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G Fink

Publications and source records attributed to G Fink.

At least 73 records · Page 4Linked to original sources
PubMed1996

Polymorphism in serotonin transporter gene associated with susceptibility to major depression.

UNLABELLED: BACKGROUND; The serotonin transporter of the brain provides the primary target for the action of selective antidepressant drugs. We set out to identify polymorphisms of the serotonin transporter gene and to find out whether there was a relation between any such polymorphisms and the occurrence of affective disorder. METHODS: A comparison of a polymorphic region of the human serotonin transporter gene was carried out between two groups. The study group comprised 83 patients (39 unipolar depressive disorder, 44 bipolar disorder) with major affective disorder. The control group comprised 122 anonymous blood donors, and 71 volunteers who had been screened for psychiatric disorders. FINDINGS: We detected three novel alleles of the variable-number-tandem-repeat (VNTR) region (STin2.9, STin2.10) and Stin2.12) containing nine, ten and 12 copies of the VNTR element, respectively. The frequencies of the different forms of the allele in the control group were compared with those in the affective disorder group. There was a significant difference between the control and affective disorder groups, largely explained by the excess of the STin2.9 allele in the unipolar group (chi2=10.05, p<0.004 [Bonferroni corrected]). The presence of the allele with nine copies of the repeat was significantly associated with risk of unipolar disorder (odds ratio=6.95 [95% CI 1.8-27.2]). INTERPRETATION: This association, for an obvious candidate gene, may provide a critical starting point for an understanding of the likely polygenic contributions towards susceptibility to affective disorder.

Alleles↗
PubMed1996

Estrogen control of central neurotransmission: effect on mood, mental state, and memory.

1. Estrogen exerts profound effects on mood, mental state and memory by acting on both "classical" monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action. 2. With respect to the effect of estrogen on central monoamine neurotransmission, low levels of estrogen in women are associated with the premenstrual syndrome, postnatal depression and post-menopausal depression. Sex differences in schizophrenia have also been attributed to estrogen. Previous studies have shown that estrogen stimulates a significant increase in dopamine2 (D2) receptors in the striatum. Here we show for the first time that estrogen also stimulates a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) binding sites in anterior frontal, cingulate and primary olfactory cortex and in the nucleus accumbens, areas of the brain concerned with the control of mood, mental state, cognition, emotion and behavior. These findings explain, for example, the efficacy of estrogen therapy or 5-HT uptake blockers such as fluoxetine in treating the depressive symptoms of the premenstrual syndrome. and suggest that the sex differences in schizophrenia may also be due to an action of estrogen mediated by way of 5-HT2A receptors. 3. With respect to the effect of estrogen on central neuropeptide transmission, estrogen stimulates the expression of the arginine vasopressin (AVP) gene in the bed nucleus of the stria terminalis (BNST) in rodents. This results in a 100-fold increase in AVP mRNA in the BNST and a massive increase in AVP peptide in the BNST and its projections to the lateral septum and lateral habenula. The BNST-AVP system enhances and/or maintains "social" or "olfactory" memory, and thus provides a powerful model for correlating transcriptional control of neuropeptide gene expression with behavior. Whether similar mechanisms operate in the human remain to be determined. 4. These two examples of the action of estrogen on central neurotransmission are discussed in terms of their immediate clinical importance for the treatment of depressive symptoms, their use as powerful models for investigations on the steroid control of central neurotransmitter mechanisms, and the role of estrogen as "Nature's" psychoprotectant.

Affect↗
PubMed1996

Contribution of cardiopulmonary indices in the assessment of patients with silent and symptomatic ischemia during exercise testing.

