Therapeutic drug monitoring in children and adolescents with schizophrenia and other psychotic disorders using risperidone.

Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose-concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20-60 ng/ml) is applicable for minors. In the 64 patients (aged 11-18 years) included, a positive correlation between daily dose and the active moiety (RISam) concentration was found (rs = 0.49, p = 0.001) with variation in dose explaining 24% (rs2 = 0.240) of the variability in serum concentrations. While the RISam concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RISam concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RISam was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.

Reasons for Attempted Suicide in Europe: Prevalence, Associated Factors, and Risk of Repetition.

To examine the prevalence of specific reasons for attempted suicide, factors associated with them, and whether reasons for attempted suicide influence risk of repetition. As part of the Monitoring Suicide in Europe (MONSUE) project, data on 4,683 suicide attempters from nine European countries were collected. Independence tests were used to study the influence of age, gender, and other factors on reported reasons. We examined risk of repetition using logistic regression analysis. Interpersonal conflict was common for all patients except those widowed, living alone, or retired. Mental health problems were prevalent among over 45 year-olds, patients unable to work, and patients with a history of at least three suicide attempts. Financial difficulties were cited more often by patients who were 45-64 years old, divorced or separated, living with children only, and unemployed. Close bereavement/serious illness and own physical illness were associated with those over 65 years of age. Two reasons for suicide attempt, interpersonal conflict and mental health problems, were associated with increased risk of repetition independent of other factors. Suicide attempters have a multitude of problems of varying prevalence depending on age, gender, and other factors. They present a range of clinical profiles that require a multidisciplinary response.

Application of continuous positive airway pressure in the delivery room: a multicenter randomized clinical trial

This study evaluated whether the use of continuous positive airway pressure (CPAP) in the delivery room alters the need for mechanical ventilation and surfactant during the first 5 days of life and modifies the incidence of respiratory morbidity and mortality during the hospital stay. The study was a multicenter randomized clinical trial conducted in five public university hospitals in Brazil, from June 2008 to December 2009. Participants were 197 infants with birth weight of 1000-1500 g and without major birth defects. They were treated according to the guidelines of the American Academy of Pediatrics (APP). Infants not intubated or extubated less than 15 min after birth were randomized for two treatments, routine or CPAP, and were followed until hospital discharge. The routine (n=99) and CPAP (n=98) infants studied presented no statistically significant differences regarding birth characteristics, complications during the prenatal period, the need for mechanical ventilation during the first 5 days of life (19.2 vs 23.4%, P=0.50), use of surfactant (18.2 vs 17.3% P=0.92), or respiratory morbidity and mortality until discharge. The CPAP group required a greater number of doses of surfactant (1.5 vs 1.0, P=0.02). When CPAP was applied to the routine group, it was installed within a median time of 30 min. We found that CPAP applied less than 15 min after birth was not able to reduce the need for ventilator support and was associated with a higher number of doses of surfactant when compared to CPAP applied as clinically indicated within a median time of 30 min.

Application of continuous positive airway pressure in the delivery room: a multicenter randomized clinical trial.

This study evaluated whether the use of continuous positive airway pressure (CPAP) in the delivery room alters the need for mechanical ventilation and surfactant during the first 5 days of life and modifies the incidence of respiratory morbidity and mortality during the hospital stay. The study was a multicenter randomized clinical trial conducted in five public university hospitals in Brazil, from June 2008 to December 2009. Participants were 197 infants with birth weight of 1000-1500 g and without major birth defects. They were treated according to the guidelines of the American Academy of Pediatrics (APP). Infants not intubated or extubated less than 15 min after birth were randomized for two treatments, routine or CPAP, and were followed until hospital discharge. The routine (n=99) and CPAP (n=98) infants studied presented no statistically significant differences regarding birth characteristics, complications during the prenatal period, the need for mechanical ventilation during the first 5 days of life (19.2 vs 23.4%, P=0.50), use of surfactant (18.2 vs 17.3% P=0.92), or respiratory morbidity and mortality until discharge. The CPAP group required a greater number of doses of surfactant (1.5 vs 1.0, P=0.02). When CPAP was applied to the routine group, it was installed within a median time of 30 min. We found that CPAP applied less than 15 min after birth was not able to reduce the need for ventilator support and was associated with a higher number of doses of surfactant when compared to CPAP applied as clinically indicated within a median time of 30 min.

