more than a team sport, and further studies are needed to define its physical load. Particularly, since no studies relating Ultimate to hydration have been performed, we aimed to determine body fluid balance, voluntary water intake and the most reliable method for assessing the hydration status of players after a typical 80-minute Ultimate match., Methods: bioimpedance, urine specific gravity and body mass changes to asses the hydration level of the players were measured., Results: It was observed that not all of the methods are adequate to determine dehydration in Ultimate players, and that measurement of body mass changes represents a reliable and accurate technique., Conclusions: These findings demonstrate that ultimate as an intense sport that can induce significant fluid loss, which is not always replaced by individual drinking.

Nicardipine is a dihydropyridine-type Ca(2+) channel blocker (CCB) with strong antihypertensive activity and with a peculiar cerebrovascular profile. This paper has reviewed the main controlled clinical studies on nicardipine in pathologies associated with cerebrovascular impairment. Subarachnoid haemorrhage (SAH) is managed with CCBs to prevent vasospasm and improve clinical outcomes. Nimodipine is the CCB licensed for this indication. Former studies did not demonstrate an advantage of nicardipine versus nimodipine in SAH. A more recent approach administering the drug intra-arterially or using implants of nicardipine prolonged-release showed a decreased incidence of vasospasm, delayed ischemic deficits and improved clinical outcome after severe SAH. Nicardipine is recommended for elevated blood pressure after acute ischemic stroke or intracerebral haemorrhage and is effective in prevention of stroke. More recent investigations were focused on the treatment of cognitive deterioration of vascular origin. In this setting nicardipine has been investigated in more than 6000 patients, with improvement of cognitive deterioration in more than 60% of patients treated. The anti-hypertensive activity of nicardipine, its safety and effectiveness in cognitive domain, suggests re-considering this drug in the treatment of cognitive impairment of vascular origin and for reducing the risk of recurrent stroke in patients at high risk of it.

The present study was designed to assess if treatment with acetylcholinesterase inhibitor galantamine and the cholinergic precursor choline alphoscerate (alpha-glyceryl-phosphoryl-choline) alone or in association has any protective effect on brain microanatomy in spontaneously hypertensive rats (SHR) used as an animal model of vascular dementia (VaD). Thirty-two-week-old SHR and age-matched normotensive Wistar Kyoto (WKY) rats were left untreated or treated for 4 weeks with an oral dose of 3 mg/kg/day of galantamine, of 100 mg/kg/day of choline alphoscerate or their association. The number of neurons and of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes, phosphorylated neurofilament, and microtubule associated protein-2 (MAP-2) and aquaporin-4 (AQP-4) was assessed by quantitative microanatomical and immunohistochemical techniques. In SHR, the number of neurons of frontal cortex, of the CA1 subfield of hippocampus and of dentate gyrus was decreased compared to WKY rats. Astrogliosis, breakdown of phosphorylated neurofilament, unchanged MAP-2 and altered AQP-4 expression were found as well. Both galantamine and choline alphoscerate countered nerve cell loss. Choline alphoscerate but not galantamine decreased astrogliosis and restored expression of AQ-4. Galantamine countered to a greater extent than choline alphoscerate phosphorylated neurofilament breakdown. The two drugs in association displayed a more remarkable effect. This study confirms a neuroprotective effect of galantamine in SHR and indicates a neuroprotective role of choline alphoscerate in the same model. A wider neuroprotective effect of the cholinergic inhibitor/precursor association was observed. These findings suggest to assess the activity of this cholinergic association in clinical trials.

Herein, we provide evidence on the expression of transient receptor potential vanilloid type 1 (TRPV1) on human urothelial cancer (UC) cells and its involvement in the apoptosis induced by the selective agonist capsaicin (CPS). We analyzed TRPV1 messenger RNA and protein expression on human UC cell lines demonstrating its progressive decrease in high-grade UC cells. Treatment of RT4 cells with CPS induced cell cycle arrest in G(0)/G(1) phase and apoptosis. These events were associated with rapid co-ordinated transcription of pro-apoptotic genes including Fas/CD95, Bcl-2 and caspase families and ataxia telangiectasia mutated (ATM)/CHK2/p53 DNA damage response pathway. CPS induced Fas/CD95 upregulation, but more importantly Fas/CD95 ligand independent, TRPV1-dependent death receptor clustering and triggering of both extrinsic and intrinsic mitochondrial-dependent pathways. Moreover, we observed that CPS activates ATM kinase that is involved in Ser15, Ser20 and Ser392 p53 phosphorylation as shown by the use of the specific inhibitor KU55933. Notably, ATM activation was also found to control upregulation of Fas/CD95 expression and its co-clustering with TRPV1 as well as RT4 cell growth and apoptosis. Altogether, we describe a novel connection between ATM DNA damage response pathway and Fas/CD95-mediated intrinsic and extrinsic apoptotic pathways triggered by TRPV1 stimulation on UC cells.

