CHRNA7 haplotypes are associated with impaired attention in euthymic bipolar disorder.

BACKGROUND: Bipolar disorder (BD) patients show a deficit in sustained attention during euthymic periods. This deficit may be relevant for genetic studies in these patients. The α7 cholinergic receptor plays an important role in attentional deficit in humans and animal models. Moreover, there is evidence suggesting the role of the alpha 7 nicotinic cholinergic receptor subunit gene (CHRNA7) in BD susceptibility. The aim of the present study was to investigate the impact of CHRNA7 in sustained attention performance. METHODS: We studied the association of a promoter variant (-86C/T) and three intronic polymorphisms, rs883473, rs6494223 and rs904952, in the non-duplicated region of CHRNA7 with sustained attention in 143 euthymic BD patients (based on DSM-IV criteria) and 101 healthy subjects. Sustained attention was assessed by the degraded stimulus (DS-CPT) version of Continuous Performance Test. Age, gender, years of education and IQ (WAIS vocabulary subtest) were controlled in the analyses as potential confounders. RESULTS: Several candidate polymorphisms showed significant associations with different measures of the neuropsychological task for bipolar group. The CTCT haplotype was associated with an improvement in the attentional task performance in the BD group (p ≤ 0.025). On the other hand, different low frequency haplotypes showed influence in bipolar attentional performance (p ≤ 0.026). LIMITATIONS: A replication study using larger samples may be required for conclusive results. CONCLUSIONS: Our results point toward a slight association of CHRNA7 genotypes and haplotypes with sustained attention performance in euthymic patients with BD.

APOE, ACT and CHRNA7 genes in the conversion from amnestic mild cognitive impairment to Alzheimer's disease.

We have investigated whether the -86 C/T promoter polymorphism in CHRNA7 gene, the signal peptide polymorphism of the alpha1-antichymotripsin (ACT) gene or the APOE genotype are associated with an increased risk of mild cognitive impairment (MCI) or affect the risk of evolution to Alzheimer's disease (AD). We have followed up 89 patients with initial diagnoses of amnestic MCI for 49 months. Patients were separated into three groups: 27 subjects who remained with MCI, 40 that converted to AD before 20 months and 22 that converted to AD after. To assess the risk associated to each genotype a control group (n=90) without cognitive impairment was included. APOE4 allele was associated with an increased risk of MCI (OR: 6.04, 95% CI: 2.76-3.23; p<0.001) but did not have an effect on the probability of evolving AD. ACT or CHRNA7 genotypes were not associated with MCI but both appear to modify the risk of progression to dementia in opposing manners: ACT polymorphism increasing the risk to evolve to AD before 20 months (HR=2.03; 95% CI: 1-4.6; p=0.06) and CHRNA7 polymorphism protecting from evolution to dementia. Cox regression model demonstrated that ACT genotype confers a higher risk of rapid evolution to dementia than age or years of schooling. We conclude that APOE is a risk gene for amnestic MCI and that ACT and CHRNA7 may act in these patients as modifier genes for the time of progression to AD.

Regional cerebral blood flow in obsessive-compulsive patients with and without a chronic tic disorder. A SPECT study.

The main goal of the present study was to explore whether regional cerebral blood flow (rCBF) differs between obsessive-compulsive disorder (OCD) patients without chronic motor tic disorder and those OCD patients with a comorbid chronic tic disorder. Twenty-seven patients suffering from OCD (DSM-IV criteria), including 7 OCD patients who met DSM-IV criteria for simple chronic motor dic disorder, and 16 healthy volunteers were examined at rest using a high resolution SPECT. Seven regions of interest (ROIs) were manually traced and quantified as a percentage of the mean cerebellar uptake. Severity of obsessive-compulsive symptoms (OCS), anxiety and depressive symptoms and presence of motor tics were assessed with the Y-BOCS, HRS-A, HRS-D, MADRS, and Yale Global Tics Severity Scale, respectively. We found a significant relative decrease in rCBF in OCD patients without motor tics compared to healthy volunteers in the right orbitofrontal cortex (OCD without tics = 0.87; healthy volunteers = 0.94; p = 0.02). No significant differences in rCBF were seen when OCD patients with and without chronic tics were directly compared. A lower severity of OCS in OCD patients with chronic tics was found. These results are consistent with previous functional neuroimaging studies at rest that have widely involved the orbitofrontal cortex in the pathophysiology of the OCD. However, our results do not support the idea that OCD patients with chronic tics may constitute a biological subgroup within the OCD.