Colorectal cancer screening in Canada: results from the first round of screening for five provincial programs.

BACKGROUND: Early implementation of programmatic colorectal cancer (crc) screening for average-risk individuals 50-74 years of age in Canada has used fecal occult blood tests [fts (guaiac or immunochemical)] and colonoscopy for follow-up of abnormal fts. This paper presents results of an evaluation of this crc screening. METHODS: Five Canadian provincial programs provided aggregated data for individuals with a first-round ft processed between January 1, 2009, and December 31, 2011. RESULTS: The 104,750 people who successfully completed a first round of screening represented 16.1% of those who had access to the programs between January 1, 2009, and December 31, 2011 (mean age: 61.2 years; men: 61.4 years; women: 61.1 years). Of those participants, 4661 had an abnormal ft (4.4%). Uptake of colonoscopy within 180 days after an abnormal ft was 80.5%, ranging from 67.8% to 89.5% by program. The positive predictive value (ppv) for adenoma was 35.9% for guaiac ft and 50.6% for immunochemical ft. Adenoma and crc detection rates were, respectively, 16.9 and 1.8 per 1000 screened. Of invasive crcs detected, 64.6% were stage i or ii. CONCLUSIONS: Considering the variation in characteristics and stage of implementation of each provincial program, the collaboration of the provinces leading to this report on the early performance of crc screening in Canada is a major milestone. Targets are met or nearly met for significant indicators such as ppv for adenoma and cancer detection rate. Participation is expected to increase as programs are fully implemented in the provinces. Additional effort may be needed to improve timely access to follow-up colonoscopy.

Irony comprehension and context processing in schizophrenia during remission--a functional MRI study.

Schizophrenic patients have Theory of Mind (ToM) deficits even during remission, but it is yet unknown whether this could be influenced. We examined the neural correlates of irony understanding in schizophrenic patients, as an indicator of ToM capacity, and evaluated how linguistic help inserted into the context phase could affect irony comprehension. Schizophrenic patients in remission and healthy controls were subjected to event-related functional MRI scanning while performing irony, 'irony with linguistic help', and control tasks. Patients understood irony significantly worse than healthy controls. The patients showed stronger brain activity in the parietal and frontal areas in the early phase of irony task, however the healthy controls exhibited higher activation in frontal, temporal and parietal regions in the latter phase of the irony task. Interestingly the linguistic help not only improved the patients' ToM performance, but it also evoked similar activation pattern to healthy controls.

Patients with difficult-to-treat depression do not exhibit an increased frequency of CYP2D6 allele duplication.

The insufficient response of patients to antidepressant medications may result from several factors, including altered drug metabolism. CYP2D6 genotyping may help assess the possible factors that contribute to difficult-to-treat depression. The aim of our study was to determine the frequency of CYP2D6 allelic variants and the prevalence of predicted CYP2D6 phenotypes in patients who were suffering from difficult-to-treat depression and compare the data with those for the healthy population of Hungary.55 patients who failed to respond to 2 or more adequate trials of different CYP2D6-dependent antidepressants were selected for genotyping.The prevalence of the predicted CYP2D6 phenotypes in the patient population was 1.8% for the UMs, 80.0% for EMs, 3.6% for IMs and 14.5% for PMs compared with 1.9% for UMs, 83.3% for EMs, 6.5% for IMs and 8.3% for PMs in the Hungarian population.The CYP2D6 allele frequencies and the predicted phenotype distributions in patients with difficult-to-treat depression were not significantly different to those found in the healthy population of Hungary. The cumulative frequency of the CYP2D6*1XN, *2XN and *35XN alleles was 0.9% in the patient population -suggesting that CYP2D6 duplication or multiplication does not play a significant role in antidepressant pharmacotherapy failure in this patient sample. The cumulative frequency of the non-functional alleles (33.5%) and the prevalence of the genetically determined PM phenotype (14.5%) were relatively high in the patient group. These figures draw attention to the possibility of unrecognised and non-reported side effects and non-adherence to drug treatment.

Pan-Canadian initiatives in colorectal cancer screening: adopting knowledge translation tools to accelerate uptake and impact.