Aim: Adipose tissue has been the object of intense research in the field of obesity and diabetes diseases in the last decade. Examination of adipocyte-secreted peptides led to the identification of a unique polypeptide, resistin (RSTN), which has been suggested as a link between obesity and diabetes. RSTN plays a clearly documented role in blocking insulin (INS)-induced hypoglycaemia. As brain injection of INS affects feeding behaviour, we studied the possible interaction between INS and RSTN in food-deprived rats, measuring effects on food intake. In addition, we examined how RSTN might affect neuropeptide Y (NPY)-induced feeding, as studies have shown that rat RSTN can interfere with the NPY system., Methods: Overnight food-deprived rats were injected into the third brain ventricle (3V) with either INS (10 or 20 mUI), RSTN (0.1-0.4 nmol/rat), or saline before access to food. Another group of rats was injected into the 3V with RSTN alone, NPY alone or RSTN plus NPY. Their food intake and body weight were measured., Results: Our results confirm the hypophagic effect of RSTN on food deprivation-induced food intake, and more importantly, show that RSTN neither potentiates nor blocks the effects of INS on food intake, but does reduce the hyperphagic effect of NPY., Conclusion: The observation that RSTN does not modify feeding INS-induced hypophagia, but does influence NPY-induced feeding, points to the possibility that RSTN may be involved in control of food intake through an NPY-ergic mechanism as INS.

Rationale: Preclinical models are needed to investigate the neurobiology and psychobiology of binge eating and to identify innovative pharmacotherapeutic strategies., Objectives: A modification of the model based on the combination of cyclic caloric restrictions and acute stress was developed to further increase its face validity and reliability and, for the first time, to assess its predictive value., Materials and Methods: Four groups of female rats were employed: group 1 was normally fed and not stressed on the test day (25th); group 2 was fed normally but was exposed to an acute stress on day 25; group 3 was exposed to three cycles (4 days 66% of chow intake + 4 days food ad libitum) of yo-yo dieting but not stressed; and group 4 was exposed to cyclic yo-yo dieting and then stressed. All groups were fed highly palatable food (HPF) for 2 h on days 5-6 and 13-14. Acute stress was elicited by exposing rats to HPF, but preventing them from access to it for 15 min., Results: The combination of cyclic food restriction and stressful exposure to food markedly increased HPF intake. Sibutramine and fluoxetine inhibited food intake in all conditions. Topiramate selectively inhibited compulsive HPF intake in rats submitted to caloric restriction and stress. Midazolam increased HPF intake., Conclusions: Pharmacological results suggest that this model, in addition to face validity as an isomorphic model of human binge eating, is endowed with good predictive validity.

In previous work, we observed that N/OFQ-induced hyperphagia is greater in DA rats, animals resistant to metabolic syndrome, than in WOKW animals, which are prone to this disease. We attributed this difference to the fact that these two strains have different Cart gene sequences and expression. As a preliminary approach to pursue this hypothesis, the present work focused on Cart gene expression by developing from DA and WOKW rats various congenic animals with exchanges of metabolic syndrome-related QTL's of different chromosomes (3, 5, 10 and 16), and analyzing their N/OFQ-induced (2.1, 4.2, and 8.4nmol/rat) food intake in terms of their CART gene expression and N/OFQ hypothalamic immunostaining. Two groupings emerged, the first, with strains 3a, 3b, and 5a with elevated N/OFQ-induced feeding similar to that of the DA rats, and the second, with strains 16 and 10, with lower feeding, like the WOKW rats. There was a perfect correlation between Cart gene expression and N/OFQ-induced feeding data at 30min for the strains DA, 3a, 3b, 5 in the first group, and 16 and WOKW for the second, but not for strain 10. As expected, the strains with low content of Cart gene expression had elevated N/OFQ-induced feeding, but contrary to expectations, strain 10, with the lowest Cart gene expression, exhibited low N/OFQ-induced feeding, on the order of that of the WOKW rats. A comparable trend was observed with N/OFQ hypothalamic immunostaining. This anomaly may be due to other satiety-related factors involved in N/OFQ-induced feeding.