[Hashimoto toxicosis: diagnostic criteria and a 10-year follow up]. / Hashitoxicosis: criterios diagnósticos y evolución a los diez años de seguimiento.

An study was carried out of the association of Basedow disease (B) and Hashimoto toxicosis (H), the response to the usual therapeutic regimens and prognostic factors for the clinical course. Seventy-one patients with the diagnosis of autoimmune hyperthyroidism were included. Sixty-one of them were prospectively followed for 8.4 +/- 2.2 years (range: 5-10 years). All patients were treated following the same criteria with antithyroid drugs and aggressive therapy (radioiodine or surgery). Two groups were differentiated: group H (62%), with titers of antimicrosomal antibodies (AMSA) > or = 1/6,400 and a positive perchlorate discharge test (PDT), and group B, with AMSA titers < 1/6,400 and negative PDT. During follow-up a three-fold number of relapses was observed in group H compared with group B, a higher frequency towards spontaneous hypothyroidism in the evolution (23% in H versus 0% in B), and higher requirements of radioiodine in H than in B. In our experience, H makes up and important percentage of autoimmune hyperthyroidism (62%) with a clinical course characterized by a higher number of relapses, higher requirements of radioiodine and a higher rate towards spontaneous hypothyroidism.

Long-term influence of anticonvulsant agents on calcitonin, parathyroid hormone and osteocalcin.

It has been reported that anticonvulsant drugs decrease serum calcitonin; this effect may be dose dependent and/or hypocalcemia dependent. The objective of the present study is to assess such a dependence and to evaluate other parameters in relation to calcitonin. Serum calcitonin, parathyroid hormone and osteocalcin were determined through RIA, and serum calcium, total protein and alkaline phosphatase through an autoanalyzer in 17 patients undergoing long-term treatment with phenytoin and phenobarbital. At the same time, 20 normal subjects were studied and served as controls. In the patients, no changes were observed in calcitonin, parathormone, osteocalcin and calcemia corrected for protein, and there was a statistically significant increase in alkaline phosphatase values (p < 0.001). Calcemia correlated positively with calcitonin (p < 0.01) and negatively with parathormone (p < 0.05). There was no calcitonin correlation with the anticonvulsant dosage or with the total doses ingested. Increased alkaline phosphatase levels in the presence of normal osteocalcin figures suggest a hepatic origin of the former. The fact that there were no calcitonin level changes but a correlation did exist between calcitonin and calcemia leads us to think that any hormonal changes induced by anticonvulsant agents may act indirectly through changes induced in serum calcium.

Association of a thyrotropin-secreting pituitary adenoma and a thyroid follicular carcinoma.

The different factors involved as etiological agents in thyroid cancer have in common long term thyroid follicle stimulation. On this base, a patient with a TSH-producing pituitary adenoma could be at high risk for developing thyroid cancer. A patient consulting for a single thyroid nodule was studied in our unit. He was diagnosed as having a TSH-producing pituitary adenoma and the Thyroid nodule was shown to be a follicular carcinoma following removed. We speculate that elevated TSH levels could have contributed to neoplastic transformation of the thyroid in this patient.

Reversion of the steroid-induced decrease of serum osteocalcin with sodium fluoride.

Osteopenia observed in corticotherapy is due, among other causes, to a decrease in bone formation as can be shown by a steroid-induced osteocalcin decrease. Although various treatments have been proposed there is no agreement as to which one is the best. Two such treatments, sodium fluoride and vitamin D administration increase osteocalcin levels. We treated a group of 12 patients under corticoid therapy (mean dose 16 mg per day) with 50 mg/day p.o. sodium fluoride, and determined osteocalcin levels before and two weeks after sodium fluoride treatment. Similarly, another group of 9 patients with a similar mean steroid dose was treated with 0.5 micrograms/day of 1 alpha (OH)2D3 in order to assess the effect of this vitamin on osteocalcin and to determine which was the best treatment. Both groups were compared with respective control groups. A significant osteocalcin increase was observed in the control groups (p less than 0.001); similar significance was observed in the sodium fluoride group, whereas a lower significance (p less than 0.01) was observed in the vitamin D group. These results suggest that sodium fluoride could be more effective than vitamin D in the treatment of steroid-induced osteopenia.

