A walk on water: comparing the influence of Ai Chi and Tai Chi on fall risk and verbal working memory in ageing people with intellectual disabilities - a randomised controlled trial.

BACKGROUND: Aquatic motor intervention has been found to be effective in reducing falls and improving verbal working memory among the general population. However, effects among older adults with intellectual disabilities (ID) have never been explored. The aim of this study was to examine the effects of aquatic motor intervention on fall risk and verbal working memory among older adults with ID. METHODS: Forty-one older adults with mild to moderate ID (age: 50-66 years) were randomly assigned to 14 weeks of aquatic motor intervention (Ai Chi: N = 19) or identical on-land motor intervention (Tai Chi: N = 22). Fall risk, measured with the Tinetti balance assessment tool (TBAT), and verbal working memory, measured with the digit span forward test, were assessed pre-intervention, after 7 weeks of intervention and post-intervention. RESULTS: Study results indicate positive effects of both aquatic and on-land motor intervention on TBAT fall risk score, while the aquatic motor intervention group improved TBAT fall risk score quicker as compared with the on-land motor intervention group. Moreover, the lower the pre-intervention TBAT score was, the higher the improvement. In addition, study findings support the positive effects of aquatic motor intervention on verbal working memory ability as measured with the digit span forward test. CONCLUSIONS: Motor intervention, and particularly in an aquatic environment, can potentially reduce fall risk. Aquatic motor intervention may help to improve verbal working memory among older adults with ID.

The decline in adolescent substance use across Europe and North America in the early twenty-first century: A result of the digital revolution?

OBJECTIVES: Increases in electronic media communication (EMC) and decreases in face-to-face peer contact in the evening (FTF) have been thought to explain the recent decline in adolescent substance use (alcohol, tobacco, cannabis). This study addresses this hypothesis, by examining associations between (time trends in) EMC, FTF, and substance use in more than 25 mainly European countries. METHODS: Using 2002-2014 data from the international Health Behaviour in School-aged Children (HBSC) study, we ran multilevel logistic regression analyses to investigate the above associations. RESULTS: National declines in substance use were associated with declines in FTF, but not with increases in EMC. At the individual level, both EMC and FTF related positively to substance use. For alcohol and cannabis use, the positive association with EMC was stronger in more recent years. Associations between EMC and substance use varied across countries, but this variation could not be explained by the proportion of young people using EMC within countries. CONCLUSIONS: Our research suggests that the decrease in FTF, but not the increase in EMC, plays a role in the recent decrease in adolescent substance use.

Molecular characterization of a novel endonuclease (Xib) and possible involvement in lysosomal glycogen storage disorders.

We cloned and partially characterized a human endonuclease (Xib) which shows sequence homologies to pancreatic DNase I but an enzymatic activity closer to DNase II. We report on the structural differences found between Xib and other recently cloned human DNases. Fluores cence microscopy analysis of transiently transfected cells with Xib::pEGFP constructs indicate that the protein is located in the cytoplasm and possibly anchored to a membrane, as deduced from a hydrophobic amino acid stretch present at the C-terminal end. Xib is overexpressed in muscle and cardiac tissues and is alternately spliced in several normal and neoplastic cells. In situ hybridization studies using human cardiac and muscle biopsies indicate accumulation of Xib transcript in the vacuoles of muscle cells from patients affected by vacuolar myopathy as acid maltase deficiency; however, no point mutations were detected in their DNA.

Size heterogeneity of circulating growth hormone in acromegaly. "Big-big" GH forms are associated with inappropriately low IGF-I levels.

