Religiosity and remission of depression in medically ill older patients

PURPOSE: The purpose of this study was to compare the fractional contributions of the three pathways of lactate transport (band 3 system, nonionic diffusion, and monocarboxylate pathway) into red blood cells (RBC) from trained and untrained humans. METHODS: Blood samples were obtained from 19 male subjects: 5 untrained, 5 aerobically-trained, 5 competitive collegiate cross-country runners, and 4 competitive collegiate sprinters. The influx of lactate into the RBC was measured by a radioactive tracer technique using [14C]lactate. Discrimination of each pathway of lactate transport was achieved by using PCMBS (1 mM) to block the monocarboxylate pathway and DIDS (0.2 mM) to block the band 3 system. Nonionic diffusion was calculated as the difference between total lactate influx and the sum of band 3 and monocarboxylate lactate influx. RESULTS: Total lactate influx into the RBC from the more aerobic individuals (trained subjects and cross-country runners) was significantly faster at 1.6 mM lactate concentration ([La]) as compared with the influx into RBC of the untrained subjects. Total influx of lactate was significantly higher (P < 0.05) in the RBC from the sprinters as compared with that in the RBC from the untrained subjects at 41 mM [La]. There were no significant differences among the four groups with regard to the total influx of lactate at 4.1, 8.1, and 20 mM [La]. In general, the percentage of total lactate influx accounted for by each of the three parallel pathways at 1.6, 8.1, and 41.0 mM [La] was not different among the four groups of subjects. CONCLUSIONS: Overall, the groups were more similar than different with regard to RBC lactate influx.     

An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer

Mounting evidence suggests that catechol metabolites of estradiol may contribute to the development of estrogen-induced cancers. O-Methylation, catalyzed by catechol-O-methyltransferase (COMT), inactivates catechol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity allele of the enzyme (COMT(LL)). We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMT(HL) and COMT(LL) genotypes were 1.30 [confidence interval (CI), 0.66-2.58] and 1.45 (CI, 0.69-3.07), respectively. Postmenopausal COMT(LL) women had a greater than 2-fold increased risk of developing breast cancer [odds ratio (OR), 2.18; CI, 0.93-5.11]. The association of COMT(LL) with the development of postmenopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m2 (OR, 3.58; CI, 1.07-11.98). When COMT(LL) was combined with either glutathione S-transferase (GST) M1 null or with GSTP1 Ile-105-Val/Val-105-Val (intermediate/low activity, respectively) genotypes, the risk for developing postmenopausal breast cancer was also significantly increased. Our findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.     

Differential electrophoretic behavior in aqueous polymer solutions of red blood cells from Alzheimer patients and from normal individuals

The recently reported phenomenon that red blood cells (RBC) from Alzheimer disease (AD) patients and normal individuals, which have identical electrophoretic mobilities (EPM) in phosphate-buffered saline (PBS), have different EPM in appropriately selected polymer solutions, has been further explored. Of a number of in vitro treatments to which AD and normal RBC were subjected prior to EPM measurements in bottom phase (from a dextran-poly(ethylene glycol) (PEG) aqueous phase system) only trypsin eliminated the difference. Thus, the differential polymer interaction between AD and normal RBC, thought to be the basis for their dissimilar EPM, can be abolished by appropriate proteolytic modification of the cell surfaces and suggests protein as a source of difference. Because young and old RBC from normal individuals, which have the same EPM in PBS, have different EPM in certain polymer solutions, and the RBC from AD patients have been reported to age abnormally, we also compared the young and old RBC subpopulations from these two sources. By the criterion of cell electrophoresis in polymer solutions the differences between AD and normal RBC and between young and old RBC are distinct. The EPM of AD and normal RBC differ in bottom phase or PEG but not in dextran solution; while the EPM of young and old RBC differ predominantly in dextran. We speculate that since the observed difference in EPM of RBC from AD patients and normals depends on protein(s) yet is anticoagulant-related (being obtained only when blood is collected in citrate or oxalate) it might be the result of an interaction (Ca(2+)-mediated?) between the surfaces of these cells and protein component(s) of their respective, compositionally differing sera.     

