Presence of cyclophilin A in synovial fluids of patients with rheumatoid arthritis.

Cyclophilins have been suggested to act as leukocyte chemotactic factors produced in the course of inflammation. Therefore we looked for the presence of cyclophilins in the synovial fluids (SF) from patients with rheumatoid arthritis (RA). Peptidyl prolyl cis-trans isomerase activity (PPIase) was measured in SF from knee punctures of 26 patients with RA and five patients with knee osteoarthritis (OA). PPIase was detected in SF from RA patients, but not in samples from OA patients. Enzyme activity was sensitive to inhibition by cyclosporin A (IC50 = 28-50 nM). Estimated concentrations of the SF-derived cyclophilin based on the enzyme activity were in the range of 11 to 705 nM. The presence of cyclophilin in the SF showed disease correlation; its concentration correlated with the number of cells in the SF (r = 0.91, P < 0.0001) and with the percentage of neutrophils in the cellular infiltrate and was higher in more acute cases of joint swelling. In immunoblots of partially purified preparations of SF from RA patients, an approximately 18-kD protein band reacted with polyclonal antibodies that recognize cyclophilin A and B, but not with antibodies specific for cyclophilin B. Sequencing of this protein revealed identity of the NH2-terminal amino acids with those of human cyclophilin A. The finding is unexpected since cyclophilin B rather than A is generally regarded as the secreted isoform, the presence of cyclophilin A being confined to the cytoplasm. Our data support the hypothesis that cyclophilins may contribute to the pathogenesis of inflammatory diseases, possibly by acting as cytokines. This may offer a possible explanation of the effectiveness of cyclosporin A in RA, in addition to the known immunosuppressive effects of the drug.

Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation.

Expression of human immunodeficiency virus type 1 (HIV-1) structural proteins requires the presence of the viral trans-activator protein Rev. Rev is localized in the nucleus and binds specifically to the Rev response element (RRE) sequence in viral RNA. Furthermore, the interaction of the Rev activation domain with a cellular cofactor is essential for Rev function in vivo. Using cross-linking experiments and Biospecific Interaction Analysis (BIA) we identify eukaryotic initiation factor 5A (eIF-5A) as a cellular factor binding specifically to the HIV-1 Rev activation domain. Indirect immunofluorescence studies demonstrate that a significant fraction of eIF-5A localizes to the nucleus. We also provide evidence that Rev transactivation is functionally mediated by eIF-5A in Xenopus oocytes. Furthermore, we are able to block Rev function in mammalian cells by antisense inhibition of eIF-5A gene expression. Thus, regulation of HIV-1 gene expression by Rev involves the targeting of RRE-containing RNA to components of the cellular translation initiation complex.

Structure, antigenic determinants of some clinically important insect allergens: chironomid hemoglobins.

Determination of the molecular structure and properties of allergens that elicit severe immediate-type hypersensitivity diseases in humans and a knowledge of the structure of their antibody-binding sites should provide new insight into the pathogenetic mechanisms of allergic diseases. Monomeric and homodimeric hemoglobins (CTT I to X) have been identified as potent allergenic components of Chironomidae, a family of Diptera. Immunologic investigations of peptides of three of these hemoglobins (CTT IV, CTT VI, and CTT VIII) showed that human antibodies of the E and G classes recognize at least two different sites within each molecule. Individual hemoglobin peptides were aligned with homologous regions of chironomid hemoglobin CTT III, whose tertiary structure has been determined by x-ray analysis at a resolution of 1.4 angstroms. The antigenic site CTT IV(91 to 101) showed the following characteristics: (i) seven polar or hydroxylated amino acids, from a total of eleven, occupying predominantly superficial regions; (ii) the property of linkage to other molecules by hydrogen bonds or solvent clusters; and (iii) high thermal mobility factors. In contrast, peptide CTT IV(102 to 108), which does not bind human antibodies, contained no polar amino acids and had low thermal mobility factors. These results support the idea that the antigenicity of clinically relevant proteins is related to regions with a predominance of polar amino acids and with low energy barriers between different conformations, which allow high flexibility, including site-specific adaptation in antibody binding.

Quetiapine in combination with citalopram in patients with unipolar psychotic depression.

