Diagnostic performance of a newly developed salivary cortisol and cortisone measurement using an LC-MS/MS method with simple and rapid sample preparation.

BACKGROUND: Late-night salivary cortisol level is one of the first-line tests recommended by the Endocrine Society for the diagnosis of endogenous hypercortisolism. Most routine laboratories measure cortisol levels using immunoassay tests which fail to determine low cortisol levels accurately due to the numerous interfering substances. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with simple and rapid sample preparation was developed for the simultaneous measurement of cortisol and cortisone and its performance in the diagnosis of endogenous hypercortisolism was evaluated. METHODS: 324 late-night saliva samples were analyzed from which 272 samples were derived from patients with a suspected diagnosis of endogenous hypercortisolism. Salivary cortisol levels were assayed using an electrochemiluminescent immunoassay (ECLIA, Cortisol II, Roche), and simultaneous measurement of cortisol and cortisone was performed using an LC-MS/MS method. RESULTS: A strong correlation between cortisol results measured using ECLIA and LC-MS/MS (r 2 = 0.892) was demonstrated. Receiver operating characteristics (ROC) analysis showed good diagnostic performance of cortisol and cortisone levels assayed using LC-MS/MS method and for cortisol measured using ECLIA. CONCLUSIONS: Late-night salivary cortisol and cortisone are useful parameters for the diagnosis of hypercortisolism. Using samples obtained from patients where the diagnosis of hypercortisolism is extremely challenging cut-off values for midnight salivary cortisol and cortisone measured by LC-MS/MS method were established.

Dexamethasone protects from renal ischemia/reperfusion injury: a possible association with SGK-1.

Previous experimental data suggest that steroids might have protective effects during hypoxic/ischemic injury of various organs. In this study, the association between dexamethason (Dexa) treatment and the anti-apoptotic SGK-1 was tested in ischemic renal injury. In vitro, HK-2 cells were exposed to 24 h hypoxia, and the effect of Dexa incubation on SGK-1 expression / activation and on cell death was studied. In an in vivo rat model of unilateral renal IR, animals were treated with Dexa, and serum renal function parameters, tissue injury and SGK-1 expression and localization were examined after different reperfusion times (2 h, 4 h and 24 h). Dexa at a dose of 2 mg/L exerted a protective effect on cell survival assessed by LDH release and vital staining paralleled by marked up-regulation of SGK-1. In rats, 2 mg/kg Dexa treatment 24 h prior to ischemia resulted in less severe tissue injury and ameliorated urea nitrogen levels 24 h after reperfusion. Furthermore, SGK-1 expression and phosphorylation were higher in Dexa animals demonstrated by Western blot and immunofluorescence technique. Our results provide novel data on the signalling mechanism of Dexa under hypoxia / ischemia and further support that Dexa emerges as an attractive pharmacological agent for the prevention of ischemic injury.

First Report of Spot Form of Net Blotch of Barley Caused by Pyrenophora teres f. maculata in Hungary.

