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.

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.

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.

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.

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.

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.

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.

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.

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.

Retarded myelination in the lumbar spinal cord of piglets born with spread-leg syndrome.

Piglets born with spread-leg syndrome, a congenital weakness of the hindlimb adductors, were investigated to determine the site of lesion leading to limb impairment. Histological and immunohistochemical studies of the motor neuron unit showed no alterations but quantitative analysis revealed a reduction of axonal diameter and myelin sheath-thickness of the fibres innervating the adductors of the affected limbs. In the lumbar spinal cord a lack of myelination was observed in the tracts descending to the lower motor neurons. Recovery from the syndrome was accompanied by a catching-up of myelination with that of the controls. The spread-leg syndrome is due to a nutritional deficiency in the sow; thus it is assumed that the deficient maternal substances, mainly choline and methionine, are essential for the normal myelin production by spinal white matter oligodendrocytes of the fetus.

A case of bilateral testicular lymphoma.

Authors report on a 75-year-old man with bilateral testicular lymphoma. He complained of painless right testicular enlargement. Orchidectomy was indicated by ultrasound examination and the diagnosis (large cell, non-Hodgkin lymphoma B-cell origin) was established by histology and immunohistochemistry. Two months later, the left testis enlarged, orchidectomy was performed, and a lymphoma with identical histology was found. PET revealed retroperitoneal spread of the tumor. Irradiation (18 Gy) was applied. Three months later, because of gastric metastases of the lymphoma the patient underwent CVP and CAVP (Cyclophosphamide, Adriablastin, Vincristin, Prednisolone) chemotherapy. Despite of the repeated courses, eleven months after the primary diagnosis the patient died due to of multiple metastases.

Bone scanning and radiography in the evaluation of patients with malignant lymphoma.

The diagnostic value of bone scintigraphy and radiography in the detection of lymphomatous bone involvement, and the role of bone scintigraphy in the evaluation of lymphomatous bone marrow involvement, were investigated in 41 patients with malignant lymphoma. 10 patients had lymphomatous bone involvement. Whereas scintigraphy detected all the 10 cases, radiography was false negative in 2 cases. The lytic bone lesions on radiography were in most cases not detected by scintigraphy. Scintigraphy is insensitive for the detection of early bone marrow metastases. The simultaneous use of bone scanning and x-ray, however, seems to be helpful in the detection of lymphomatous bone involvement and consequently in the clinical management of patients with malignant lymphoma.

Sexual dysfunction among patients treated with antidepressants--a Hungarian retrospective study.

The authors have investigated the incidence and several aspects of sexual problems in Hungarian outpatients (N = 637) treated by antidepressive medication. In this multicentre epidemiological survey the sexual dysfunctions (SD) was assessed by psychiatrists using structured interviews. Seventy-eight of the sample has sexual problems, more than half of them mentioned SD after starting antidepressive medication. Comparing various groups of antidepressants, patients taking a RIMA compound reported the occurrence of SD not so often as in TCA or SSRI groups, where the rate of SD was very high. Authors pointed out that physicians have to pay special attention to this problem in everyday clinical practice, since the recognition and treatment of sexual dysfunction is critical for the patient's satisfaction, medication compliance and the quality of life.

Fertile estrus induced in bitches by bromocryptine, a dopamine agonist: a clinical trial.

The dopamine agonist bromocryptine, probably through amplifying gonadotroph (mainly FSH) secretion, was found to be suitable for provoking fertile estrus during the anestrous phase in bitches without functional cycles and/or ovarian activity. We studied estrus induction in 48 bitches after treatment with semisynthetic ergot alkaloid bromocryptine. For habituation a fractional dose of 0.3 mg/bitch was administered for three days followed by larger doses within the range of 0.6 to 2.5 mg/bitch by selecting dose rates on the basis of individual responsiveness and body weight. The long-term daily bromocryptine dose did not exceed 0.6 mg/bitch and 2.5 mg/bitch in small and large sized bitches, respectively. Gradual habituation and individual dose rates have almost completely eliminated the unwanted side effect of emesis. The period between treatment and onset of estrus varied but the average was 19 days. After the onset of estrus bromocryptine administration was usually continued for another 3 to 6 days. Occurrences of estrus, ovulation and pregnancy were monitored by cytological evaluation of vaginal epithelium, rapid ELISA for plasma progesterone and ultrasonography, respectively. Samples for progesterone were taken on Days 7, 9, 12 and 15 and sonograms of ovarian follicles and of fetuses were taken on Days 0, 22 and 35. The bitches involved in the study either regular or irregular cycles. Bromocryptine treatment induced estrus in all of the bitches including 40 of 48 (83%) with ovulation within a regular estrus and 6 of 48 (12.5%) that showed estrus but did not ovulate. Mating or artificial insemination of bitches in their fertile periods twice at two day intervals resulted in an 83% pregnancy rate (40 cases) and 39 (97.5%) of them gave birth to puppies. However, the average litter size was small with 4.8 +/- 1.6 pups.

Ovarian consequences of low dose peroral Fusarium (T-2) toxin in a ewe and heifer model.