This 6-week, open-label, multicenter study evaluated the efficacy and safety of quetiapine in combination with citalopram in adult patients (n=25) with ICD-10/DSM-IV unipolar psychotic depression. The primary endpoint was change from baseline to Week 6 in the Hamilton Depression Rating Scale (HAM-D-21) score. Secondary endpoints were change from baseline to Week 6 in the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale scores. Spontaneously reported adverse events (AEs), the Simpson Angus Scale (SAS), and the Udvalg for Kliniske Undersogelser (UKU) side effects rating scale scores were recorded. Patients' average age was 51.4 years and baseline weight was 72.6 kg. Quetiapine (50-750 mg/day, mean dose+/-SD: 303+/-118 mg/day), in combination with citalopram (20-60 mg/day, mean dose+/-SD: 34+/-12 mg/day), provided significant improvements in depression. Mean (+/- SD) HAM-D-21 was reduced to 13.25+/-10.87 at Week 6 from a baseline value of 31.21+/-5.18. Significant improvement of psychotic symptoms (mean+/-SD) was indicated by the decrease from baseline (59.25+/-6.60) to Week 6 (35.25+/-15.60) in BPRS scores. No serious AEs occurred. The mean change in weight was +2.1 kg. Mean (+/- SD) weight at visit 1 was 72.72 (+/-16.34) kg and mean (SD) weight at visit 4 was 74.79 (+/-18.69) kg. Quetiapine in combination with citalopram appears to be effective and is well tolerated in the treatment of unipolar psychotic depression. Further studies of larger, double-blind, parallel-group design are warranted to confirm these findings.

Pimecrolimus and tacrolimus differ in their inhibition of lymphocyte activation during the sensitization phase of contact hypersensitivity.

BACKGROUND: As reported previously, oral administration of the calcineurin inhibitors (CNI) pimecrolimus and tacrolimus resulted in equipotent inhibition of the elicitation phase of contact hypersensitivity (CHS) in mice. The sensitization phase was inhibited by tacrolimus but was unaffected by pimecrolimus, even at higher doses. OBJECTIVE: The kinetics of lymph node hyperplasia and up-regulation of T and B cell activation antigens were analyzed to obtain a better understanding of the divergent CNI profile in CHS. METHODS: Lymph node (LN) cells of CNI-untreated and treated mice were examined with flow cytometry at various time points after sensitization with oxazolone. LN hyperplasia and drug levels were also determined. RESULTS: Sensitization induced a higher portion of LN cells expressing the activation antigens CD25, CD69 and CD134 and an increase in activated B cells (B220(+)/CD40(+)) compared to naïve mice. Up-regulation of these markers was completely or profoundly blocked with tacrolimus, whereas pimecrolimus at the three-fold higher dose caused significantly less inhibition. Tacrolimus also completely blocked the sensitization-associated increase of CD11c(+) antigen presenting cells (APC) in LN, whereas pimecrolimus showed significantly less inhibition. In contrast to tacrolimus, LN weight and cellularity were not affected by pimecrolimus at any time point after sensitization. Concentration of tacrolimus in blood and in the draining LN substantially exceeded that of pimecrolimus by factors 6.7-14 and 5.6-5.8, respectively, at the same dose levels. CONCLUSION: In contrast to tacrolimus, systemic treatment of mice with pimecrolimus only weakly interferes with lymphocyte activation and does not affect hyperplasia of the draining lymph nodes during sensitization.

Response of thyrotropin to thyrotropin-releasing hormone as predictor of treatment outcome. Prediction of recovery and relapse in treatment with antidepressants and neuroleptics.

We determined whether the response of thyrotropin (TSH) to thyrotropin-releasing hormone could predict the outcome of treatment with antidepressant and neuroleptic drugs. We studied 114 female patients diagnosed as having major and minor depressive, manic, schizoaffective, and schizophrenic disorders. A blunted TSH response (less than 5 microU/mL [less than 5 mU/L]) at admission was associated with recovery after nine weeks of inpatient treatment using clomipramine hydrochloride for depression and haloperidol for psychosis. A blunted TSH response at discharge was associated with early relapse in depressives receiving clomipramine maintenance therapy. Our findings support the notion that the thyrotropin-releasing hormone test is a "state" marker that may be of use in predicting the outcome of treatment with antidepressant and neuroleptic drugs.

No association of clock gene T3111C polymorphism and affective disorders.