Effect of calcium pidolate on biochemical and hormonal parameters in involutional osteoporosis.

The purpose of this study was to determine the value of calcium pidolate in the treatment of involutional osteoporosis. This compound has been reported to be better absorbed than other calcium salts, to lower the levels of parathyroid hormone (PTH) and to raise those of growth hormone (GH). We accordingly treated one group of 10 women suffering from involutional osteoporosis with the equivalent of 1 g elemental calcium and administered a placebo to a second group of 10 osteoporotic women whose mean age and body surface area were comparable. Basal sequential multiple analysis (SMA-12) was performed in all subjects to determine calcium, phosphorus, alkaline phosphatase (ALP) and total protein levels, the same blood samples being used for the evaluation of mean PTH, GH and osteocalcin (BGP). Urinary 24-h calcium excretion was determined and the calcium/creatinine (Ca/Cr) and hydroxyproline/Cr (HP/Cr) ratios were measured in 12-h fasting urine samples, the results being corrected for glomerular filtrate. The same parameters were measured again following a month of uninterrupted treatment. After 30 days, we observed no differences in either group as regards calcaemia, phosphataemia, ALP, total proteins, PTH, GH, BGP or 24-hour calciuria. The only noteworthy changes seen were significant decreases (P less than 0.001) in the Ca/Cr and HP/Cr ratios in the group treated with calcium pidolate. These results show that calcium pidolate at the dose administered inhibits bone resorption but does not affect the levels of PTH, GH, BGP or ALP in the medium term. Our findings indicate that it has no influence on bone formation.

Lower serum osteocalcin levels in pregnant drug users and their newborns at the time of delivery.

Osteocalcin was evaluated by radioimmunoassay at the time of delivery in mothers and in the umbilical arteries of newborns in a group of pregnant drug users (eight heroin users and seven cocaine users) and compared with findings from a group of normal mothers and their newborns (N = 18). Drug users had lower osteocalcin values than did the normal women (1.3 +/- 0.7 versus 2.7 +/- 0.8 ng/mL, P less than .001); and infants of drug users had lower values than normal infants (14.1 +/- 3.8 versus 19.0 +/- 4.0 ng/mL, P less than .005). The birth weights of drug users' infants were smaller (3160 +/- 402 versus 3591 +/- 374 g, P less than .05) and there was a significant negative correlation (P less than .001) between osteocalcin and drug intake during pregnancy, but no changes in osteocalcin dependent on the type of drug used. These results suggest a toxic effect of these drugs on the osteoblast, which could account for the lower birth weights and skeletal alterations reported in the infants of drug users.

Osteopenia in rheumatoid arthritis: a biochemical, hormonal and histomorphometric study.

To determine whether the osteopenia of rheumatoid arthritis (RA) is due to reduction of trabecular bone mass (TBV) and/or cortical width (CW), we evaluated these parameters by bone histomorphometry; we also measured the calciotropic hormones parathormone(PTH) and calcitonin (CT), vitamin D [25(OH)D] and the biological markers of bone remodeling in a group of patients with RA. Study subjects were divided into Group C - premenopausal patients, and Group A - menopausal patients and men of the same ages. These groups were compared to two age-matched control groups, B and D. In both A vs. B and C vs. D, TBV and CW were significantly lower in patients. There were no differences in PTH or CT, but 25(OH)D was significantly reduced, and BGP, OHP/Cr and AP were raised in patients. Patients also exhibited TBV loss in more than 55% and CW loss in more than 98%. These changes suggest that the decline in bone mass, mainly cortical, but also trabecular, is due to increased bone turnover and enhanced resorption and seem to reflect intrinsic alterations of RA.

Hyperparathyroidism in metastases of prostatic carcinoma: a biochemical, hormonal and histomorphometric study.