A countrywide survey of fungal diseases of barley (Hordeum vulgare L.) was conducted from 2005 to 2009. Unusual leaf necrosis varying in shape from 1 × 2 mm necrotic flecks to 15 × 20 mm ovoid spots was found. Sometimes a chlorotic halo surrounding the dead area was observed. Lesions appeared on various cultivars in many commercial fields and experimental plots at a number of sampling sites. Symptomatic leaves were taken to the laboratory and incubated in a moist chamber at room temperature on the bench to induce sporulation of the pathogen. Conidiophores on the diseased tissues were single or in small groups, dark brown, and bore several hyaline-to-olive brown, almost cylindrical conidia with three to seven pseudosepta. Dimensions of conidia were 75.2 to 100.9 × 16.5 to 18.8 µm. Under a stereo microscope, single conidia were transferred aseptically from the leaves onto potato dextrose agar (PDA) with a sterile needle. Plates were kept in the dark at 20°C for 2 weeks. Cultures were gray to olive green, cottony, and did not form conidia and sexual structures. These characteristics indicated that the pathogens belonged to the genus Pyrenophora. Species identity was confirmed by PCR assays with specific primers developed for the barley pathogenic Pyrenophora spp. (3,4). Of 169 isolates, 41 were identified as P. teres Drechs. f. maculata Smed.-Pet., the spot form of net blotch pathogen (2), and two of them have been deposited at an international culture collection under accession nos. CBS 123929 and CBS 123930. The remaining isolates were either P. graminea or P. teres f. teres, the leaf stripe and net form of net blotch pathogens of barley, respectively. Pathogenicity of four P. teres f. maculata and two P. teres f. teres isolates from different regions was confirmed by Koch's postulates. Each isolate was grown on two 9-cm PDA plates at 22°C in darkness. After 10 days, aerial mycelia were scraped off, blended in 100 ml of sterile distilled water, and filtered through two layers of cheesecloth. Ten seedlings of cv. Botond were sprayed at the two-leaf stage with the mycelium suspension of each isolate and a water control until runoff. Seedlings were kept in a growth chamber at 100% relative humidity and 20°C in the dark for 24 h, then at 70% relative humidity and 24/20°C (day/night) with a 12-h photoperiod. Within 3 weeks, one to four brownish ovoid spots, typical of the spot form of net blotch symptoms, developed on the leaves inoculated with P. teres f. maculata. In contrast, the seedlings inoculated with P. teres f. teres exhibited characteristic net-like lesions, whereas the control plants sprayed with sterile water remained healthy. All strains were reisolated and identified by specific PCRs as described above. To our knowledge, this is the first report of the occurrence of P. teres f. maculata in Hungary. Resistance of barley against P. teres f. maculata and P. teres f. teres is inherited independently (1). Therefore, knowledge regarding the frequency and distribution of these pathogens is important for disease management and resistance breeding. References: (1) O. S. Afanasenko et al. J. Phytopathol. 143:501, 1995. (2) V. Smedegård-Petersen. Page 124 in: R. Vet. Agr. Univ. Yearbook. Copenhagen, 1971. (3) E. J. A. Taylor et al. Plant Pathol. 50:347, 2001. (4) K. J. Williams et al. Australas. Plant Pathol. 30:37, 2001.

Voice quality improvement after management of unilateral vocal cord paralysis with different techniques.

The aim of this study was to objectively evaluate the voices of patients suffering from unilateral vocal cord paralysis, before and after endoscopic augmentation and thyroplasty. In the past, we used injectable Teflon to treat this condition; later techniques included collagen injection and Isshiki thyroplasty. In the last 7 years, preferred treatment methods have included Bioplastique injection and lipoaugmentation of the vocal cords as well as medialization thyroplasty using a titanium implant according to Friedrich. Pre- and postoperative data was evaluated and compared to 25 patients. Appropriate glottic closure of the vocal cords was achieved in every case, in most cases after the first intervention. We used voice range profile measurements to evaluate the results. An objective evaluation was performed using the Friedrich dysphonia index. Significant improvements were found: the dysphonia index decreased in every case, from an average of 2.47, preoperatively, to an average of 1.18 postoperatively. In agreement with earlier studies, voice pitch range was the only parameter that not significantly improved. There was no statistical difference between the lipoaugmentation and thyroplasty according to Friedrich. We concluded that both endoscopic methods and thyroplasty can be used to achieve an optimal result. Cases must be evaluated individually so that the best technique, or combination of methods can be determined.

Positional relationships between photoperiod response QTL and photoreceptor and vernalization genes in barley.

Winterhardiness has three primary components: photoperiod (day length) sensitivity, vernalization response, and low temperature tolerance. Photoperiod and vernalization regulate the vegetative to reproductive phase transition, and photoperiod regulates expression of key vernalization genes. Using two barley mapping populations, we mapped six individual photoperiod response QTL and determined their positional relationship to the phytochrome and cryptochrome photoreceptor gene families and the vernalization regulatory genes HvBM5A, ZCCT-H, and HvVRT-2. Of the six photoreceptors mapped in the current study (HvPhyA and HvPhyB to 4HS, HvPhyC to 5HL, HvCry1a and HvCry2 to 6HS, and HvCry1b to 2HL), only HvPhyC coincided with a photoperiod response QTL. We recently mapped the candidate genes for the 5HL VRN-H1 (HvBM5A) and 4HL VRN-H2 (ZCCT-H) loci, and in this study, we mapped HvVRT-2, the barley TaVRT-2 ortholog (a wheat flowering repressor regulated by vernalization and photoperiod) to 7HS. Each of these three vernalization genes is located in chromosome regions determining small photoperiod response QTL effects. HvBM5A and HvPhyC are closely linked on 5HL and therefore are currently both positional candidates for the same photoperiod effect. The coincidence of photoperiod-responsive vernalization genes with photoperiod QTL suggests vernalization genes should also be considered candidates for photoperiod effects.