Ubiquitin is conjugated to the cytoskeletal protein alpha-spectrin in mature erythrocytes

Ubiquitination of red blood cell (RBC) proteins was investigated by encapsulation of 125I-ubiquitin into human erythrocytes using a procedure of hypotonic dialysis, isotonic resealing, and reannealing. Incubation (37 degrees C, up to 2 h) of 125I-ubiquitin-loaded cells resulted in the recovery of 125I-ubiquitin with the cytosolic proteins (9.22 +/- 0.4 micrograms/ml RBC) and conjugated to membrane proteins (2.18 +/- 0.05 micrograms/ml RBC). This conjugation was time-dependent, and the predominant membrane protein band that became labeled showed an apparent molecular mass of 240 kDa on SDS-polyacrylamide gel electrophoresis (PAGE). Western blotting experiments with three different anti-ubiquitin antibodies revealed that this protein is also ubiquitinated in vivo. Cell-free experiments have shown that fraction II (a DEAE-bound protein fraction eluted by 0.5 M KCl) prepared from both mature erythrocytes and reticulocytes is able to conjugate ubiquitin to this protein. Ubiquitin conjugation was ATP-dependent (Km 0.09 mM), time-dependent, and fraction II-dependent (8 +/- 0.5 pmol of 125I-ubiquitin/h/mg of fraction II). Isolation of the major RBC membrane protein that is ubiquitinated was obtained by using biotinylated ubiquitin. Membrane proteins, once ubiquitinated with this derivative, were extracted and purified by affinity chromatography on immobilized avidin. The major components retained by the column were two peptides of molecular masses 220 and 240 kDa. Both proteins are recognized by a monoclonal anti-spectrin antibody, but only the 240-kDa component is detected by streptavidin peroxidase conjugate. That indeed the ubiquitinated membrane protein of 240-kDa is alpha-spectrin was confirmed by immunoaffinity chromatography using 125I-ubiquitin and a monoclonal anti-spectrin antibody. Antigen-antibody complexes were purified by protein A chromatography and analyzed by SDS-PAGE and autoradiography. Again two bands of 240 and 220 kDa were eluted (alpha- and beta-spectrin), but only one band corresponding to the electrophoretic mobility of alpha-spectrin was detected by autoradiography. Thus, alpha-spectrin is a substrate for the ATP-dependent ubiquitination system, suggesting that the cytoskeleton is covalently modified by ubiquitination both in reticulocytes and mature RBC.     

Higher cortical dysfunctions in preterm diplegia: how to evaluate and treat for their pedagogical difficulties]

OBJECTIVE: The aim of this investigation was to study the variation of catechol-O-methyltransferase (COMT) activity in the human liver, duodenal mucosa and renal cortex, and to investigate the inhibition of COMT by entacapone and tolcapone. This study included 87 samples of human liver, 94 samples of the duodenum and 72 samples of the renal cortex. RESULTS: The activity of COMT was measured with 3,4-dihydroxybenzoic acid (242 micromol x l(-1)), the methyl acceptor substrate, and adenosyl-L-methionine (44 micromol x l(-1)), the methyl donor substrate. The hepatic activity of COMT activity was significantly higher in men than in women, whereas it was not sex-dependent in the duodenum or renal cortex. The activity of COMT varied 4.4-fold in the liver of men, 2.6-fold in the duodenum and 5.3-fold in the renal cortex. The median estimates of COMT activity were 577, 499, 103 and 159 pmol x min(-1) x mg(-1) in the liver of men and women, in the duodenum and in the renal cortex, respectively. CONCLUSION: Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P = 0.008), respectively, in the liver; consistent results were obtained with the other tissues.     

