Distinct biopsychosocial profiles emerge among nonpatients.

OBJECTIVES: The cross-sectional study comprised 30- to 55-year-old permanent employees (N=1784) of the Finnish Broadcasting Company (YLE). METHODS: The participants (N=1339, response rate 75%) completed standardised questionnaires covering demographic items, physical health, work performance, stress symptoms, pain and musculoskeletal symptoms, and overall biopsychosocial health. RESULTS: Physical symptoms (present often or continually) were reported by 15%, psychosomatic by 19% and psychosocial by 14%. The intercorrelations between 73 biopsychosocial variables revealed nine factors explaining 54.5% of variance for intrapersonal profiles and four factors explaining 59.2% of variance for interpersonal profiles. The Cronbach alphas for reliability ranged from.76 to.83. Three distinct biopsychosocial cluster profiles were found: Cluster 1 (n=290, 27%) loaded positively with the somatic and psychosocial variables, Cluster 2 (n=558, 51%) loaded negatively with the various biopsychosocial symptoms, and Cluster 3 (n=235, 22%) loaded positively with anxiety. CONCLUSION: Discriminant function analysis confirmed that this cluster solution correctly classified 95.2% of the subjects in a nonpatient multiprofessional population, which supports the biopsychosocial approach also in work life issues.

Possible association but no linkage of the HSD11B2 gene encoding the kidney isozyme of 11beta-hydroxysteroid dehydrogenase to hypertension in Black people.

OBJECTIVE: The HSD11B2 (HSD11K) gene encoding the kidney isozyme of 11beta-hydroxysteroid dehydrogenase is mutated in the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of salt-sensitive hypertension. This gene is thus a logical candidate locus for risk of essential hypertension. DESIGN AND METHODS: Because hypertension in Black people tends to be of the low-renin, salt sensitive type, we genotyped independent sets of hypertensives of Afro-American (59 kindreds) and Afro-Caribbean (66 kindreds) origin using a highly polymorphic (heterozygosity index 0.84) CA repeat polymorphism in the first intron of HSD11B2. Linkage was assessed by the affected pedigree member method. RESULTS: No linkage of hypertension to this locus could be demonstrated, but statistically significant allelic associations were noted. CONCLUSIONS: HSD11B2 does not have a strong influence on the development of essential hypertension in Black people, but weaker effects on blood pressure cannot be ruled out.

Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia.

We compared the cerebrospinal fluid (CSF) cytology of 30 acutely psychotic patients at the initial phase of their hospital treatment with that of 46 control individuals with no psychiatric disorder or central nervous system (CNS) disease. The cytological profile of May-Grünwald-Giemsa stained CSF cell slides of the patients was significantly different from that of the control population. The most striking finding was a significantly increased frequency of lymphoid cells showing morphological features of activation/stimulation and a decreased proportion of normal small lymphocytes. Many of the cells with aberrant morphology displayed structural details similar to those of the 'P cells' previously described in the blood of schizophrenic patients. The patients' CSF also contained elevated proportions of monocytes/macrophages, some of which were found in 'rosettes' with activated lymphocytes indicating an increased intercellular adhesion. Possible pathogenic mechanisms behind lymphocyte activation and macrophage dominance in the CSF of acutely ill psychotic patients are discussed.

Sequence similarities between a novel putative G protein-coupled receptor and Na+/Ca2+ exchangers define a cation binding domain.