The Vrn-H2 locus is a major determinant of flowering time in a facultative x winter growth habit barley (Hordeum vulgare L.) mapping population.

With the aim of dissecting the genetic determinants of flowering time, vernalization response, and photoperiod sensitivity, we mapped the candidate genes for Vrn-H2 and Vrn-H1 in a facultative x winter barley mapping population and determined their relationships with flowering time and vernalization via QTL analysis. The Vrn-H2 candidate ZCCT-H genes were completely missing from the facultative parent and present in the winter barley parent. This gene was the major determinant of flowering time under long photoperiods in controlled environment experiments, irrespective of vernalization, and under spring-sown field experiments. It was the sole determinant of vernalization response, but the effect of the deletion was modulated by photoperiods when the vernalization requirement was fulfilled. There was no effect under short photoperiods. The Vrn-H1 candidate gene (HvBM5A) was mapped based on a microsatellite polymorphism we identified in the promoter of this gene. Otherwise, the HvBM5A alleles for the two parents were identical. Therefore, the significant flowering time QTL effect associated with this locus suggests tight linkage rather than pleiotropy. This QTL effect was smaller in magnitude than those associated with the Vrn-H2 locus and was significant in two-way interactions with Vrn-H2. The Vrn-H1 locus had no effect on vernalization response. Our results support the Vrn-H2/Vrn-H1 repressor/structural gene model for vernalization response in barley and suggest that photoperiod may also affect the Vrn genes or tightly linked loci.

Spasmodic dysphonia combined with insufficient glottic closure by phonation.

The authors describe the case history of a patient who suffered from symptoms deriving from two different origins. The patient's voice was spasmodic dysphonia-like interrupted and pressed. At the same time, his voice was powerless, too. The reason for this was that besides the spasmodic dysphonia caused by hyperkinesis, an incomplete closure of the vocal cords during phonation in the middle third was present. It was caused by the atrophy of the vocal cords. In order to eliminate the symptoms, initially we injected 25 IU Botox into the left vocal cord transcutaneously under the direction of EMG control. It resulted in a fluent, though breathy voice. In order to manage the closing insufficiency during phonation, we performed lipoaugmentation on the left vocal cord under high-frequency jet anaesthesia. The result of the two-step procedure was a fluent and clear voice. The speech without interruption lasted for 5 months, until the drug was eliminated. Of course, to prolong the result, the Botox injection should be repeated.

Core heritable personality characteristics and relapse in alcoholics.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were David S. Janowsky and Jan Fawcett. The presentations were (1) The tridimensional personality questionnaire: Predictor of relapse in detoxified alcoholics, by Kurt Meszaros; (2) Novelty seeking predicts clinical trial attrition in alcoholics, by Jan Fawcett; (3) Personality and alcohol/substance use disorder patient relapse and attendance at self-help group meetings, by David S. Janowsky; and (4) A three-pathway psychobiological model for craving for alcohol, by Roel Verheul.

Neurodevelopmental schizophrenia: obstetric complications, birth weight, premorbid social withdrawal and learning disabilities.

Neurodevelopmental schizophrenia seems to be caused by impaired cerebral development and is supposed to be associated with obstetric complications (OCs), poor premorbid adjustment, schizotypal or schizoid personality traits and negative symptoms. In the present study, 36 schizophrenic and schizoaffective patients and their same-sex, healthy siblings were recruited. They were diagnosed according to DSM-III-R, using structured psychiatric interviews and a consensus of 2 psychiatrists. Information on OCs, birth weight, premorbid social and learning functioning was obtained from their mothers. The main results show significant differences in OCs, birth weight, premorbid social and learning functioning between patients and their same-sex, healthy siblings. Using multivariate analyses, both premorbid variables were again identified to discriminate well between affected and unaffected siblings. Our findings seem to confirm the concept of schizophrenia as a neurodevelopmental process.

Genome scan for susceptibility loci for schizophrenia.