Cardiopulmonary and radionuclear indices were used to evaluate and compare cardiac function during exercise testing in patients with symptomatic and silent ischemia. The study comprised 58 patients aged 35-74 years, divided into three groups: Group I-20 patients (controls) with neither ST depression nor chest pain; Group II-22 patients with ST depression > 1 mm and no chest pain; Group III-16 patients with both ST depression and chest pain. All patients in Groups II and III demonstrated significant coronary artery disease. No antianginal medication was taken at least 24 h before testing. All patients underwent a cardiopulmonary exercise test and a multigated acquisition radionuclear study. The following variables were measured: oxygen consumption (VO2), CO2 output (VCO2), minute ventilation (VE), O2-pulse, ventilatory anaerobic threshold (VAT), left ventricular ejection fraction (LVEF) at rest (r) and at maximal effort (ex). Probability values were significant for all variables (P < 0.01-0.0001) except left ventricular ejection fraction-rest (P not significant between the three groups). No significant differences in extent of coronary artery disease were noted between Groups II and III. These findings suggest that during exercise testing patients with silent ischemia have better overall cardiac function than patients with symptomatic ischemia. Their value for both cardiopulmonary and radionuclear indices are closer to those of the control group than to the symptomatic group, regardless of the severity of the coronary artery disease Summary of results: (mean +/- 1 S.D.) Group VO2-max O2-Pulse max VAT (%) VAT (ml/min) LVEF-rest delta LVEF (ex-r) I 25.2 +/- 6.3 15.7 +/- 3.4 51.2 +/- 6.6 1075 +/- 289 54.7 +/- 7 5.4 +/- 4.85 II 22.4 +/- 2.8 14.5 +/- 2 47.0 +/- 5.3 854 +/- 136 52 +/- 10 1.2 +/- 6.7 III 16.0 +/- 2.5 11.4 +/- 2 41.6 +/- 7.7 683 +/- 105 51 +/- 8.5 -5.87 +/- 6.3

Adult↗
PubMed1996

Tissue-specific regulation of glutamine synthetase gene expression in acute pancreatitis is confirmed by using interleukin-1 receptor knockout mice.

BACKGROUND: Acute pancreatitis causes a pronounced depletion of plasma and muscle glutamine pools. In several other catabolic disease states expression of the enzyme glutamine synthetase (GS) is induced in lung and muscle to support glutamine secretion by these organs. The hormonal mediators of GS induction have not been conclusively identified. We used mice deficient for the expression of the type 1 interleukin-1 receptor (IL-1R1 knockout mice) to investigate the expression of GS during acute edematous pancreatitis. METHODS: Acute edematous pancreatitis was induced in adult male wild-type and IL-1R1 knockout mice by means of the intraperitoneal administration of cerulein, and their conditions were monitored. Five organs, including lung, liver, gastrocnemius muscle, spleen, and pancreas, were assayed for relative GS messenger RNA (mRNA) content by Northern blotting. RESULTS: The ultimate severity of pancreatitis was reduced by IL-1R1 deficiency. GS mRNA levels increased during progression of pancreatitis in lung, spleen, and muscle tissue from each group. No consistent increase in GS mRNA level was observed in liver. IL-1R1 deficiency did not affect GS mRNA expression in lung tissue but consistently retarded GS induction in the spleens of knockout animals. IL-1R deficiency altered the kinetics of GS induction in muscle. CONCLUSIONS: Cerulein-induced experimental pancreatitis causes an induction in GS mRNA levels in a tissue-specific fashion. IL-1R1 deficiency reduced the ultimate severity of the condition and altered the induction of GS mRNA in the spleen and muscle.

Animals↗
PubMed1996

Active interleukin-1 receptor required for maximal progression of acute pancreatitis.