CLOCK was hypothesised to be related to susceptibility of affective disorders. To test subsamples of affectively disordered patients, we examined age of onset (AoO), numbers of episodes and melancholic type of clinical manifestation. Using PCR and RFLP, we investigated in patients with unipolar depression and bipolar disorder (BP) whether the CLOCK T3111C SNP is associated with affective disorders (n=102) compared to healthy controls (n=103). No differences were found either in genotype or allele frequency distributions of T3111C polymorphism between patients compared to healthy controls (p>0.2). No deviations from Hardy-Weinberg Equilibrium (HWE) were detected either in patients, or healthy controls. Results suggest that there is no association between the T3111C SNP and affective disorders in general. Data of our sample replicate prior findings of Desan et al. [Am. J. Med. Genet. 12 (2000) 418]. Subsamples of patients with high numbers of affective episodes did show some deviations in genotypes (p=0.0585).

Expression of epidermal keratins and the cornified envelope protein involucrin is influenced by permeability barrier disruption.

In previous studies we have shown that experimental permeability barrier disruption leads to an increase in epidermal lipid and DNA synthesis. Here we investigate whether barrier disruption also influences keratins and cornified envelope proteins as major structural keratinocyte proteins. Cutaneous barrier disruption was achieved in hairless mouse skin by treatments with acetone +/- occlusion, sodium dodecyl sulfate, or tape-stripping. As a chronic model for barrier disruption, we used essential fatty acid deficient mice. Epidermal keratins were determined by one- and two-dimensional gel electrophoresis, immunoblots, and anti-keratin antibodies in biopsy samples. In addition, the expression of the cornified envelope proteins loricrin and involucrin after barrier disruption was determined by specific antibodies in human skin. Acute as well as chronic barrier disruption resulted in the induction of the expression of keratins K6, K16, and K17. Occlusion after acute disruption led to a slight reduction of keratin K6 and K16 expression. Expression of basal keratins K5 and K14 was reduced after both methods of barrier disruption. Suprabasal keratin K10 expression was increased after acute barrier disruption and K1 as well as K10 expression was increased after chronic barrier disruption. Loricrin expression in mouse and in human skin was unchanged after barrier disruption. In contrast, involucrin expression, which was restricted to the granular and upper spinous layers in normal human skin, showed an extension to the lower spinous layers 24 h after acetone treatment. In summary, our results document that acute or chronic barrier disruption leads to expression of keratins K6, K16, and K17 and to a premature expression of involucrin. We suggest that the coordinated regulation of lipid, DNA, keratin, and involucrin synthesis is critical for epidermal permeability barrier function.

Possible association between childhood absence epilepsy and the gene encoding GABRB3.

BACKGROUND: Childhood Absence Epilepsy (CAE) is considered to have a predominantly, perhaps exclusively, genetic background. To date, genes responsible for susceptibility to CAE have not been identified. The object of the present study was to test association between CAE and the genes encoding the gamma-aminobutyric acid (GABA) type-A receptor subunits alpha 5 (GABRA5) and beta 3 (GABRB3) located on the long arm of chromosome 15 (15q11-q13). METHODS: A family-based candidate gene approach was applied: 50 Austrian nuclear families ascertained for the presence of an affected child were investigated. GABRA5 and GABRB3 subunit genes were genotyped using DNA gained from peripheral blood samples by Polymerase Chain Reactions (PCR). Genetic association was tested using a Monte Carlo Version of the multi-allele Transmission-Disequilibrium Test (TDT). RESULTS: The TDT displayed significant overall association with GABRB3 (p = .0118). CONCLUSIONS: The present data suggest that the tested polymorphism may be either directly involved in the etiology of CAE or in linkage disequilibrium with disease-predisposing sites.

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism.

BACKGROUND: A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS: SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS: Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS: Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.

The membrane-proximal part of FcepsilonRIalpha contributes to human IgE and antibody binding--implications for a general structural motif in Fc receptors.