cDNA clones encoding a novel putative G protein-coupled receptor have been characterized. The receptor is widely expressed in normal solid tissues. Consisting of 1967 amino acid residues, this receptor is one of the largest known and is therefore referred to as a very large G protein-coupled receptor, or VLGR1. It is most closely related to the secretin family of G protein-coupled receptors based on similarity of the sequences of its transmembrane segments. As demonstrated by cell surface labeling with a biotin derivative, the recombinant protein is expressed on the surface of transfected mammalian cells. Whereas several other recently described receptors in this family also have large extracellular domains, the large extracellular domain of VLGR1 has a unique structure. It has nine imperfectly repeated units that are rich in acidic residues and are spaced at intervals of approximately 120 amino acid residues. These repeats resemble the regulatory domains of Na+/Ca2+ exchangers as well as a component of an extracellular aggregation factor of marine sponges. Bacterial fusion proteins containing two or four repeats specifically bind 45Ca in overlay experiments; binding is competed poorly by Mg2+ but competed well by neomycin, Al3+, and Gd3+. These results define a consensus cation binding motif employed in several widely divergent types of proteins. The ligand for VLGR1, its function, and the signaling pathway(s) it employs remain to be defined.

CA-Repeat polymorphism in intron 1 of HSD11B2 : effects on gene expression and salt sensitivity.

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214, P=0. 0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89+/-0.04 [mean+/-SE]) compared with 34 salt-resistant subjects (0.71+/-0.04, P<0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription-polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated.

Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia.

The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0.001). These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process.

Current antipsychotic dose correlates to mononuclear cell counts in the cerebrospinal fluid of psychotic patients.

Elevated cerebrospinal fluid (CSF) angiotensin I-converting enzyme (ACE) levels have been evidenced in patients with schizophrenia who have been treated with antipsychotics. In order to explore a possible mononuclear cell origin of CSF ACE, the authors determined CSF ACE and CSF mononuclear cell counts from 25 acutely psychotic patients, who had been drug-free for at least 4 months but started on conventional antipsychotic medication within a few days before sampling. No correlations were found between CSF to serum ACE ratio and CSF mononuclear cell counts. However, CSF total mononuclear cell count, CSF lymphocyte count, and CSF mononuclear phagocyte count evidenced significant positive correlations with current dose of antipsychotic medication expressed as chlorpromazine equivalents. The authors conclude that no indication of a relationship between mononuclear cells and CSF ACE activity was found. Surprisingly, a relationship between chlorpromazine dose and CSF mononuclear cell counts was found, which may indicate drug-related changes in cell-mediated immunity. This finding needs replication and further corroboration in well-designed studies.

Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes.

OBJECTIVE: There have been numerous reports of organic or structural abnormalities in the central nervous system (CNS) of patients with schizophrenia. Given that pathological conditions in the CNS are frequently reflected in the cell profiles of CSF, the authors compared the cytology of CSF from schizophrenic patients with that from a reference population in order to find out trails of elementary pathogenetic events in this serious psychiatric disease. METHOD: CSF samples from 35 patients with acute schizophrenia and 46 comparison subjects were prepared by Millipore filtration. The total and differential counts of CSF mononuclear cells were performed by light microscopy. RESULTS: At the beginning of treatment, the proportion of mononuclear phagocytes/macrophages in the patients' CSF was significantly higher than that in the comparison subjects. During treatment with conventional neuroleptic medication, the cytology returned to normal in several patients. CONCLUSIONS: The high proportion of macrophages in schizophrenia without a significantly higher total cell count may reflect neurodevelopmental disorder, a neurodegenerative process, or subtle CNS immunoactivation with mobilization of microglia.

Associations between aldosterone synthase gene polymorphism and the adrenocortical function in males.