OBJECTIVE: The authors' aim was to determine the requirement for an active interleukin (IL)-1 receptor during the development and progression of acute pancreatitis. SUMMARY OF BACKGROUND DATA: Interleukin-1 is a pro- inflammatory cytokine that has been shown to be produced during acute pancreatitis. Earlier animal studies of moderate and severe pancreatitis have shown that blockade of this powerful mediator is associated with attenuated pancreatic destruction and dramatic increases in survival. The exact role played by IL-1 and the requirement for activation of its receptor in the initiation and progression of pancreatitis is unknown. METHODS: Conventional and IL-1 receptor "knockout" animals were used in parallel experiments of acute pancreatitis induced by intraperitoneal injection of cerulean (50 microg/kg every 1 hour X 4). The conventional mouse strain had the IL-1 receptor blocked prophylactically by means of a recombinant IL-1 receptor antagonist (10 mg/kg injected intraperitoneally every 2 hours). The second mouse strain was genetically engineered by means of gene targeting in murine embryonic stem cells to be devoid of type 1 IL-1 receptor (IL-1 receptor knockout). Animals were killed at 0, 0.5, 1, 2, 4, and 8 hours, with the severity of pancreatitis determined by serum amylase, lipase, and IL-6 levels and blind histologic grading. Strain-specific controls were used for comparison. RESULTS: The genetic absence of the IL-1 receptor or its pharmacologic blockade resulted in significantly attenuated pancreatic vacuolization, edema, necrosis, inflammation, and enzyme release. Serum IL-6, a marker of inflammation severity, was dramatically decreased in both groups. CONCLUSIONS: Activation of the IL-1 receptor is not required for the development of pancreatitis but apparently is necessary for the maximal propagation of pancreatic injury and its associated inflammation.

Acute Disease↗
PubMed1996

Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder.

We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the serotonin transporter gene may contribute to susceptibility for both major depression and bipolar disorder.

Alleles↗
PubMed1995

Estrogen increases the density of 5-hydroxytryptamine(2A) receptors in cerebral cortex and nucleus accumbens in the female rat.

Estrogen exerts a profound effect on mood and mental function in man. Based on our finding that estradiol selectively stimulates the expression of 5-hydroxytryptamine(2A) (5-HT2A) receptor mRNA in the dorsal raphe nucleus of the female rat, we investigated the effects of estradiol on the density of 5-HT2A receptors in brain. The distribution and density of 5-HT2A receptors were determined by in vitro binding of [3H]ketanserin in the presence of prazosin to exclude binding to alpha 1-adrenoreceptors. Brains were collected, processed and analysed in pairs from six estradiol- and six vehicle-treated animals. Our results show that a single pulse of estradiol induces a significant increase in the density of 5-HT2A receptors in female rat forebrain, particularly the anterior frontal, anterior cingulate and primary olfactory cortex and the nucleus accumbens. Since these brain regions play a pivotal role in cognition and emotion, as well as neuroendocrine and motor control, our findings provide the first experimental evidence for the fact that estrogen could alter mood and mental state by increasing the density of 5-HT2A receptors in cerebral cortex and nucleus accumbens.

Animals↗
PubMed1995

Dysfunction of visual cortex contributes to disturbed processing of visual information in Alzheimer's disease.

The relation between visual impairment and regional cerebral metabolic rate of glucose (rCMRGl) was studied in 31 patients with probable Alzheimer's disease (AD) by using positron emission tomography with 18F-2-fluoro-2-deoxy-D-glucose. To exclude any precortical cause of visual dysfunction only patients were included who had amplitudes and latencies of visually evoked potentials (flash and pattern reversal) within the normal range. Visual information processing was evaluated psychometrically by a fragmented picture test (FPT), which is a combined perception (identification score) and memory (reidentification score) task and refers to Gollin's incomplete pictures. The identification and reidentification scores were significantly worse than in normals. Reductions of the rCMRGl in the primary visual fields, and in the secondary visual fields were found. A significant partial correlation with adjustment for age between the reidentification score of the FPT and the rCMRGl of the secondary visual fields (r = -.39, p < .05) in AD patients was found, indicating involvement of the secondary visual cortex in the pathological changes in AD.

Aged↗
PubMed1994

Effects of glucocorticoids on 5-HT1A presynaptic function in the mouse.