UNLABELLED: Circulating GH consists of several molecular size species with different biological activity. A reduced sensitivity of some monoclonal antibodies towards high-molecular weight GH variants has been reported. The aim of the present work was to evaluate the molecular size species of circulating GH using Sephadex G-100 gel filtration chromatography in acromegalic patients and in normal subjects employing both RIA and an immunoradiometric assay for all GH determinations. In 6 normal subjects, studied under GHRH stimulation, little GH was 69.8 +/- 6% (mean +/- SD), big GH (44 kD) 26.4 +/- 6% and big-big GH (greater than 80 kD) 2.8 +/- 4%, in IRMA, with a good correspondence with RIA results (70.8 +/- 8, 27.0 +/- 4, and 3.2 +/- 2%, respectively). In 13 untreated acromegalic patients, studied in basal conditions, the little form constituted 76.2 +/- 7%, the big form 18.3 +/- 4%, which is significantly lower than in normals (p less than 0.05), and the big-big form 5.5 +/- 7%. Similar results were obtained with RIA. A clear elevation of big-big GH (21% for both in IRMA, and 15.7 and 27.8% in RIA) was found in 2 patients with IGF-I levels lower than expected on the basis of mean GH concentrations. The study was extended to an additional acromegalic patient, previously operated and irradiated on, characterized by discrepant serum GH levels in RIA (4.6 micrograms/l), and in IRMA (1.4 micrograms/l), and by normal IGF-I levels. Serum GH showed a lack of parallelism to standard GH in RIA, but not in IRMA. RIA immunoreactivity was almost completely composed (92%) of a high molecular weight GH form (greater than 90 kD), not recognized by IRMA. All IRMA immunoreactivity eluted with a Kav corresponding to 19-50 kD. IN CONCLUSION: a. the three main molecular size isomers of serum GH are similarly recognized by IRMA and RIA methods in normal subjects. b. in acromegaly, both quantitative and qualitative modifications of the GH chromatographic profile may be present. In particular, increased amounts of big-big forms, whether or not recognized by monoclonal antibodies, have been observed. Their lower bioactivity, suggested by the normal or lower than expected IGF-I levels, can account for the discrepancy between serum GH levels and the clinical picture or IGF-I levels sometimes observed in acromegaly.

Maternal thyroid function in early and late pregnancy.

Thyroid function was investigated during and after pregnancy in 12 healthy euthyroid women. During pregnancy, serum total T4 (TT4) levels were significantly elevated and nearly stable, while thyroxine-binding globulin (TBG) levels progressively increased till the 7th month. A slight elevation, though not significant, of free T4 (fT4) was recorded in early pregnancy. In the following months, fT4, free T3 (fT3) and the T4/TBG ratio progressively diminished, reaching a plateau at the 7th month. Serum TSH levels, measured by an ultrasensitive immunofluorometric assay, were comparable to postpartum values during the first trimester and showed a moderate upward trend with the progression of pregnancy. The evaluation of 24-hour TSH profiles was performed in 5 women during the first trimester of pregnancy. In all women, the circadian rhythm of TSH was present with a normal nocturnal surge, though anticipated in 1 case. In summary (1) during the first trimester of pregnancy, the increased thyroid activity does not seem to be only sustained by pituitary TSH which remains unmodified; the negative correlation between TSH and hCG levels might suggest that hCG also stimulates the gland to increase thyroid hormone output, and the presence of a normal TSH circadian rhythm indicates that the central mechanism of neuroregulation of the pituitary-thyroid axis is preserved in early pregnancy, and (2) in late pregnancy, a marked decrease in free thyroid hormone fractions is accompanied by serum TSH levels still in the normal range, indicating a modification of thyroid homeostasis which might recognize various etiological factors.

Thyrotropin-secreting pituitary adenomas: clinical and biochemical heterogeneity. Case reports and follow-up of nine patients.