The high affinity receptor for human IgE (FcepsilonRI) on tissue mast cells and blood basophils is responsible for immediate hypersensitivity reactions. Binding of human IgE (hIgE) to FcepsilonRI has been shown to be mediated via three independent regions in the extracellular part of the alpha-subunit of FcepsilonRI (ecFcepsilonRIalpha). By site-directed mutagenesis we investigated the contribution of amino acids within the ecFcepsilonRIalpha FG loop (residues Lys154-Leu165) to binding to hIgE and two monoclonal anti-FcepsilonRIalpha antibodies (15/1, 5H5/F8). The mutated receptors were expressed and secreted from eukaryotic cells as amino-terminal fusion to HSA. We show that the proposed loop region contributes partly to hIgE binding and that the epitope of mAb 15/1, which inhibits hIgE/FcepsilonRIalpha interaction, maps to this region whereby a single W156A mutation results in complete loss of mAb 15/1 binding. In contrast, hIgE binding is not affected by the W156A mutation indicating that different amino acid residues within the loop are recognized by the mAbs 15/1 and hIgE. MAb 5H5/F8 does not recognize a receptor mutant truncated to Ile170. By screening a random dodecapeptide library displayed on bacterial flagella the epitope for mAb 5H5/F8 was mapped to P173REKY177 whereas one of the 15/1 binding clones displayed a peptide with an amino acid sequence homologous to Leu158-lle167. Based on the epitopes identified for the inhibitory mAb 15/1 and the non-inhibitory mAb 5H5F8 and on binding data obtained with polyclonal antisera raised against two ecFcepsilonRIalpha peptides, we propose a structural element in the membrane proximal part of ecFcepsilonRIalpha which forms a 3D structure which might facilitate specific and efficient attachment of hIgE.

The soluble hyaluronidase from bull testes is a fragment of the membrane-bound PH-20 enzyme.

The membrane-bound PH-20 hyaluronidase is known to be essential for fertilization. Here we addressed the question whether the soluble hyaluronidase from bull teste is related to the PH-20 polypeptide. The sequence of the membrane-bound PH-20 hyaluronidase from bovine sperm was determined via cDNA cloning. In parallel, from a commercial preparation of bovine hyaluronidase the major 60-kDa form was purified to apparent homogeneity. The soluble enzyme was digested with two different proteases and with cyanogen bromide and the amino acid sequence of 44 different fragments was determined. All the peptide sequences could be aligned to the sequence deduced from the cloned cDNAs. Our results thus show that the soluble 60-kDa hyaluronidase from bovine testes is a glycoprotein derived from the sperm PH-20 enzyme. As compared to the primary translation product of the PH-20 mRNA, it lacks the signal peptide at the amino terminus and 56 amino acids at the carboxyl end. These results demonstrate that the soluble 60-kDa enzyme is a fragment of the PH-20 hyaluronidase. It is currently not known whether the soluble testes hyaluronidase has a distinct biological function.

Purification, crystallization and preliminary X-ray diffraction analysis of recombinant human neutrophil-activating peptide 2 (rhNAP-2).

The potent activator and chemoattractant for human neutrophils, neutrophil-activating peptide 2 (NAP-2), has been cloned and expressed in Escherichia coli. The protein has been purified to homogeneity (> 98%) by a series of chromatographic techniques, including reversed phase HPLC. The biological activity of recombinant human NAP-2 (rhNAP-2), characterized by the induction of elastase release from human neutrophils, was found to be comparable to natural NAP-2. rhNAP-2 has been crystallized by the hanging drop vapor diffusion method. The crystals belong to space group P222 with unit cell dimensions of a = 30.8 A, b = 39.5 A and c = 95.3 A. A packing density of 3.8 A3/Da with a solvent content of approximately 68% is obtained when one molecule per asymmetric unit is assumed. The crystals were shown to diffract to beyond 2.0 A on a conventional X-ray source. They are stable to X-rays for several days and are thus suitable for high resolution structure determination.

Lytic effector cell function in schizophrenia and depression.

Natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) were tested in patients with schizophrenia or depression. It was found that NK activity as well as ADCC were significantly lower in both groups, as compared to healthy control individuals (P less than 0.001). Psychopharmacologic treatment with neuroleptics and antidepressives resulted in a significant increase in NK activity and ADCC (P less than 0.005) in patients with schizophrenia but not in treated patients with depression. In patients with schizophrenia, no correlation could be established between the dose of neuroleptic given and the increase in NK activity. Lithium also did not produce an increase in NK activity and ADCC. The addition of serum, derived from untreated patients with schizophrenia, to cell cultures in concentrations of 10 and 20% had an inhibitory effect upon the ADCC and, to a lesser degree, upon NK activity (20% serum concentration only); sera from treatment schizophrenics produced no inhibition of NK activity, but did affect ADCC. No serum-derived inhibitory effect upon either NK activity or ADCC was found to be present in sera from patients with depression. We conclude that lytic effector mechanisms are impaired in patients with schizophrenia or depression and that this defect is reversed in schizophrenic patients on treatment, but not in depressives on therapy. Patients with schizophrenia also tend to have a reversible serum-mediated inhibition of NK activity which is absent in patients with depression.