The effect of low dose peroral Fusarium produced T-2 toxin intake upon the ovarian function was evaluated in ewes (n = 30; Trial 1) and heifers (n = 7; Trial 2). Half of the ewes and all of the heifers were fed rich, acidosis-inducing concentrate. The 30 ewes were divided into 6 groups of 5 animals each. They were given 0, 0.3 or 0.9 mg/day (0, 5 or 15 ug/kg) purified T-2 toxin per os for 21 days (3x2 factorial design). Four of the 7 heifers were fed 9 mg/day (25 ug/kg) of the same purified T-2 toxin for 20 days while 3 remained untreated. The estrus cycles in all animals were synchronized prior to the trials and the T-2 exposure was started in the mid-luteal phase. The acidic condition in the rumen was estimated by the determination of urinary net acid-base excretion. The ovarian activity was followed with blood sampling for progesterone on alternate days (Trial 1) or with ultrasonography and sampling for progesterone daily (Trial 2). All of the heifers and concentrate-fed ewes showed a compensated acidosis, during first two thirds of T-2 exposure. In Trial 1, ovarian malfunction manifested as lower P4 peak concentration in the midluteal phase, shortening of the CL lifespan and prolonged follicular phases. These malfunctions were detected in 3 and 3 ewes fed concentrate and 0.3 mg and 0.9 mg T-2 toxin. Lower P4 peak concentration was observed in 1 ewe fed regular diet and 0.9 mg T-2 toxin. None of the control and acidotic groups (0 mg T-2), or ewes fed regular diet with 0.3 mg T-2 showed any ovarian malfunction. In Trial 2, after PGF2, administration the ovulation occured later and the plasma progesterone level remained low (< 3 nmol/l) for a longer period in T-2 treated heifers, than their untreated control mates (5.0+/-0.7 vs 3.7+/-0.5 d, P<0.05 and 8.3+/-0.4 vs 6.3+/-0.9 d, P<0.01, respectively). These results show that the peroral T-2 intake can significantly retard the folliculus maturation and ovulation and perhaps the subsequent luteinisation also in ruminants kept on concentrate-rich diet.

Studies on the energy content of pigeon feeds II. Determination of the incorporated energy.

The effect of breed and sex on adult body composition of four pigeon breeds: Texan (TEX), Mondain (MON), Szeged Tumbler (SZT), and homing (HOM) and on the digestibility coefficients (DC) and metabolizable energy (ME) content of their feeds was studied. A total of eight groups, each comprising five males and five females of each breed, were used. All birds were fed the same pelleted pigeon feed (17.27% CP) ad libitum. After the metabolic study, the whole body was analyzed for dry matter (DM), ash, CP, and ether extract (EE) contents. The DC of DM, TEX, MON, and HOM pigeons did not differ significantly, whereas DC for the SZT breed were consistently lower. In the majority of cases, the DC values obtained for males were higher, irrespective of the breed. The body composition of the two sexes was first compared within a given breed, and no major differences were detected. Interbreed differences were greater. The DM content of the body of HOM pigeons exceeded that of the other three breeds for both sexes. For ash and CP content of the body, the reverse was found, i.e., the values of both parameters were lower in HOM pigeons. The HOM pigeons had significantly (P < 0.05) higher body fat (EE) content as compared with the other three breeds except TEX females. The NFE value for HOM also tend to be higher than in the other three breeds.

Studies on the energy content of pigeon feeds I. Determination of digestibility and metabolizable energy content.

The digestibility coefficient and metabolizable energy (ME) content of the most important pigeon feeds (corn, wheat, barley, red and white millet, sorghum, canary seed, peas, lentils, sunflower, and hemp) were determined. The experiment was carried out using 10 adult male homing pigeons. All feeds were fed alone, in a whole-grain form, ad libitum. Drinking water and grit were offered to the birds on a continuous basis. Each feedstuff was fed to five pigeons in 1-wk cycles. There was no significant difference between the values determined in pigeons and those reported in the literature for chickens among the digestibilities of the CP of the various feeds. For pigeons, the digestibility of carbohydrates (N-free extracts, NFE) was lower (e.g., 62.37 vs 83.00% for barley and 63.45 vs 77.00% for peas), whereas the ether extract (EE) was higher (e.g., 75.58 vs 61.00% for barley and 82.59 vs 80.00% for peas) in pigeons compared with chickens. As a result, the AMEn values determined in pigeons did not differ significantly from those reported for chickens but tended to be slightly higher. For feeds of high-oil content, that difference may be somewhat larger. The correlation between the CP, EE, crude fiber (CF), and NFE contents of the feeds and the ME values determined in this experiment were calculated by multivariate linear regression. It was concluded that it was more accurate to determine and tabulate the ME contents of other potential pigeon feeds directly by experimental methods rather than using an equation.

Mass media, cultural attitudes, and suicide. Results of an international comparative study.

Many studies indicate that the suicidal behavior in a society is affected by the suicide stories publicized. Cultural valuations appear in the way media present self-destruction. The reflection of sociocultural attitudes toward suicide can be observed and analyzed in these texts. In this research, reports about suicide (n = 2203) in the years from 1981 and 1991 taken from daily newspapers were gathered--three central and regional papers in each country. A content analysis was performed of the suicide reports in Hungary (n = 244), Japan (n = 684), the United States (n = 265), Germany (former West n = 458, former East n = 60), Austria (n = 405), and Finland (n = 81), on the basis of the following variables: mentioning of the name, personal data, prominence of the suicidal person, qualification of the suicide, methods, motives, positive or negative consequences, alternatives, and the expression(s) used to refer to the act. After a coding process, an analysis was conducted as to whether any significant differences existed in the rate of the several characteristics in the countries from the point of view of the possible imitation-identification and of the cultural differences are the most important findings interpreted.

Animal models in experimental atherosclerosis: a critical review.

The most important features of lipoprotein metabolism are demonstrated and receptor-mediated endocytosis is emphasized. The different lipoprotein makeup of different animal species and humans is shown. The role of fibre, protein and polyunsaturated fatty acids in diet-induced hypercholesterolaemia is evaluated. The criteria of choosing the appropriate animal model for atherosclerosis research are discussed.