OBJECTIVES: Two diallelic polymorphisms, one in the transcriptional regulatory region (promoter) and the other in the second intron, have been identified in the aldosterone synthase (CYP11B2) gene encoding aldosterone synthase, the enzyme catalysing the last steps of aldosterone biosynthesis. We have examined the associations between these genetic variations and adrenocortical function in a cohort of Finnish males. DESIGN: A cross-sectional study. SETTING: Helsinki University Central Hospital, Finland. SUBJECTS: Ninety-two males aged 30-55 years. MAIN OUTCOME MEASURES: Basal adrenocortical function was assessed by measuring urinary excretion of aldosterone and cortisol. Functional activity was determined by responses of several adrenal steroids to dexamethasone suppression followed by ACTH stimulation. Polymerase chain reactions were used to identify the polymorphisms in the CYP11B2 gene. RESULTS: The -344TT genotype group in the CYP11B2 promoter had lower systolic blood pressures (P=0.039), but higher urinary aldosterone excretion (P=0.016), and 11-deoxycortisol responses to ACTH stimulation (P=0.021) than the-344CC genotype group. Urinary aldosterone excretion (P=0.033), 11-deoxycortisol (P=0.026), and aldosterone (P=0.013) responses to ACTH were higher in the intron 2 conversion than the nonconversion genotype groups. CONCLUSIONS: Polymorphisms in or near the aldosterone synthase gene are associated with variations in aldosterone and 11-deoxycortisol production in males. This may modulate the activity of the renin-angiotensin system and thereby contribute to blood pressure regulation.

Higher cerebrospinal fluid angiotensin-converting enzyme levels in neuroleptic-treated than in drug-free patients with schizophrenia.

The aim of this study was to replicate our earlier finding of elevated angiotensin-converting enzyme (ACE) in cerebrospinal fluid (CSF) in schizophrenia and to elucidate the role of neuroleptic treatment in this phenomenon. Drug-free and medicated patients with acute schizophrenic psychoses, as well as healthy controls were recruited. Levels of ACE were measured in CSF and serum from 7 drug-free patients, 36 neuroleptic-treated patients, and 19 healthy control subjects. Although ACE levels in CSF did not differ between patients and controls, the drug-free patients showed significantly lower levels than the neuroleptic-treated patients. Serum ACE did not differ between groups. The elevation of CSF ACE may be more prominent in patients with deficit symptoms than in those with mainly psychotic symptoms. The possible enhancement of CSF ACE production or solubility by neuroleptic treatment is discussed. Elevated ACE levels in CSF may, together with other possible factors, cause polydipsia, stimulate secretion of arginine vasopressin, and even affect neuron growth and differentiation in schizophrenic psychoses.

Associations between human aldosterone synthase (CYP11B2) gene polymorphisms and left ventricular size, mass, and function.

BACKGROUND: Aldosterone has direct and indirect effects on the heart, and genetic variations in aldosterone synthesis could therefore influence cardiac structure and function. Such variations might be associated with polymorphisms in the gene encoding aldosterone synthase (CYP11B2), the enzyme catalyzing the last steps of aldosterone biosynthesis. METHODS AND RESULTS: A Finnish population sample of 84 persons (44 women) aged 36 to 37 years was studied by M-mode and Doppler echocardiography to assess left ventricular size, mass, and function. Subjects were genotyped through the use of the polymerase chain reaction for two diallelic polymorphisms in CYP11B2: one in the transcriptional regulatory region (promoter) and the other in the second intron. In multiple regression analyses, the CYP11B2 promoter genotype predicted statistically significant variations in left ventricular end-diastolic diameter (beta=.40, P<.0001), end-systolic diameter (beta=.33, P=.0009), and mass (beta=.17, P=.023). These effects were independent of potentially confounding factors, including sex, body size, blood pressure, physical activity, smoking, and ethanol consumption. Genotype groups also differed in a measure of left ventricular diastolic function, the heart rate-adjusted atrial filling fraction (P=.018). Increased dietary salt, which is known to predict increased left ventricular mass, had this effect only in association with certain CYP11B2 genotypes (P<.001). CONCLUSIONS: Genetic variations in or near the aldosterone synthase (CYP11B2) gene strongly affect left ventricular size and mass in young adults free of clinical heart disease. These polymorphisms may also influence the response of the left ventricle to increases in dietary salt.

A longitudinal study of cerebrospinal fluid angiotensin-converting enzyme in neuroleptic-treated schizophrenia.