The activity of catechol-O-methyltransferase and monoamine oxidase in the uterine artery of pigs during the oestrous cycle

Activities of catechol-O-methyltransferase (COMT), total monoamine oxidase (MAO) and both types of MAO-A and MAO-B activities were examined in uterine artery on the 0-2nd, 13-14th and 16-18th days of the oestrous cycle in pigs. It was shown that activity of COMT was the lowest on the 0-2nd day, while on the 16-18th day of the oestrous cycle it increased by 52.4% (p < 0.05). Total activity of MAO was the highest at periovulatory phase, whereas on days 13-14 and 16-18 of oestrous cycle is was lower by 83.5% (p < 0.01) and 58.1% (p < 0.01) compared with its activity at periovulatory phase, and was higher on day 16-18 by 153.3% (p < 0.01) in relation to the luteal phase (13-14th day). MAO-A activity was 31.3% (p < 0.01) and MAO-B 62.5% (p < 0.05) of the total activity of MAO. Their activities were also highest at periovulatory phase, then decreased by 86.8-87.4% (p < 0.01) on 13-14th day and by 54.8-57.5% (p < 0.01) or 16-18th day of oestrous cycle. Activities of MAO-A and MAO-B were higher by 223.0-258.2% (p < 0.01) on 16-18th day in relation to the luteal phase (13-14th day). On that base we suppose that variations of COMT and MAO activities can significantly change the catecholamines content in the blood vessels of reproductive organs of pigs.     

Brain and erythrocyte anion transporter protein, band 3, as a marker for Alzheimer's disease: structural changes detected by electron microscopy, phosphorylation, and antibodies

Band 3, a ubiquitous membrane transport, regulatory, and structural protein, is represented in brain by at least 4 isoforms. Bands 3 in brain performs the same functions as it does in erythrocytes (RBC). It is susceptible to oxidative damage, which, ultimately, terminates its life and that of the cell. We examined the changes band 3 undergoes in Alzheimer's disease (AD) because our previous studies suggest that band 3 is a pivotal protein in neurological disease. Because we hypothesize that AD is a total body disease, we examined peripheral blood cells as well as brain tissue to determine whether the same changes occur in both. Our results indicate that posttranslational changes occur in RBC band 3 that parallel changes in brain band 3. These include decreased 32P-phosphate labeling in vitro of band 3 polypeptides in brain and RBC, increased degradation of band 3, alteration in band 3 recognized by polyclonal and monoclonal antibodies, and decreased anion and glucose transport by blood cells. Serum autoantibodies to band 3 peptides 588-602 and 822-839 were increased in AD patients compared to controls. These band 3 residues lie in anion transport/binding regions. This is consistent with alteration of this region in AD since it is recognized as antigenically different by the patients' immune system. Our data support an immunological component to AD. The finding that changes in RBC in AD reflect those in brain and can be recognized by antibodies should facilitate development of blood tests for diagnosis and monitoring, and early therapy. It is anticipated that identification of molecular sites of posttranslational modification of band 3 will enable us to design specific preventive and treatment strategies, and target drugs to crucial molecular sites.     

Task difficulty and cognitive deficits in schizophrenia.

Investigators of schizophrenic cognition often produce 2 or more tasks of differing difficulty levels by manipulating a variable that affects the accuracy of both normal and schizophrenic individuals; the investigators find that the variable also affects the difference between the groups in accuracy and conclude that the variable taps a schizophrenic differential deficit. An alternative hypothesis is that task differences in true-score variance artifactually produce the finding. For free-response tasks, group differences tend to be larger when difficulty is near 50%. The authors illustrate a new method of controlling this artifact by selecting items for hard and easy tasks on opposite sides of 50% difficulty and equidistant from it. Using this design with an anagram task, they found that schizophrenic and normal individuals differ no more on hard anagrams than on easy ones, and they propose the design for testing hypotheses concerning schizophrenic deficit on tasks that differ in difficulty. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

High and low activity alleles of catechol-O-methyltransferase gene: ethnic difference and possible association with Parkinson's disease

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates catecholamines such as adrenaline, noradrenaline, dopamine, and levodopa. Recently an amino acid change (Val-108-Met) of the COMT protein was found to determine high and low activity alleles of the COMT gene. We genotyped 109 Japanese patients with Parkinson's disease (PD) and 153 controls by using polymerase chain reaction (PCR) amplification and digestion by the restriction enzyme NlaIII. The frequency of low activity allele in the controls was 0.29, which was significantly different from that reported in Caucasians (0.50). When comparison was made between patients with PD and controls, homozygosity for the low activity allele was significantly more common among the patients than among the controls (P = 0.017; odds ratio, 2.8, 95% CI 1.2-6.5), suggesting that homozygosity for the low activity allele may increase susceptibility to PD.     