Secondary hyperparathyroidism can develop as a result of bone metastases from prostatic cancer, but this has not been studied from the multiple aspects of biochemistry, hormonal status and histomorphometry. In 20 patients with stage-D prostatic cancer, a transiliac bone biopsy was performed for histomorphometric study. In all of them, molecular parathormone (PTH-M) and osteocalcin were determined by radioimmunoassay together with other parameters considered to be biological markers of bone remodelling. Of these 20 patients, only 2 (10%) had elevated PTH-M (240 +/- 20.6 pmol/l), differing significantly from the other 18 (58.6 +/- 11.7 pmol/l) and from controls (60.4 +/- 7.2 pmol/l). In the high PTH-M patients, corrected calcium was low (7.8 +/- 0.4 mg/dl) as compared to normal PTH-M patients (9.2 +/- 0.5 mg/dl, p less than 0.001), and this was also the case for serum phosphorus (2.2 +/- 0.6 vs. 3.2 +/- 0.3 and 3.4 +/- 0.4 mg/dl, respectively p less than 0.001). Alkaline phosphatase was raised in the patient groups as compared to controls (p less than 0.001) and was higher in the high PTH-M group (362 +/- 58 vs. 224 +/- 62 U/l, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Prolactin-lowering effect of luteinizing hormone-releasing hormone agonist administration in prolactinoma patients.

We studied the effect of LHRH agonist administration on serum PRL levels in five women with microprolactinomas and two women and a man with intrasellar macroprolactinomas. Each patient received either D-Trp6-LHRH or buserelin for 90 days. Serum PRL levels decreased significantly in the patients with microprolactinomas by 65%, from 156 +/- 93 (+/- SD) to 54 +/- 49 micrograms/L on day 90 (P = 0.011), but it did not decrease in the macroprolactinoma patients. Mean serum LH and FSH decreased by 43% and 62.5%, respectively, in all eight patients. There was no statistically significant correlation between the serum PRL and LH or FSH levels in the microprolactinoma patients. We conclude that LHRH agonists can counteract the hyperprolactinemia produced by microprolactinomas and that the effect probably is not exerted by an action on the gonadotrophs.

Suggestion of a deficient osteoblastic function in diabetes mellitus: the possible cause of osteopenia in diabetics.

The mechanism underlying diabetic osteopenia is still unclear and may involve osteoblastic activity and/or the deficit of insulin's anabolic action. Bone gla protein (BGP) is synthesized by the osteoblast and its synthesis increases with 1,25(OH)2D3 and fluoride. Because 1,25(OH)2D3 also stimulates insulin secretion, sodium fluoride administration can be used to investigate deficient osteoblastic activity in diabetics, as reflected by BGP levels. BGP was determined before and after administering sodium fluoride at a dosage of 50 mg/day/15 days to three groups: 14 patients with insulin-dependent diabetes, 16 diabetics on oral antidiabetic treatment, and 25 controls, all of similar age, sex, and characteristics. Basal BGP values (mean +/- SD) were low in diabetics on insulin treatment (4.3 +/- 1.1 ng/ml) and in diabetics on oral antidiabetics (5.8 +/- 1.2 ng/ml) as compared with controls (6.5 +/- 0.7 ng/ml) (P less than 0.001 and less than 0.05, respectively). After giving fluoride, BGP values did not change in the two diabetic groups but did vary in controls (8.1 +/- 0.6 ng/ml, P less than 0.001). These results suggest that deficient osteoblast function could be responsible for osteopenia in diabetics.

Clinical response and plasma haloperidol levels in chronic and subchronic schizophrenia.

Levels of haloperidol were determined by radioimmunoassay (RIA) in 30 schizophrenic patients (diagnosed according to the criteria of DSM-III), who were treated with fixed doses of this neuroleptic for a period of 21 days. An inverted U-shaped relationship was found between the percent improvement observed in the BPRS global score and the steady state of haloperidol. The interval of effective concentration of haloperidol was set between 12.0 and 35.5 ng/ml. However, the limits of such an interval found in the subchronic schizophrenic subgroup (SS) ranged from 7.4 to 24.9 ng/ml, whereas in the chronic schizophrenic subgroup (CS), it ranged from 14.8 to 38.5 ng/ml. This finding suggests that the interval of effective concentrations may vary as a function of the number of years of evolution of the subjects' illness. This may be compatible with the development of tolerance in the mesolimbic and/or mesocortical dopaminergic systems as a response to prolonged neuroleptic treatments.