Aim: This work monitored changes in oxidative stress and antioxidant defence during an endurance exercise in over 40 years old athletes., Methods: Subjects were monitored during the 24-hours mountain bike Idro Lake (North of Italy) competition which took place in June 2008. The race lasted for 24 h, starting at 10.00 a.m., ending at 10.00 a.m. of the following day and was based upon riding for as many kilometers as possible in the 24-hours time schedule in a 5.5 km circuit trail. The study included 6 men bikers, aged 44.8 +/- 2 years, who raced on an individual basis. Blood samples were collected and the oxidative stress was measured performing the d-ROMs test which determined the reactive oxygen metabolites (ROMs), whereas the antioxidant defence status was assessed determining the biological antioxidant potential (BAP test)., Results: The ROMs levels significantly increased after 8 h from the beginning of the competition (122 %), at the end of the race (162%), 24 h (158%) and 48 h (144%) post-race. The biological antioxidant potential significantly increased at the end of the race (128%) and remained elevated 48 h later (114%). After 72 h post-race, ROMs and BAP levels differed significantly amongst subjects, thus showing an individual response to oxidative stress., Conclusions: In conclusion, exposure to intense and prolonged exercise induced a marked increase in dROMs levels in master athletes, only partially counterbalanced by antioxidants in blood plasma. The long-term effects of oxidative agents on the human body requires further studies, but it is likely that a diet potentially rich in antioxidants would help preventing oxidative damage of body cells and tissues and enhancing recovering from the endurance performance.

Rhodiola rosea L. is one of the most popular adaptogen and an antistress plant in European and Asiatic traditional medicine. Our previous studies have confirmed the adaptogenic and antistress properties of a single administration of R. rosea L. extract in rats exposed to acute stress. There is increasing evidence that prolonged exposure to stressful life events and depression are both related to significant behavioural, endocrinological and neurobiological changes in human and animal subjects. The aim of this study was to determine whether chronic treatment with a hydroalcoholic R. rosea extract (RHO) standardized in 3% rosavin and 1% salidroside can prevent alterations induced in female rats following 6 weeks of a chronic mild stress (CMS) procedure. This was analysed through the behavioural and physiological parameters of consumption of 1% sucrose solution, locomotor and exploratory activities, body weight gain and oestrous cycle length. After the first 3 weeks of stress, RHO was administered daily by gavage at doses of 10, 15 and 20 mg/kg for the remaining 3 weeks. In addition, the antidepressant drug fluoxetine (10 mg/kg os), which has been shown to reverse CMS-induced disruptions, was used as the reference treatment. Rats subjected to the CMS procedure demonstrated decreased sucrose intake, reduced moving behaviour, minimized weight gain and dysregulation of their oestrous cycle. Treatment with RHO completely reverted all of these changes. The effects of RHO were comparable to those of fluoxetine. Interestingly, neither RHO nor fluoxetine influence the behavioural and physiological parameters tested in non-stressed animals. These findings strongly showed that chronic administration of RHO results in potent inhibition of the behavioural and physiological changes induced by chronic exposure to mild stressors.

Background: In this study, we investigated the effect of CRM197 treatment in human adrenocortical carcinoma (AC) implanted in nude mice. CRM197 is a non-toxic mutant of diphtheria toxin that binds heparin-binding epidermal growth factor-like growth factor (HB-EGF) which is implicated in the proliferative activity of several tumor cells., Methods: HB-EGF expression in AC cells was evaluated by reverse transcription PCR and Western blot. AC tumors were implanted in nude mice and then treated with CRM197. Effects of treatment on angiogenesis and apoptosis were investigated by immunohistochemistry and Western blot. The effects on cell invasion and migration were investigated with a matrigel invasion assay., Results: We demonstrated that human AC cells express HB-EGF. A treatment with CRM197 blocked growth, reduced angiogenesis and induced apoptosis in AC tumors implanted in nude mice. CRM197 also inhibited invasion and migration of these tumor cells., Conclusions: These data support the evidence for anticancer properties of CRM197 in AC tumors., (Copyright 2009 S. Karger AG, Basel.)