BACKGROUND: Despite the positive conclusions of several randomized controlled trials and the publication of national recommendations on colorectal cancer (crc) screening, uptake remained low. The inauguration of the National Colorectal Cancer Screening Network in 2007, the same year that the first screening program was announced in Canada, provided an opportunity for integrated knowledge translation to accelerate the processes of program implementation and screening uptake. AIM: Two primary aims were identified. The first focused on means to monitor the effects of various implementation plans in delivering high-quality population-based crc screening. The second focused on identifying and addressing knowledge gaps that may impair screening participation. METHOD: The methods used are described in the context of the knowledge-to-action cycle and demonstrate that the initiative itself dictates the point in the cycle at which to start. RESULTS: The identified need to monitor various implementation plans resulted in the shared development of a quality determinants document. All programs committed to designing data collection so that core components could be measured and compared; 6 operating programs have conducted the first data collection, which will allow for monitoring and for new knowledge creation as the process develops further. The knowledge gap identification project started with new knowledge creation, which identified a higher-than-expected willingness of Canadians to discuss crc screening with physicians, but a low level of understanding of screening as a wellness-related behaviour. Knowledge translation interventions have been developed with the stakeholders to address those gaps, and ongoing surveys to be carried out later in 2011 will help to gauge progress in the understanding and acceptance of crc screening by the population. CONCLUSIONS: A national network that engaged all programs, policymakers, experts, and lay representatives successfully used knowledge translation principles to enhance the trajectory of crc screening in Canada.

Regional gray matter reduction and theory of mind deficit in the early phase of schizophrenia: a voxel-based morphometric study.

OBJECTIVE: We tested the association between theory of mind (ToM) performance and structural changes in the brains of patients in the early course of schizophrenia. METHOD: Voxel-based morphometry (VBM) data of 18 patients with schizophrenia were compared with those of 21 controls. ToM skills were assessed by computerized faux pas (FP) tasks. RESULTS: Patients with schizophrenia performed significantly worse in FP tasks than healthy subjects. VBM revealed significantly reduced gray matter density in certain frontal, temporal and subcortical regions in patients with schizophrenia. Poor FP performance of schizophrenics correlated with gray matter reduction in the left orbitofrontal cortex and right temporal pole. CONCLUSION: Our data indicate an association between poor ToM performance and regional gray matter reduction in the left orbitofrontal cortex and right temporal pole shortly after the onset of schizophrenia.

Effects of oral L-carnitine, L-lysine administration and exercise on body composition and histological and biochemical parameters in pigeons.

The purpose of this study was to examine whether L-carnitine and its precursor L-lysine could have any beneficial effect in racing pigeons, and if so, whether this effect is influenced by the extent of exercise (short-distance flight: 135 km vs. long-distance flight: 580 km). Birds were divided into seven groups of animals. Group 1: negative control, no flight, no treatment, Group 2: positive control, placebo treatment before the short-distance flight, Group 3: 200 mg/day L-carnitine treatment before the short-distance flight, Group 4: 400 mg/day L-lysine treatment before the short-distance flight, Group 5: positive control, placebo treatment before the long-distance flight, Group 6: 200 mg/day L-carnitine treatment before the long-distance flight, Group 7: 400 mg/day L-lysine treatment before the long-distance flight. L-carnitine, L-lysine and distilled water (placebo) were orally administered (tube feeding) for 7 days before flight. Just after returning home, blood samples were collected and analyzed for glucose, fructosamine, cholesterol, triglycerides and thiobarbituric acid reactive substances. Pigeons were euthanized using carbon dioxide as an inhalation agent, and the whole body was subjected to proximate analysis. The status at arrival was referred to as a basis for comparison. Sex did not affect the measured parameters. As a result of the L-carnitine and L-lysine administrations, the body fat mobilization was higher during the 580 km flight, whereas no changes were noted during the 135 km flight. The main changes in the measured blood parameters were caused by the extent of exercise. This experiment considered the extent of exercise as a factor potentially modulating L-carnitine supplementation effects. In conclusion, flight distance affected several parameters but the supplements of L-carnitine and L-lysine were not effective in the tested situations.

Rare provisional entity: primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma in a young woman.

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is a rare and provisional entity, characterised by cutaneous involvement and aggressive clinical behaviour. The case is here presented of a young woman with concurrent cutaneous and systemic involvement. Despite multi-agent chemotherapy, only partial remission could be achieved, and the patient died from therapy-resistant respiratory and circulatory failure. This case report is intended to add to the data collected on this rare entity, with only about 20 cases as yet described.