1. The aim of the study was to replicate our earlier finding of elevated cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) in neuroleptic-treated schizophrenia and to elucidate the correlations between CSF ACE, neuroleptic treatment, and psychotic symptoms in a longitudinal study. 2. Levels of ACE were measured in CSF and serum from 9 acutely psychotic schizophrenic patients at two separate points of time; within a few days of admission and at follow-up after 3-4 weeks. CSF ACE was also determined from 9 healthy controls. 3. The schizophrenic patients showed non-significantly higher levels of CSF ACE than the controls. Although a significant clinical improvement was observed and the neuroleptic medication was reduced during the follow-up period, there were no significant differences in serum or CSF ACE between the two observation points in the schizophrenia group.

Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase.

The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of human hypertension thought to result from a deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme normally converts cortisol to inactive cortisone and is postulated to thus confer specificity for aldosterone upon the mineralocorticoid receptor. We have analysed the gene encoding the kidney isozyme of 11 beta HSD and found mutations on both alleles in nine of 11 AME patients (eight of nine kindreds). These mutations markedly affect enzymatic activity. They thus permit cortisol to occupy the renal mineralocorticoid receptor and thereby cause sodium retention and hypertension.

Abnormal distributions of T-lymphocyte subsets in the cerebrospinal fluid of patients with acute schizophrenia.

We analysed the percentages of CD4+ and CD8+ T lymphocytes in the cerebrospinal fluid (CSF) from 31 acutely ill schizophrenic patients. The psychotic patients had in their CSF clearly altered proportions of CD4+ and/or CD8+ T cells. As compared to the distribution of T cell subsets in the CSF from non-psychotic controls, the schizophrenic patients displayed both abnormally high and abnormally low frequencies of CD4+ and/or CD8+ cells. Changes in the distribution of T cell subsets corresponding to those seen in the CSF were not observed in paired blood samples from schizophrenic patients.

Genetic analysis of 11 beta-hydroxysteroid dehydrogenase.

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) catalyzes the interconversion of cortisol and cortisone. This activity is postulated to protect the Type I (mineralocorticoid) receptor from excessive concentrations of cortisol, allowing aldosterone to function as a mineralocorticoid. An enzyme with 11 beta-OHSD activity was isolated from rat liver and the corresponding rat and human cDNA and genomic clones isolated. This enzyme is a member of the short-chain dehydrogenase family. Using site-directed mutagenesis, it was demonstrated that the amino terminus and two highly conserved residues, Tyr-179 and Lys-183, are required for enzymatic function. Examination of patients with apparent mineralocorticoid excess, a syndrome of juvenile hypertension thought to represent 11 beta-OHSD deficiency, did not reveal any mutations in the HSD11 gene. This disorder may involve an additional enzyme with 11 beta-OHSD activity or possibly another cortisol metabolizing enzyme.

Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency.

The syndrome of apparent mineralocorticoid excess (AME) is a form of low renin hypertension that is thought to be caused by congenital deficiency of 11 beta-hydroxysteroid dehydrogenase (11HSD) activity. This enzyme converts cortisol to cortisone and apparently prevents cortisol from acting as a ligand for the mineralocorticoid (type I) receptor. It also catalyzes the reverse oxoreductase (cortisone to cortisol) reaction. Four patients with AME and the parents of the first patient described (now decreased) were analyzed for mutations in the cloned HSD11 gene encoding an 11HSD enzyme. A patient with suspected cortisone reductase deficiency was also studied. No gross deletions or rearrangements in the HSD11 gene were apparent on hybridizations of blots of genomic DNA. Direct sequencing of polymerase chain reaction-amplified fragments corresponding to the coding sequences, intronexon junctions, and proximal untranslated regions of this gene revealed no mutations. AME may involve mutations in a gene for another enzyme with 11HSD activity or perhaps another cortisol-metabolizing enzyme.

Moclobemide versus imipramine in depressed out-patients: a double-blind multi-centre study.