OBJECTIVE: Schizophrenia is a relatively common, often chronic and debilitating mental illness. Evidence from various studies has clearly demonstrated that genetic factors contribute substantially to the etiology. The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. METHODS: A genome-wide map of 388 microsatellite DNA markers was genotyped in 5 schizophrenia families. Nonparametric linkage analysis (Genehunter) was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. RESULTS: Nonparametric linkage scores did not reach a genome-wide level of statistical significance (p < 0.00002) or a p value suggestive of linkage (p < 0.007) for any marker; however, one p value suggested replicated linkage (p < 0.01) at chromosome 6p24 in region D6S309 (p = 0.0047). Furthermore, 11 markers resulted in p < 0.05 at chromosomes 6p, 6q, 10q, 12q and 14q. CONCLUSIONS: Despite the differences in diagnostic schemes, in markers used and methods of analyses between studies published so far, we think that our result supports the notion that there is possibly some consistent evidence for replicated linkage of a schizophrenia susceptibility locus around the region of D6S309 at chromosome 6p24.

Association studies of candidate genes in bipolar disorders.

The aim of the investigation was to test genes for predisposition to bipolar affective disorder. Therefore, we studied candidate genes in a sample of unrelated patients (n = 102) and healthy controls (n = 79) of Austrian origin, searching for a possible association between polymorphic DNA markers of 5 candidate genes (serotonin transporter, 5-HTT; serotonin 2a receptor, 5-HT2a; dopamine D2 receptor, DRD2; dopamine D3 receptor, DRD3; dopamine transporter, DAT1) and bipolar disorder. There was an association between allelic and genotypic frequencies of 5-HTT and affection status (p = 0.014 and p = 0.017, respectively). However, after correction for multiple comparisons (Bonferroni), these results did not remain significant. Nevertheless, the findings might suggest that alterations in the structure of 5-HTT are involved in the pathogenesis of bipolar disorder, which could have major implications in treatment. No association between 5-HT2a, DRD2, DRD3, DAT1 and bipolar disorder was found.

A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat.

This study was initiated to develop an animal model of type 2 diabetes in a non-obese, outbred rat strain that replicates the natural history and metabolic characteristics of the human syndrome and is suitable for pharmaceutical research. Male Sprague-Dawley rats (n = 31), 7 weeks old, were fed normal chow (12% of calories as fat), or high-fat diet (40% of calories as fat) for 2 weeks and then injected with streptozotocin (STZ, 50 mg/kg intravenously). Before STZ injection, fat-fed rats had similar glucose concentrations to chow-fed rats, but significantly higher insulin, free fatty acid (FFA), and triglyceride (TG) concentrations (P < .01 to .0001). Plasma insulin concentrations in response to oral glucose (2 g/kg) were increased 2-fold by fat feeding (P < .01), and adipocyte glucose clearance under maximal insulin stimulation was significantly reduced (P < .001), suggesting that fat feeding induced insulin resistance. STZ injection increased glucose (P < .05), insulin (P < .05), FFA (P < .05), and TG (P < .0001) concentrations in fat-fed rats (Fat-fed/STZ rats) compared with chow-fed, STZ-injected rats (Chow-fed/STZ rats). Fat-fed/STZ rats were not insulin deficient compared with normal chow-fed rats, but had hyperglycemia and a somewhat higher insulin response to an oral glucose challenge (both P < .05). In addition, insulin-stimulated adipocyte glucose clearance was reduced in Fat-fed/STZ rats compared with both chow-fed and Chow-fed/STZ rats (P < .001). Finally, Fat-fed/STZ rats were sensitive to the glucose lowering effects of metformin and troglitazone. In conclusion, Fat-fed/STZ rats provide a novel animal model for type 2 diabetes, simulates the human syndrome, and is suitable for the testing of antidiabetic compounds.

Association study of schizophrenia spectrum disorders and dopamine D3 receptor gene: is schizoaffective disorder special?

Alterations in dopamine neurotransmission have been hypothesized to play a role in the etiology of schizophrenia. We considered the dopamine D3 receptor gene on chromosome 3 as a candidate gene for an association analysis. We compared PCR-based genotype markers for healthy controls (n=120) and patients (n=95) with schizophrenia and schizophrenia spectrum disorders as diagnosed by consensus according to DSM-III-R. Our results possibly indicate an association of schizoaffective disorder with DRD3 homozygosity (P=0.056).

Chronic overexpression of membrane-bound flt3 ligand by T lymphocytes in severe aplastic anaemia.