The factorial structure of the Suicide Intent Scale: a comparative study in clinical samples from 11 European regions.

Although the Suicide Intent Scale (SIS) is a widely used instrument in research on suicidal behavior, comparative research on the latent structure of the SIS has been neglected. To determine whether a general factor model of the SIS is supported, alternative factor models of the SIS were evaluated comparatively in 11 clinical samples. The SIS was applied as part of a structured clinical interview to patients after an episode of non-fatal suicidal behavior. The samples were drawn from 11 study centers within the frame of the WHO/EURO multicenter study on suicidal behavior. Three different two-factor and two three-factor models of the SIS were examined in each sample using principal component analysis with orthogonal Procrustes rotation. The factorial structure of the 'subjective part' of the SIS (items 9-14) was strongly supported, whereas an acceptable model fit for the 'objective part' was not found. Possible future revisions of 'objective' SIS items may be worth consideration. As a limitation, the results of the study might not generalize to other samples that use different definitions of non-fatal suicidal behavior.

Veterinary aspects and perspectives of nutrigenomics: a critical review.

Nutrigenomics examines nutrient-gene interactions on a genome-wide scale. Increased dietary fat or higher non-esterified fatty acids (NEFA) from starvation-induced mobilisation may enhance hepatic oxidation and decrease esterification of fatty acids by reducing the expression of the fatty acid synthase gene. The key factors are the peroxisome proliferator-activated receptors (PPARs). Dietary carbohydrates--both independently and through insulin effect--influence the transcription of the fatty acid synthase gene. Oleic acid or n-3 fatty acids downregulate the expression of leptin, fatty acid synthase and lipoprotein lipase in retroperitoneal adipose tissue. Protein-rich diets entail a shortage of mRNA necessary for expression of the fatty acid synthase gene in the adipocytes. Conjugated linoleic acids (CLAs) are activators of PPAR and also induce apoptosis in adipocytes. Altered rumen microflora produces CLAs that are efficient inhibitors of milk fat synthesis in the mammary gland ('biohydrogenation theory'). Oral zinc or cadmium application enhances transcription rate in the metallothionein gene. Supplemental CLA in pig diets was found to decrease feed intake and body fat by activating PPARgamma-responsive genes in the adipose tissue. To prevent obesity and type II diabetes, the direct modulation of gene expression by nutrients is also possible. Nutrigenomics may help in the early diagnosis of genetically determined metabolic disorders and in designing individualised diets for companion animals.

Study of the energy and protein balance of pregnant rabbit does using two comparative methods.

The total body composition of 4 x 10 female, 5-month-old New Zealand White rabbits was determined, using direct chemical analysis and computerised tomography (CT). Ten non-pregnant rabbits (control) and 3 x 10 pregnant rabbits at days 14, 21 and 28 of gestation, respectively, were included in the study. With the advancement of pregnancy, the body weight (BW) of does significantly (P < 0.05) increased (control: 3255 g, day 28: 3938 g), while the dry matter, DM (control: 43.02%, day 28: 40.94%), ether extract, EE (control: 20.15%, day 28: 18.13%), crude protein, CP (control: 20.15%, day 28: 18.13%), and energy concentration decreased (control: 12.41 MJ/kg BW, day 28: 11.81 MJ/kg BW). During pregnancy the protein content of uteri (control: 12.24%, day 28: 49.45% of DM) and the retained energy in the form of uterus with fetuses (day 14: 0.824 MJ, day 28: 2.189 MJ) increased, while the dry matter (control: 82.39%, day 28: 28.96%) and ether extract content (control: 86.05%, day 28: 45.92% of DM) of uteri decreased. With the advancement of pregnancy the dry matter (day 14: 39.70%, day 28: 18.65%) and crude protein (day 14: 75.74%; day 28: 63.63% of DM) content and the number of fetuses (day 14: 8.8; day 28: 6.4) decreased, while their fat concentration (day 14: 10.13%, day 28: 24.34% of DM) increased. According to the equations created from the CT pictures, body fat (R2 = 0.871) and energy (R2 = 0.926) content can be predicted with high accuracy. The accuracy of predicting body protein content is much lower (R2 = 0.356), which can be improved by introducing the body weight as a new dependent variable (R2 = 0.797). It can also be concluded that, in contrast to other animal species, rabbit fetuses show considerable development not only in the last trimester of gestation but already from the second half of pregnancy.