Clinical implications of determination of plasma haloperidol levels.

The aim of this study was to analyze the clinical utility of monitoring plasma levels, since the utility of monitoring is not yet well established. After a washout period, 30 schizophrenic patients were given fixed doses of haloperidol for 3 weeks. A U-shaped second-grade polynomic relationship (R = 0.69) was found between steady state of haloperidol and percentage improvement in total score on the Brief Psychiatric Rating Scale. The interval of effective concentrations was between 12 and 59 ng/ml. Fourteen of the 15 patients who had a steady state of haloperidol within that therapeutic interval were responders: only 5 out of the 15 patients below the therapeutic interval were responders. None of the 5 patients who had concentrations below 8 ng/ml was a responder. Furthermore, responder patients showed a steady-state level of haloperidol significantly higher than that of nonresponders. These data suggest that plasma levels of haloperidol are predictors of therapeutic response in schizophrenic disorders.

Determination of plasma haloperidol concentrations by radioreceptor assay in schizophrenia: clinical utility.

1. Haloperidol concentrations were determined by radioreceptor assay (RRA) and prolactin concentrations were measured in 20 patients diagnosed as schizophrenia (DSM-III). 2. The patients were treated with a fixed dose of haloperidol for 21 days. 3. Our results suggest the existence of a curvilinear relationship, in the form of an inverted U, between stable haloperidol levels and clinical improvement assessed by total BPRS score. 4. We also found a curvilinear relationship between the improvement observed in positive symptoms and state steady levels. 5. No relationship was seen between improvement in negative symptoms and state steady levels. 6. An interval of optimal haloperidol concentration was found: 8.1 ng/ml to 19.6 ng/ml. 7. No relation was found between the dose of haloperidol administered and plasmatic concentration, nor between haloperidol and prolactin levels. 8. Our findings suggest that haloperidol concentrations determined by RRA have clinical utility as predictors of response in schizophrenia.

Differential effects of direct and indirectly acting cholinergic agonists on growth hormone release in man, and lack of effect on cortisol secretion.

Abstract Acetylcholine plays a key role in the modulation of growth hormone secretion. In fact, growth hormone release after provocative stimuli is blocked by muscarinic cholinergic antagonists, and conversely, indirect cholinergic agonists potentiate growth hormone secretion. To further understand the mechanism by which cholinergic pathways exert their effects, we have compared the growth hormone and cortisol secretion elicited on normal volunteers by pyridostigmine and by RS-86 (2-ethyl-8-methyl-2,8-diazaspiro-((4,5))-decan-1,3-dion hydrobromide). The former acts by inhibiting acetylcholinesterase, thus being an indirect muscarinic agonist, while the latter is a muscarinic receptor agonist which binds directly to and stimulates cholinergic receptors. In six subjects, pyridostigmine (120 mg po) induced an increase of growth hormone of 11.0+/-2.4 mug/L at 90 min, significantly greater than following placebo administration (1.4 +/- 0.3 mug/L). In another group of five volunteers, RS-86 was administered in separate tests at a dose of 0.5, 1 and 2 mg po. Growth hormone levels were not altered by any RS-86 dose compared with placebo values. Neither pyridostigmine nor RS-86 altered cortisol values. These results suggest that the mechanism of action of the cholinergic agonists is of great importance for their growth hormone-releasing capabilities, and question the accepted view of a cholinergic regulation of cortisol secretion in man.

Somatomedin-C and growth hormone levels in anorexia nervosa in relation to the puberal or post puberal stages.

1. Plasma concentrations of somatomedin-C and GH were determined in 21 patients diagnosed as anorexia nervosa (AN) and in 44 controls. 2. Somatomedin-C concentrations were significantly lower in pubertal AN patients than in controls, but not in post pubertal patients. 3. GH was increased in both pubertal and post pubertal AN patients, although more in pubertal AN patients. 4. Our results suggest that the hormonal alterations that appear in AN constitute a mechanism of defense against starvation. The activation of these defense mechanisms and the degree of modification produced in normal hormonal patterns depend not only on caloric intake but also on metabolic requirements.