Aplastic anaemia (AA) is an immune-mediated bone marrow failure associated with high serum levels of flt3 ligand (FL). We examined expression of the membrane-bound isoform of FL in peripheral blood and bone marrow cells from AA patients at diagnosis (n = 16) and after immunosuppressive (IS) treatment (n = 36). Flow cytometry demonstrated strongly increased FL levels on the cell surface of T lymphocytes in AA relative to normal controls (P < 0.0001). T-cell-specific expression of membrane-bound FL was confirmed by confocal microscopy. FL mRNA and total cellular FL protein levels were increased about threefold. Overexpression of FL in AA was observed for up to 20 years after IS treatment. FL levels correlated inversely with CD34+ cell numbers and the colony-forming ability of AA bone marrow (R = -0.68 and -0.85 respectively). Histological examination of spleen specimens and bone marrow biopsies gave no evidence of degeneration or fibrosis due to prolonged exposure to high FL. Levels of membrane-bound FL were not increased in autoimmune diseases (n = 23), including rheumatoid arthritis and lupus erythematosus, nor in graft-versus-host disease (n = 8). Chronic overexpression of FL on the surface of T lymphocytes in AA, but not in other T-cell-mediated disorders, suggests that membrane-bound FL plays a role in cell-cell interactions in bone marrow failure and may be important for long-term haemopoietic recovery.

Extended suicide attempt: psychopathology, personality and risk factors.

Delinquency among depressed patients plays a minor role in criminal behavior. Among the most tragic associations between depression and criminality are cases of extended suicide or suicide attempt. We studied psychopathology, personality, and psychosocial stressors of 9 Austrian females who committed a serious extended suicide attempt. They were admitted for treatment at a special department of the Justizanstalt Wien-Josefstadt, Aussenstelle Wilhelmshöhe. Patients were diagnosed according to ICD-10 as severely depressed with (n = 6) or without (n = 3) psychotic features. After stabilization we diagnosed the following personality disorders: anxious-avoidant (n = 5), paranoid (n = 1), combined (n = 1) and borderline type (n = 1). Traits of the typus melancholicus were found in 5 patients. Seven females were pretreated before the offence by a psychiatrist or a psychologist; 4 of them had committed at least one suicide attempt in the past. Main psychosocial stressors mentioned by patients in the context of the offence were overstrain, marital and/or financial problems. One female killed her child under the influence of acoustic hallucinations. Patients with traits of the melancholic type showed an altruistic and hypernomic motive for killing as well as a psychotic identification with the victim, whereas in the other cases egocentric motives were in the forefront. Potential risk factors for an extended suicide attempt will be discussed.

Efficacy of fluoxetine in Austrian patients with obsessive-compulsive disorder.

In an 8-week double-blind placebo-controlled trial we studied the efficacy of fluoxetine (FLX) in 53 Austrian patients with obsessive compulsive disorder (OCD) diagnosed according to DSM-III-R. The dosage of FLX was fixed at either 20, 40, or 60 mg per day. Response was prospectively defined as an at least 25% reduction on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and an improvement on Clinical Global Impression (CGI) rating to at least "much improved" at the endpoint. Patients treated with at least 40 mg FLX per day showed significantly higher response rates than did those receiving either placebo or FLX 20 mg/day. Compulsions were more reduced than obsessions and we also observed a strong placebo effect which is largely attributable to an improvement in the Y-BOCS compulsion subscore.

The Tridimensional Personality Questionnaire as a predictor of relapse in detoxified alcohol dependents. The European Fluvoxamine in Alcoholism Study Group.

Personality traits have been found as strong predictors for treatment response in different psychiatric disorders. We administered the Tridimensional Personality Questionnaire, which measures the three personality dimensions: novelty seeking, harm avoidance (HA), and reward dependence, as introduced by Cloninger in a multicenter study (11 centers in the United Kingdom, Eire, Switzerland, and Austria) with detoxified alcohol-dependent patients (n = 521). The objective of this study was to evaluate a possible predictive value of these three dimensions on relapse over 1 -year follow up. A logistic regression analysis showed that novelty seeking is a strong predictor for relapse in detoxified male alcoholics (p = 0.0007; p values adjusted for treatment), but not in females. In both sexes, HA and reward dependence were of no predictive value. However, we found a trend for significance of HA for predicting "early" relapse (4 weeks) in females (p = 0.074). Our results show that Tridimensional Personality Questionnaire personality traits have direct clinical applications for prediction of relapse in detoxified alcohol dependents and indicate the necessity of additional therapeutic treatment in risk groups.

Anticipation in schizophrenia.