Background: Since obesity and related diseases are now considered epidemic, new and more accurate formulas for epidemiological studies are of interest to the scientific community. Several equations have been proposed to estimate the body composition simply from anthropometric measurements. However, with time, the body composition of the populations studied changes in relation to their food habits and lifestyle, and, therefore, the equations must be regularly updated and corrected., Aim of the Study: The aim of the study was to develop new equations to determine the body composition among the Italian population using the body mass index and independently by variables such as age and body structure., Methods: Bioelectrical impedance and anthropometric analysis of 764 Italian Caucasian subjects (342 females and 422 males), 11 to 80 years of age, were analysed. Females and males were analysed separately. Multiple regression analyses were performed in order to estimate the body composition of the subjects. The estimated masses were then compared with the measured masses using Bland and Altman plots. We also calculated the differences between the estimated and measured masses, reported as % of the body weight, for the 95, 85 and 75 degrees percentile of the female and male groups. Finally we compared our formulas with the Watson equations, which are used to estimate the total body water., Results: All body masses estimated were positively correlated to the measured values. Moreover, at any percentile analysed, our formulas resulted more precise than the Watson formula. Equations: Females: FM = 1.9337 BMI - 26.422; FFM = BW - FM; BCM = 0.3655 FFM + 4.865; TBW = 0.5863 FFM + 7.1732; Males: FM = 1.407 BMI - 21.389; FFM = BW - FM; BCM = 0.4485 FFM + 3.3534; TBW = 0.6997 + 1.4567., Conclusions: Although an inevitable inaccuracy must be expected in epidemiological studies, our equations are adequate to analyze the body composition state and changes occurring among the Italian population by simply considering weight and height.

The activity of substance P (SP) in the rat thymus seems to be tightly controlled by its bioavailability. In this study, we provide evidence for the expression of the SP-degrading enzyme, neutral endopeptidase (NEP)/CD10, by rat thymocyte subsets, and we illustrate its involvement in the in vivo SP/neurokinin-1 receptor (NK(1)R)-mediated regulation of thymocyte survival and proliferation. NEP/CD10 was expressed at both mRNA and protein levels on a substantial portion (45.5%) of CD5(+) thymocytes, namely on the CD4(+)CD8(+) (double positive; DP) and CD4(+) subsets. Continuous administration of thiorphan, a specific NEP/CD10 inhibitor, by means of miniosmotic pumps, enhanced rat thymocyte preprotachykinin-A (PPT-A) and NK(1)R mRNA expression as well as SP and NK(1)R protein levels in an NK(1)R-dependent manner. Thiorphan increased CD10(+)CD4(+) and CD10(+)DP thymocyte numbers, and an NK(1)R antagonist, (S)1-{2-[3(3-4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)-piperidine-3-yl]ethyl}-4-pheny-1-azoniabicyclo[2.2.2]octane, chloride (SR140333), abrogated these stimulatory effects. In addition, the NEP/CD10 inhibitor stimulated interleukin (IL)-2 production, IL-2 receptor alpha chain expression, and concanavalin A-induced proliferation of CD5(+) thymocytes, and it inhibited spontaneous and NK(1)R-dependent thymocyte apoptosis. The thiorphan-protective antiapoptotic and proliferative effects involved the activation of Akt serine-threonine kinase, subsequent up-regulation of survivin mRNA, down-regulation of procaspase-3 mRNA levels, and suppression of caspase-3 activity, which were inhibited by SR140333 and mimicked by exogenous SP administration. Overall, our findings suggest that by controlling SP availability, NEP/CD10 negatively regulates thymocyte homeostasis and development.

Pyrethroids are important insecticides used largely because of their high activity as an insecticide and their low mammalian toxicity. Some studies have demonstrated that these products show neurotoxic effects on the mammalian central nervous system. The aim of the present study was to investigate the propensity of permethrin to induce oxidative stress in adolescent rats and its possible attenuation by Vitamin E alone or+Coenzyme Q(10). Data indicated that adolescent rats exposed to permethrin exhibited alteration in the locomotor activity and plasma membrane fluidity of striatum. Vitamin E+Q(10) and Vitamin E alone supplementation reversed the negative effect on central nervous system. Permethrin alteration of striatum plasma membrane fluidity was restored by Vitamin E+Q(10). Data obtained from red blood cells showed that permethrin did not induce any modification of plasma membrane fluidity in adolescent rats, whereas antioxidants supplementation induced pro-oxidant effect. In summary some differences between antioxidant treatments were observed at striatum level: Coenzyme Q(10)+Vitamin E maintains plasma membrane fluidity, while Vitamin E is more effective to preserve GSH level.