8-OH-DPAT, a selective 5-HT1A agonist, produced a hypothermic response in mice at a dosage of 0.5 mg/kg. Administration of corticosterone-21-acetate (0.5, 5 and 50 mg/kg, daily for 3 and 10 days) produced a dose-dependent attenuation of this hypothermic response in mice. When all controls and corticosterone treated mice were retested, 14 days after initial testing, they did not differ in the hypothermic responses induced by 8-OH-DPAT. Mice treated with aldosterone (50 mg/kg), dexamethasone (50 mg/kg) and the specific type 2 corticosteroid receptor agonist, 11b,17b-dihydroxy-21-methyl-17a-pregna-1,4,6-trien-20-yn+ ++-3-one (RU26988, 30 mg/kg) for 10 days, did not differ from vehicle treated controls in the hypothermic response to 8-OH-DPAT. Mice administered corticosterone-21-acetate (30 mg/kg, daily) for 10 days displayed a motor behavioural syndrome, which was not seen in controls, when injected with 5-hydroxytryptophan (5-HTP, 100 mg/kg) 15 min after the injection of carbidopa (25 mg/kg). This was significantly decreased by pretreatment with the 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)-piperazine (NAN-190 5 mg/kg, 30 min prior to administration of carbidopa). Taken together, this evidence is compatible with a specific corticosterone induced facilitation of 5-HT release due to attenuation of inhibitory 5-HT1A autoreceptor function.

5-Hydroxytryptophan↗
PubMed1994

ANP(5-28) is the major molecular species in hypophysial portal blood of the rat.

We have previously demonstrated that the concentrations of immunoreactive atrial natriuretic peptide (IR-ANP) are significantly higher in hypophysial portal compared with peripheral blood of the rat, and that ANP suppresses the pituitary release of ACTH and beta-endorphin in vitro and in vivo. Using HPLC, we have now shown that the predominant species of IR-ANP in extracts of portal blood from adult male and female rats is ANP(5-28), whereas in peripheral blood, ANP(1-28) predominates. The ratio of ANP(5-28) in portal compared with peripheral blood was 4.2 in male and 4.8 in female animals.

Animals↗
PubMed1994

Mechanisms of activation of the pituitary-adrenal axis by tissue injury in the rat.

To characterize the mechanisms of the pituitary-adrenal (P-A) response to tissue injury, rats were injected intramuscularly (IM) with turpentine. This resulted in marked elevations in the plasma concentrations of ACTH and corticosterone within the first hour after injection, which were attenuated by either total deafferentation of the medial basal hypothalamus (MBH) or neonatal capsaicin pretreatment. The plasma concentrations of corticosterone remained elevated for 18 h in the turpentine-injected rats, despite a return of ACTH toward control values (by 2-4 h). Bioactive concentrations of interleukin-6 (IL-6) in plasma rose markedly after turpentine, and its concentrations were significantly correlated with plasma corticosterone concentrations 4-8 h after turpentine. Pretreatment with IL-1 receptor antagonist (IL-1ra) attenuated the release of IL-6 and had a marginal effect on the corticosterone response 6 h after turpentine. These results suggest that the early and late phase of the P-A response to tissue injury are mediated by different mechanisms.

Acute-Phase Reaction↗
PubMed1994

A central 5-HT2 receptor mechanism plays a key role in the proestrous surge of luteinizing hormone in the rat.

The role of serotonin (5-HT) in generating the spontaneous preovulatory surge of luteinizing hormone (LH) has been investigated by studying the effect of ketanserin (a mixed 5-HT2/alpha 1 adrenoreceptor antagonist); the selective 5-HT2 receptor antagonist, ritanserin; and the selective alpha 1 adrenoreceptor antagonist, prazosin, on the plasma concentrations of LH during the afternoon of proestrus in conscious Wistar rats. Sequential blood samples for hormone estimation were taken through intra-atrial cannulae previously implanted under halothane anesthesia. All three drugs blocked the LH surge; ketanserin, but not ritanserin or prazosin, also blocked basal LH release. These results provide the first robust evidence for the fact that a 5-HT2 receptor as well as an alpha 1 adrenoreceptor mechanism is involved in the LH surge generator.

Animals↗
PubMed1994

An alpha 1 adrenergic mechanism mediates estradiol stimulation of LHRH mRNA synthesis and estradiol inhibition of POMC mRNA synthesis in the hypothalamus of the prepubertal female rat.