In various genetic disorders it has been observed that the severity of illness increases and the age at onset decreases in successive generations. This phenomenon is termed anticipation. We sampled 15 families, totalling 123 individuals with at least one person affected by a disease of the schizophrenia spectrum in the index generation in each family (IG; n = 33 affected out of a total of 67 individuals) and in the parental generation (PG; n = 16 affected out of a total of 56 individuals). The pedigrees had originally been identified for linkage studies in schizophrenia. We found a significant difference between IG and PG regarding severity of illness as defined by Kendler et al's hierarchical model of categories of the schizophrenia spectrum (p = 0.001). Age at onset was significantly earlier in the IG (21.6 +/- 6.6 years) than in the PG (40.2 +/- 9.2 years) (p = 0.0001). We excluded a potential birth cohort effect by investigating a control sample consisting of two non-overlapping birth cohorts of patients with schizophrenia. Age at onset between the two groups of the control sample did not differ. Anticipation is an important aspect in the investigation of a possible genetic basis, at least for the familial form of schizophrenia. Active research on a molecular level with special emphasis on trinucleotide repeats might be able to shed further light on this phenomenon.

Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of Type II diabetes.

Extracts of the creosote bush (Larrea tridentata, family Zygophyllaceae) have long been used as a folk remedy for Type II (non-insulin-dependent) diabetes by native Americans in southwestern North America. In this study we have evaluated the metabolic effects of masoprocol, a pure compound isolated from the creosote bush, in a rat model of Type II diabetes. Animals were fed a 20% fat (by weight) diet for 2 weeks prior to intravenous injection with streptozotocin (STZ, 0.19 mmol/kg). Diabetic animals (glucose 16-33 mmol/l) were treated with vehicle, metformin (0.83 mmol/kg body weight) or masoprocol (0.83 mmol/kg body weight) twice a day for 4 days. Masoprocol treatment lowered glucose concentrations an average of 35% compared with vehicle (14.2+/-1.1 vs 21.7+/-1.0 mmol/l, p < 0.001), a reduction similar to metformin treatment (12.8+/-0.9 mmol/l), without any change in insulin concentration. Masoprocol treatment also lowered triglyceride concentrations 80% compared with vehicle (1.0+/-0.1 vs 4.8+/-0.3 mmol/l, p < 0.001), a reduction far greater than following metformin treatment (3.6+/-0.3 mmol/l). Non-esterified fatty acid and glycerol concentration were decreased by approximately 65% by masoprocol compared with vehicle, a reduction approximately twice as great as seen with metformin (p < 0.001). The effect of masoprocol on in vivo insulin-mediated glucose disposal was evaluated by infusing fat-fed/STZ rats with glucose (0.22 mmol kg x min(-1)) and insulin (30 pmol x kg x min(-1)) for 5 h. In response to the infusion, steady-state plasma glucose concentrations were reduced 30% in masoprocol-treated animals compared with vehicle controls (p < 0.05) with no change noted in rats treated with metformin. The effect of masoprocol treatment was also tested in primary adipocytes isolated from normal animals. Adipocytes treated with masoprocol (30 micromol/l) had higher basal and insulin-stimulated glucose clearance than did adipocytes treated with vehicle (p <0.05). These data show that masoprocol decreases both plasma glucose and triglyceride concentrations in fat-fed/STZ rats, presumably as a result of its ability to both increase glucose disposal and decrease lipolysis.

Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia.

In the present study, the occurrence of tardive dyskinesia (TD) in chronic schizophrenia patients was investigated in relation to pharmacogenetic polymorphisms. It is known that the metabolism of important neuroleptic drugs is influenced by polymorphisms of the CYP2D6 gene, which encodes the cytochrome P450 enzyme debrisoquine/spartein hydroxylase. Forty-five patients meeting the DSM IV criteria for schizophrenia, chronic course, were recruited. The patients were examined for the mutations CYP2D6*3, CYP2D6*4 and CYP2D6*5. The CYP2D6 genotype distribution in the patient group did not differ from that in healthy Caucasian populations. Tardive dyskinesia was found in 26 patients (57.8%). When comparing patients without CYP2D6 mutations with patients heterozygous for one mutation, we found a higher incidence of TD in the latter (81.3% vs. 46.4%, p = 0.031, multiple regression analysis), which demonstrates a significant influence of the CYP2D6 genotype of the manifestation of TD. As slight differences in the metabolism of drugs in patients heterozygous for CYP2D6 mutations and patients without such mutations are known, we conclude that heterozygous carriers of 2D6 mutated alleles may show an increased susceptibility to developing TD.