Investigations on the effects of Ca-soap of linseed oil on rumen fermentation in sheep and on milk composition of goats.

Six rumen-cannulated wethers were fed by a diet composed of alfalfa hay and concentrate and supplemented by 75 g Ca-soap of linseed oil (5.4% in dry matter, DM) daily. A model trial was performed to detect the effects of the Ca-soap on rumen fermentation parameters and on fibre digestion. Approximately 3 h after feeding Ca-soap, ratio of C2:C3 decreased (from 4.33 to 4.02) and the production of i- and n-butyrate and i- and n-valeriate increased by 28, 5.3, 11.76% and 6.80% respectively. Total volatile fatty acid concentration in rumen fluid did not change (126.1 vs. 126.4 mm) as a result of Ca-soap supplementation. The in vitro trial showed no detrimental influence of Ca-soap on the acid detergent fibre (ADF) degradation. Using feed samples containing Ca-soap to be incubated in tubes, ADF digestion proved to be significantly higher (p < 0.001). Approximately 14 goats (Saanen breed, 30-70 days in lactation) were used to test the effects of Ca-soap on milk composition. Their ration contained alfalfa hay, millet straw and a concentrate. In the experimental group (seven goats) the diet was supplemented with Ca-soap of linseed oil (75 g/animal/day). The milk composition was changed (slightly reduced solid content, sometimes significantly reduced milk fat contents), when Ca-soap was included in the diet of lactating goats.

Comparison of feed preference and digestion of three different commercial diets for cats and ferrets.

Diet preference and digestibility experiments were conducted using a total of 10 cats and 10 ferrets. The composition of the three different kinds of dry cat feed was as follows (each data are given in dry matter, DM): (i) normal diet (N): 95.3% DM, 33.7% crude protein (CP), 20.4% ether extract (EE), 37.6% nitrogen-free extract (NFE); (ii) 'light diet' (L): 94.2% DM, 31.6% CP, 10.7% EE, 52.2% NFE; (iii) 'veterinary diet' (D): 94.57% DM, 38.7% CP, 9.6% EE, 47.2% NFE. During the period of the preference test, the average daily dry matter intake (calculated with the mean of the three diets: 94.7% DM) was 98.0, 15.0 and 16.7 g DM in cats and 25.0, 7.3 and 8.1 g DM in ferrets. The preference rates of the three different diets, expressed in percentage of their total consumption, were as follows: 60.4% N (54.4 g DM), 12.4% L (12.1 g DM) and 27.2% D (26.6 g DM) in cats, and 46.2% N (11.6 g DM), 29.9% L (7.5 g DM) and 23.9% D (6.0 g DM) in ferrets. This indicates that cats and ferrets have a clear preference for diets of higher fat content. In all three diets, the digestibility of CP was significantly (p < 0.05) lower (70.1 +/- 5.4 vs. 75.9 +/- 5.8) while that of EE was significantly (p < 0.05) higher (95.6 +/- 1.5 vs. 89.4 +/- 5.3) in ferrets than in cats. The average digestible/metabolizable energy (DE/ME) ratio of feeds turned to be 95.6% for cats and 90.6% for the ferrets. From the data one can conclude that the ferret cannot be used as a model animal for cats either for preference or digestibility studies.

Changes in daily energy amounts of main milk components (lactose, protein and fat) during the lactation of high-yielding dairy cows.

The aim of this study was to examine the changes of the daily energy amount of lactose, protein and fat throughout the lactations, and compare them to each other. A total of 309 Israeli Holstein-Friesian cows from one kibbutz were investigated in three lactations, and information was given for a period of five years from 1996 to the end of 2000. The distribution of milk components and milk yield during lactation, and changes of the absolute and relative energy amount in the different milk components were calculated and evaluated. The results showed changes in the energy content of milk and its different components throughout the lactation. Each component (fat, lactose and protein) is dominant in different periods during the lactation. The energy amount from fat reaches a peak first, between days 40 and 50. Lactose has a peak at about day 66 of lactation, and protein reaches the peak last, approximately at day 104 of lactation. It seems that this peak sequence is constant and it is considered to be physiological. It might be suggested that there is a regulation governing the secretion of the different components at different times, and only one component is dominant in a given period. Each component exerts negative and positive influences on the secretion of the other components, which interact with each other and are not fully independent.