Objective: To evaluate the expression of transient receptor potential vanilloid type 2 (TRPV2) in normal human bladder and urothelial carcinoma (UC) tissues., Methods: Bladder specimens were obtained by transurethral resection or radical cystectomy. TRPV2 mRNA expression in normal human urothelial cells (NHUCs), UC cell lines, and formalin-fixed paraffin-embedded normal (n=6) and cancer bladder tissues (n=58) was evaluated by polymerase chain reaction (PCR) and quantitative real-time PCR (RT-PCR). TRPV2 protein expression was assessed by cytofluorimetric and confocal microscopy analyses in NHUCs and UC cells and by Western blotting and immunohistochemistry in normal and UC tissues., Results: Enhanced TRPV2 mRNA and protein expression was found in high-grade and -stage UC specimens and UC cell lines. Both the full-length TRPV2 (hTRPV2) and a short splice-variant (s-TRPV2) were detected in NHUC and normal bladder specimens, whereas a progressive decline of s-TRPV2 in pTa, pT1, and pT2 stages was observed, up to a complete loss in pT3 and pT4 UC specimens., Conclusions: Normal human urothelial cells and bladder tissue specimens express TRPV2 at both the mRNA and protein levels. A progressive loss of s-TRPV2 accompanied by a marked increase of hTRPV2 expression was found in high-grade and -stage UC tissues.

There is much concern about the increasing presence in the environment of synthetic chemicals that are able to disrupt the endocrine system. Among these compounds, 4-nonylphenol (4-NP) is one of the most studied xenoestrogens, due to its widespread accumulation in water sediment and consequent presence in fatty acid of aquatic organisms. Here, we have used a zebrafish microarray representing 16,399 genes to study the effects of 4-NP and estradiol-17beta (E2) in adult male zebrafish in order to elucidate the mechanism of action of 4-NP compared with that of E2. The microarray results showed that both 4-NP and E2 induced a strong expression of vitellogenin (VTG), the sex related precursor of the yolk proteins in oviparous vertebrates. Both treatments induced elevated protein turnover upregulating genes involved in proteolysis and those that are constituents of the ribosome. Many genes regulated by 4-NP and E2 are involved in energy metabolism, oxidative stress defense mechanisms, xenobiotic metabolism, and lipid metabolism. A different pattern of expression in the two treatments was found for genes involved in oxidative stress, since E2 seems to induce the mechanism of detoxification, while 4-NP seems to inhibit this protective mechanism of the cell. Overall, these findings demonstrate that the microarray approach can contribute significantly to the understanding of expression patterns induced by E2 and 4-NP in male zebrafish. The results also demonstrate that 4-NP is able to act through an alternative pattern to that of estradiol-17beta, modulating the expression of the same genes in a different manner.

Background: Alcoholism is a complex behavioral disorder in which interactions between stressful life events and heritable susceptibility factors contribute to the initiation and progression of disease. Neural substrates of these interactions remain largely unknown. Here, we examined the role of the nociceptin/orphanin FQ (N/OFQ) system, with an animal model in which genetic selection for high alcohol preference has led to co-segregation of elevated behavioral sensitivity to stress (Marchigian Sardinian alcohol-preferring [msP])., Methods: The msP and Wistar rats trained to self-administer alcohol received central injections of N/OFQ. In situ hybridization and receptor binding assays were also performed to evaluate N/OFQ receptor (NOP) function in naïve msP and Wistar rats., Results: Intracerebroventricular (ICV) injection of N/OFQ significantly inhibited alcohol self-administration in msP but not in nonselected Wistar rats. The NOP receptor messenger RNA expression and binding was upregulated across most brain regions in msP compared with Wistar rats. However, in msP rats [(35)S]GTPgammaS binding revealed a selective impairment of NOP receptor signaling in the central amygdala (CeA). Ethanol self-administration in msP rats was suppressed after N/OFQ microinjection into the CeA but not into the bed nucleus of the stria terminalis or the basolateral amygdala., Conclusions: These findings indicate that dysregulation of N/OFQ-NOP receptor signaling in the CeA contributes to excessive alcohol intake in msP rats and that this phenotype can be rescued by local administration of pharmacological doses of exogenous N/OFQ. Data are interpreted on the basis of the anti-corticotropin releasing factor (CRF) actions of N/OFQ and the significance of the CRF system in promoting excessive alcohol drinking in msP rats.