Plasma and red cell lipids in sickle cell disease

Lipids, in particular phospholipids, are essential components of membrane systems, and the measurement of phospholipids and cholesterol in plasma and tissues is helpful in diagnosis. Phospholipids represent about 60 to 70% of total red cell (RBC) lipids, while about 25% is free cholesterol. Lipids in RBC are present in a dynamic state of equilibrium, and the RBC have the capacity for rapid exchange of lipids with plasma in several ways. The present study examined the cholesterol and phospholipid levels of plasma and erythrocytes in male patients with sickle cell anemia and in healthy male individuals of comparable age. This was performed with a view to detecting possible differences that might be related to some of the RBC abnormalities which accompany the disease. The results show that plasma lipids are significantly reduced in patients with sickle cell anemia and that RBC cholesterol was higher in sickle cell patients than in normal subjects.     

Association study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenics

Catechol-O-methyltransferase (COMT) is an enzyme which inactivates catecholamine neurotransmitters by methylation, and is considered a candidate for involvement in schizophrenia. A functional COMT gene polymorphism influencing the enzyme activities, the high activity (val-108) and the low activity allele (met-108), was recently confirmed. We investigated a genetic association between schizophrenia and the COMT gene polymorphism in 150 Japanese schizophrenics and controls. We detected the low activity met-108 allele more frequently in schizophrenics than in the controls, and found that subjects sharing the met-108 allele (val/met and met/met) are significantly more common in the patients than in the controls. The results suggest that the low activity met-108 allele may be involved in susceptibility for schizophrenia.     

Interaction of glucose and metformin with isolated red cell membrane

Isolated human erythrocyte membranes (red blood cell (RBC) ghosts) were incubated with glucose at 5, 10, 20 and 100 mmol/l concentrations, with insulin (0.01 to 200 mU/l) and metformin (CAS 657-24-9) 0.5 up to 50.0 mumol/l). Binding studies with 14C-glucose and subsequent gel electrophoresis revealed 60% of the radioactivity around ban 4.2-4.5 at 5 mmol/l, whereas a random distribution of radioactivity over all protein bands of the RBC membrane was found at 20 mmol/l concentration after incubation for 30 min or 48 h. Metformin does not bind covalently to RBC membranes, however, after photochemical linkage of 14C-metformin via the aminoreactive linker azidophenylglyoxal the highest radioactivity (21%) was counted in the range of band 4.2-4.5. In parallel with an increase of order parameters of 5-doxyl-stearic acid the thiol status of the membranes decreases as determined by monobromobimane fluorescence. 20 and 100 mmol/l concentrations of glucose decrease the reactivity of membrane thiols towards bromobimane significantly to 73 and 62% of the controls. Concomitantly, membrane fluidity at polar sites is diminished as measured by order parameters of spin label 5-doxyl stearic acid. In RBC membranes pretreated with 20 mmol/l glucose the decreased fluorescence is significantly raised again by insulin and metformin. This effect is even more pronounced, if insulin and metformin are incubated together. Reaction of membrane thiols with a maleimido spin label detects modification in the ratio of mobile and immobilized spin label populations in the electron paramagnetic resonance signal under the above conditions, indicative of conformational changes of membrane proteins.     

COMT genetic variation affects fear processing: Psychophysiological evidence.