One hundred and twenty seven patients with major depressive episode were included in a double-blind, four-week, prospective, randomized, multi-centre parallel-group trial comparing moclobemide and imipramine. The dose of moclobemide was 150-525 mg/day and that of imipramine 50-175 mg/day; the mean daily doses during the last week of treatment were 307 mg and 100 mg of moclobemide and imipramine, respectively. The decrease of the total scores of the Hamilton Depression Scale (HDRS) as well as the Overall Assessment of Efficacy by the Investigators showed significant amelioration of depression in both treatment groups (p < 0.001). No significant differences were found between the moclobemide and imipramine groups with regard to treatment outcome. The onset of the antidepressant activity was faster in the moclobemide group as measured by the Assessment of the Investigators. This difference was not observed when the therapeutic index figures calculated on the basis of the changes in the HDRS scores were scrutinized. Treatment-emergent side effects were somewhat more frequent during imipramine than during moclobemide treatment. Nevertheless, a total of only four patients discontinued the trial prematurely because of poor tolerability. Imipramine-treated patients reported more anticholinergic side effects, whereas tiredness and headache were observed more frequently in the moclobemide-treated patients. Restlessness, nervousness and sleep disturbances were noted with equal incidence in both patient groups.

Cloning and expression of the gene encoding the soluble cytochrome b562 of Escherichia coli.

The gene for the soluble cytochrome b562 from Escherichia coli B has been cloned on a SalI fragment. The analysis of the gene reveals the presence of a leader sequence in front of the sequence encoding the mature protein. Expression of cytochrome b562 using the lac-promoter produced the protein to a level of 3-5% of total protein. This over-production enables employment of a simple, high-yield purification protocol to obtain homogeneous cytochrome b562. Spectroscopic and N-terminal sequence analyses of the purified protein demonstrate that it is identical to the chromosomally expressed cytochrome b562 purified and characterized from E. coli B [Itagaki, E. & Hager, L.P. (1966) J. Biol. Chem. 241, 3687-3695]. It is demonstrated that the genomic sequence codes for a classic N-terminal signal sequence and that mature cytochrome b562 is translocated to the periplasmic space.

Rat hemopexin. Molecular cloning, primary structural characterization, and analysis of gene expression.

A full-length hemopexin cDNA was isolated from a rat liver cDNA library and the derived amino acid sequence was obtained. Rat hemopexin shows a 76% amino acid homology with human hemopexin. The amino-terminal domain of rat hemopexin contains two histidine residues that are conserved in the human and rat sequences and are the most likely heme axial ligands. Analogous to human hemopexin, the rat hemopexin consists of 10 internal repeating peptide motifs characteristic of the pexin gene family. A complete conservation of cysteine residues is seen between the human and rat sequences suggesting an identical disulfide bridge structure in both proteins. Our analysis of the primary structure of rat hemopexin reveals characteristics typical for members of the pexin gene family and suggests a conserved evolutionary role for the C-terminal (non-heme-binding) domain of this protein. The full-length rat hemopexin cDNA was used to analyze changes in hemopexin gene expression during development and experimental inflammation. RNA blot analysis showed a single 2.0-kb hemopexin mRNA present in fetal liver at day 14. Hemopexin-specific mRNA was not detected in embryonic or fetal tissues at earlier stages of development and was confined to the liver throughout fetal, newborn, and adult life. The abundance of hemopexin mRNA was found to increase throughout gestation, with a sharp increase in the first postnatal weeks, reaching maximum levels in adult animals. Endotoxin-induced inflammation resulted in a 5-fold increase in hepatic hemopexin mRNA content within 48 h without associated changes in hemopexin transcript size. Adult animals exposed to hyperoxia (95% oxygen) showed a 3-fold increase in hepatic hemopexin mRNA content.(ABSTRACT TRUNCATED AT 250 WORDS)