Lytic effector cell activity and major depressive disorder in patients with breast cancer: a prospective study.

The study examined lymphokine-activated killer cell (LAK) and natural killer (NK) cell activity in breast cancer patients prior to surgery as compared to effector cell lysis in patients with non-malignant breast tumors, further in connection with lifetime diagnosis of major depression, severity of current depression, anxiety and coping styles. Follow up studies covered a period of 6 and 12 months. Prior to surgery, life time diagnosis of major depressive disorder, trait anxiety and coping styles did not discriminate patients as far as effector cell lysis is concerned. LAK activity but not NK activity was reduced in patients with actual depressive symptoms (P < 0.01) and high state anxiety (P < 0.05). These findings support the hypothesis that LAK activity is a state marker of actually existing depression and anxiety prior to surgery. Affective rather than coping measures showed significant differences in LAK activity. For LAK activity, 1 year after surgery the only predicting factors were Tamoxifen therapy and chemotherapy.

No evidence for a schizophrenia susceptibility gene in the vicinity of IL2RB on chromosome 22.

Pulver et al. [1994a] reported modest linkage evidence for a dominantly (D) inherited "schizophrenia gene" in the vicinity of IL2RB on chromosome 22q12, and Coon et al. [1994] adduced moderate evidence under a recessive (R) model. We report here a replication study to test the hypothesis that one of these two models (or a third, intermediate (I) model) adequately describes the co-segregation of schizophrenia and chromosome 22q12 markers in an independent sample of 23 multiplex families. Altogether nine transmission models were evaluated. The models differed depending on whether the 15 family members with a diagnosis of schizophrenia spectrum disorders were considered unaffected (a "narrow" (N) definition), affected (a "wide" (W) definition), or declared "unknown" (U). The entire region between D22S268 and D22S307 is excluded (i.e., lod <-2) for models RN, RW, RU, and IW. Lod scores for the remaining models are uniformly negative; albeit, equivocal with respect to the dominant hypothesis over a small region between D22S268 and IL2RB. Nonparametric analysis under both diagnostic criteria also failed to yield any evidence for a susceptibility locus in this region of chromosome 22.

European Multicentre Association Study of Schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms.

As part of the European Multicentre Association Study of Schizophrenia (EMASS), we studied polymorphisms in the dopamine DRD2 and DRD3 receptor genes. The EMASS collaboration was established to create a large, statistically powerful sample of schizophrenic patients and controls from different European centres. Previous studies have suggested associations between schizophrenia and the Ser311Cys polymorphism in exon 7 of the dopamine DRD2 receptor gene [Arinami et al., (1994): Lancet 343:703-704] and a polymorphism Ser9gly in exon 1 of the dopamine DRD3 receptor gene [Crocq et al. (1992): J Med Genet 29:858-860]. We tested for these associations in samples of 373 and 413, and 311 and 306 patients and controls, respectively. We found no evidence for allelic association between schizophrenia and the Cys311 variant of the DRD2 receptor gene and no homozygotes for this variant were observed by any group. However, an excess of homozygotes for both alleles of the DRD3 polymorphism was observed in schizophrenic patients (chi2 = 8.54, P = 0.003, odds ratio = 1.64, 95% CI = 1.18-2.29). We also observed a significant excess of the 1-1 (Ser9Ser) genotype (chi2 = 8.13, P = 0.004, odds ratio = 1.7, 95% CI = 1.18-2.4). No evidence of heterogeneity between samples was detected and there was no evidence of an allelic association. These findings suggest that the rare Cys311 variant in exon 7 of the DRD2 receptor gene does not play a role in the pathogenesis of schizophrenia in European populations. Currently, our results do support the previous findings of an association between increased homozygosity of the Ser/Gly variant of the Dopamine D3 receptor gene and schizophrenia.

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: a multicenter association study.

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.

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.

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.