Emotional dysregulation is a core characteristic of many psychiatric diseases, including the anxiety disorders. Although heritable influences account for a significant degree of variation in risk for such disorders, relatively few candidate susceptibility factors have been identified. A coding variant in one such gene, encoding the dopamine catabolic enzyme catechol-O-methyltransferase (COMT Val158Met), has previously been associated with anxiety and with anxiety-related temperament and altered neural responses to affective stimuli in healthy individuals. In 96 healthy women recruited from a sample of 800 participants according to genotype, the authors tested for an association between the DRD2/ANKK1 Taq Ia, the COMT Val158Met, and a psychophysiological measure of emotion processing, the acoustic affective startle reflex modulation (ASRM) paradigm, and found that COMT genotype significantly affected startle reflex modulation by aversive stimuli, with Met158 homozygotes exhibiting a markedly potentiated startle reflex compared with Val158 carriers. A trait measure of anxiety (Gray's Behavioral Inhibition System; J. A. Gray & N. McNaughton, 2000) was also associated with ASRM. The functional polymorphism in the dopamine D2 receptor (DRD2/ANKK1 Taq Ia) had no effect on startle modulation. The findings support prior genetic and neuroimaging associations of the COMT 158Met allele to affective psychopathology and alterations in neural systems for emotional arousal and regulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A-B therapist perceptions and preferences for schizophrenic and psychoneurotic clients.

Administered an extended version of the a-b scale to 141 experienced, practicing psychotherapists. Ss also completed scales designed to assess therapist attitudes toward working with schizophrenic and psychoneurotic clients, personal liking for specific schizophrenic and psychoneutrotic clients, and orientation toward interpersonal relationships. Analysis of variance results revealed no evidence suggesting that a and b therapists differentially perceive or prefer schizophrenic or psychoneurotic clients. There was evidence suggesting that a therapists initially like both schizophrenic and psychoneurotic clients as individuals more than b therapists. By the time therapy had ended, these differences between a and b therapists tended to dissipate with schizophrenic clients. However, b therapists' personal liking of their psychoneurotic clients actually declined during therapy. (18 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

PET studies of peripheral catechol-O-methyltransferase in non-human primates using [18F]Ro41-0960

We previously reported the results of PET (positron emission tomography) studies of [18F]Ro41-0960, a potent COMT inhibitor, in baboon brain. Here we report an evaluation of the pharmacokinetics and specificity of binding of [18F]Ro41-0960 in the peripheral organs of baboon. We observed a rapid clearance of the tracer from the heart and no significant uptake in the lung. In contrast, there was a high uptake and slow clearance in both kidney and liver, consistent with a high level of COMT in these peripheral organs. We also observed a dose-dependent inhibition of [18F]Ro41-0960 uptake by unlabeled Ro41-0960 (ED50 was 0.5 mg/kg in liver, and <0.01 mg/kg in kidney), with a halftime for recovery of COMT of about 25 h at the dose of 2 mg/kg of unlabeled Ro41-0960. This indicates a reversible tight binding interaction between COMT and Ro41-0960 in both liver and kidney and suggests that [18F]Ro41-0960 may be a useful radiotracer for future examination of the functional activity of COMT in the human body.     

Anhedonia as a phenotype for the Val1??Met COMT polymorphism in relatives of patients with schizophrenia.

The Val1??Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been associated with aspects of schizophrenia that are possibly related to the disorder's pathogenesis. The present study investigated the Val1??Met polymorphism in relation to anhedonia--a construct central to negative schizotypy. Anhedonia and other schizotypal characteristics were assessed in relatives of patients with schizophrenia, relatives of patients with bipolar disorder, and nonpsychiatric controls using the Chapman schizotypy scales and the Schizotypal Personality Questionnaire. Compared with controls, relatives of individuals with schizophrenia had elevated scores on Chapman scales for social anhedonia and physical anhedonia, while relatives of patients with bipolar disorder exhibited only increased scores on the Social Anhedonia Scale. As a group, relatives of patients with schizophrenia who were homozygous for the val allele of the COMT polymorphism showed the highest elevations in self-reported social and physical anhedonia. Associations with the COMT polymorphism were absent in relatives of patients with bipolar disorder and control participants. Findings suggest that anhedonia is manifest in individuals who carry genetic liability for schizophrenia and is associated with the Val1??Met polymorphism of the COMT gene. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