We showed previously that the surge of luteinizing hormone-releasing hormone (LHRH) induced by estradiol-17 beta (E2) in the female rat can be blocked by an alpha 1 adrenergic antagonist. The aim of the present study was to determine whether this was due to a direct action of E2 on noradrenergic projections to LHRH neurons or whether it also involved other systems such as the arcuate pro-opiomelanocortin (POMC) neurons which are thought to inhibit LHRH biosynthesis and release. The experimental preparation was the prepubertal female rat in which an LHRH surge is induced by pregnant mare serum gonadotropin. Prazosin was used as a specific alpha 1 adrenergic antagonist and LHRH and POMC mRNA concentrations and cell numbers, in the medial preoptic area and rostral arcuate nucleus, respectively, were determined by in situ hybridization. Prazosin significantly reduced the total number of LHRH mRNA expressing cells, and increased the total number of POMC mRNA expressing cells and the concentration of POMC mRNA per cell. These results suggest that the inhibition of E2-stimulated LHRH biosynthesis and release by alpha 1 adrenergic blockade may be mediated by two mechanisms; (i) increased POMC synthesis leading to inhibition of LHRH neurons and (ii) direct inhibition of a stimulatory alpha 1 adrenergic/LHRH mechanism.

Animals↗
PubMed1994

Effect of theophylline on exercise performance in patients with severe chronic obstructive pulmonary disease.

BACKGROUND: Theophylline is a well known bronchodilator which has been used for more than 50 years in the treatment of obstructive pulmonary diseases. In patients with severe chronic obstructive pulmonary disease whose cardiopulmonary performance is limited by their ventilatory capacity the administration of theophylline may improve exercise performance. METHODS: A randomised, placebo controlled, double blind, crossover trial was conducted in 22 patients with severe but stable disease. The patients (mean age 68 years) were studied before and after one month of placebo and one month of treatment with a sustained release preparation of theophylline administered orally. The theophylline dose was adjusted until a blood level above 55.5 mumol/l was achieved. The two treatments were administered in random order and separated by a two week washout period. After theophylline was administered for one month a mean level of 68.2 mumol/l was achieved. Pulmonary function tests, arterial blood gas measurements, maximal voluntary ventilation (MVV), and an incremental exercise test were performed before (baseline) and at the end of the first and second month of treatment. RESULTS: Pulmonary function tests showed no improvement in the flow parameters but showed an improvement in MVV after treatment with theophylline. Pulmonary gas exchange was improved after theophylline (resting arterial PO2 8.91 v 8.59 kPa, PCO2 5.38 v 5.56 kPa). The incremental exercise study showed improvement in maximal work rate (86.5 v 75.0 watts) and maximal ventilation (VEmax) (46.7 v 43.01/min). The dyspnoea index on maximal effort (VEmax/MVV), anaerobic threshold, and oxygen pulse remained unchanged. Resting and exercise heart rate were higher after theophylline. CONCLUSIONS: Theophylline improved cardiorespiratory performance in these patients with severe chronic obstructive pulmonary disease mainly by increasing the ventilatory capacity.

Aged↗
PubMed1994

Pituitary adenylate cyclase-activating peptide-38 (PACAP)-38 is released into hypophysial portal blood in the normal male and female rat.

Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated from ovine hypothalamus as two molecular forms, the basic 38 residue amidated peptide PACAP-38 and the N-terminal 27 amino acid sequence PACAP-27. A dense plexus of PACAP immunoreactive fibres is present in the internal and external layers of the median eminence and in other parts of the hypothalamus with PACAP cell bodies in the paraventricular and supraoptic nuclei. The present study shows, for the first time, that, as assessed by radioimmunoassay of extracted plasma, the amount of PACAP-38 in hypophysial portal is significantly greater than in peripheral blood, and that as assessed by reversed phase high performance liquid chromatography, PACAP 1-38 is the major form in portal blood. This evidence is crucial for the fact that PACAP-38 may be a hypothalamic-pituitary regulatory factor.

Animals↗