No association between Parkinson's disease and low-activity alleles of catechol O-methyltransferase

Idiopathic Parkinson's disease (IPD) is characterised by the loss of pigmented neurones in the substantia nigra, leading to reduced tyrosine hydroxylase activity and depletion of dopamine. Treatments attempt to correct this deficit by the use of levodopa and inhibitors of dopamine metabolising enzymes such as catechol-O-methytransferase (COMT). A common amino-acid polymorphism in COMT, valine-108-methionine, results in a low activity form of the enzyme which we hypothesised may influence susceptibility to IPD. We examined this polymorphism in 139 Caucasian subjects with IPD and 173 control subjects, using a PCR-RFLP and a novel Amplification Refractory Mutation System (ARMS) assay. Allele and genotype frequencies were similar in the affected and control subjects, indicating that variation of COMT activity is not an aetiological factor in IPD. We have also characterised a new polymorphism, 256C/G, which is not associated with IPD. However it remains possible that allelic variation in COMT influences severity, type of pathology or treatment response to levodopa or COMT inhibitors.     

COMT val158Met and executive control: A test of the benefit of specific deficits to translational research.

The role of catechol-O-methyltransferase (COMT) val158met in prefrontal cortical deficits associated with the liability to schizophrenia remains controversial. This study evaluated 464 healthy adult participants using three measures of executive functions in working memory: a 3-back version of the N-back continuous performance task (CPT) and two variants of the AX-CPT. The interpretability of N-back performance was confounded by possible generalized deficits, whereas the AX variants included internal controls for uncovering specific deficits. There was no relationship between the COMT genotype and N-back performance, whereas val/val individuals had a specific deficit on a dot-pattern version of the AX-CPT. In this case, a specific executive function known as context processing appeared to be compromised. These data suggest that the interpretability gained by including task manipulations to uncover specific deficits can enhance associations between cognitive and genetic levels of analysis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Decrease in red blood cell L-tryptophan uptake in schizophrenic patients: possible link with loss of impulse control

1. Kinetic parameters of erythrocyte L-tryptophan (TRP) uptake (Vmax, maximal velocity and Km, Michaelis constant) were determined in 19 neuroleptic-free schizophrenic patients and in 19 healthy volunteers. Both Vmax and Km values were significantly lower in schizophrenic patients than in controls. 2. Mean Vmax value was found to be lower in patients who had attempted suicide than in patients who had not. No difference was observed when patients were subdivided on the basis of the violence of suicide attempts. 3. A significant negative correlation was observed between Vmax and scores on the loss of impulse control item as assessed on the PANS scale. 4. Decrease in red blood cell L-TRP uptake reflects a disturbance in the peripheral metabolism of TRP that may result in a deficiency of the plasma L-TRP availability on which the central serotonin (5HT) synthesis closely depends. 5. In addition, the results suggest that the alteration in RBC L-TRP uptake is associated with loss of impulse control in schizophrenic patients.     

Catechol-O-methyltransferase and breast cancer risk

Recent studies suggest that a polymorphism in catechol-O-methyltransferase (COMT) is associated with increased risk of breast cancer. Methylation by COMT is the principal pathway for inactivation of catechol estrogens, which are hypothesized to participate in estrogen-induced carcinogenesis. We examined the association of COMT genotype and breast cancer risk in a population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 654 cases and 642 controls, with approximately equal numbers of African-American and white women and women under the age of 50 and aged 50 or over. Contrary to previous reports, we did not observe an association between one or more copies of the low activity COMT allele (COMT-L) and breast cancer risk. Multivariate relative risks (RRs) were 0.8 (95% confidence interval: 0.6-1.1) for COMT-HL and 0.8 (0.6-1.1) for COMT-LL, compared with the COMT-HH genotype. RRs for COMT did not differ among African-American and white women and we did not observe strong modification of RR estimates by menopausal status, body mass index, physical activity or other covariates. Our results suggest that COMT genotype is not related to breast cancer risk.