STUDY OBJECTIVE: To evaluate the clinical and biochemical features of patients with TSH (thyroid-stimulating hormone, thyrotropin)-secreting pituitary tumors; to measure the biologic activity in vitro of circulating TSH from selected patients before and after pituitary surgery. DESIGN: Case series. SETTING: Patients in an endocrinology unit. PATIENTS: Nine patients with TSH-secreting pituitary tumors. MEASUREMENTS AND MAIN RESULTS: All patients had hyperthyroidism, elevated free thyroxine and triiodothyronine levels, and detected levels of TSH. The free alpha subunit, a tumor marker for neoplasms of gonadotropic or thyrotropic cell origin, was elevated in all nine patients. Seven of the nine patients had been treated with thionamides, radioactive iodine, or thyroidectomy for presumed primary hyperthyroidism. The delay from the initial treatment of hyperthyroidism to the correct diagnosis of a pituitary neoplasm was 6.2 +/- 4.8 (mean +/- SD) years. Two of the seven patients with macroadenomas died in the perioperative period (one at NIH, one at a referring hospital). Of the remaining five patients with macroadenomas, four have residual tumor and inappropriate TSH secretion, despite surgery and radiation therapy, at follow-up from 3.5 to 6 years. In contrast, the two patients with microadenomas are clinically cured 2.5 and 4 years after transsphenoidal adenomectomy. The biologic to immunologic (B/I) ratio of serum TSH, determined preoperatively in five patients with TSH-secreting tumors, was elevated compared with euthyroid subjects. In three patients the B/I ratio of serum TSH was also measured after pituitary surgery; in two the elevated B/I ratio returned to normal after successful pituitary adenomectomy, while in the third this ratio remained elevated after incomplete adenoma resection. CONCLUSIONS: With the routine availability of ultrasensitive TSH assays and their increasing use to confirm thyrotoxicosis from all causes, we expect that TSH-secreting pituitary tumors will be diagnosed earlier, before inappropriate antithyroid therapy, permitting an improved outcome.

Studies of two thyrotrophin-secreting pituitary adenomas: evidence for dopamine receptor deficiency.

Of 22 previously reported patients with TSH-secreting pituitary adenomas challenged with dopamine agonists, 18 showed no decrease in serum TSH. There have been few in-vitro studies of these rare tumours so the mechanism of the dopaminergic resistance has remained obscure. We describe two further patients with thyrotrophinomas; the first was thyrotoxic (T3 6.1 nmol/l, TSH 7 mU/l) and the second was diagnosed after radioiodine for presumed Graves' disease. The second patient had an alpha-subunit: TSH molar ratio less than unity (0.27). In-vivo TSH responses to TRH, bromocriptine and domperidone were compared with those of the resected tumour cells in vitro, the latter studied using a continuous perifusion system. Dopamine receptors were sought in membranes from each tumour using a radioreceptor assay employing 3H-spiperone. Patient 1 showed significant increases in serum TSH (7 to 13 mU/l) and alpha-subunit (18.7 to 385 ng/ml) after 200 micrograms TRH (i.v.) but patient 2 showed no such increases (TSH: 69 to 72 mU/l, alpha-subunit: 4.9 to 5.2 ng/ml). Neither patient showed a change in serum TSH following bromocriptine 2.5 mg (orally) or domperidone 10 mg (i.v.), though serum PRL responded normally. Serum TSH from patient 1 was of apparently normal molecular size but increased bioactivity (B/I ratio 3.8) and that from patient 2 was of increased molecular size but reduced bioactivity (B/I ratio 0.1). Tumour cells from each patient immunostained for TSH beta and alpha-subunit, and secreted TSH in vitro. The first showed dose-dependent TSH release after TRH (1-100 ng/ml) which could not be inhibited by dopamine (5 mumol/l) but the second was unresponsive to TRH in vitro. Neither tumour showed inhibition of TSH release by dopamine (5 mumol/l) or bromocriptine (0.01-10 nmol/l) and neither contained membrane-bound dopamine receptors. The results suggest that the dopaminergic resistance typical of most TSH-secreting pituitary adenomas may be due to altered or absent membrane-bound dopamine receptors.

A sensitive thyrotropin (TSH) bioassay based on iodide uptake in rat FRTL-5 thyroid cells: comparison with the adenosine 3',5'-monophosphate response to human serum TSH and enzymatically deglycosylated bovine and human TSH.

A sensitive in vitro assay based on the uptake of 125I by the FRTL-5 rat thyroid cell line has been applied to the measurement of TSH bioactivity from different sources. In this bioassay various human pituitary reference preparations showed similar potencies; the limit of detection and the half-maximal response were 1.60 +/- 0.1 (+/- SE) and 9.70 +/- 0.40 microU/0.5 ml, respectively; however, when compared to pituitary TSH from other species, human TSH was 29- and 10-fold less biopotent than bovine and rat TSH, respectively. The iodide uptake response to TSH was inhibited by the presence of human serum in a dose-dependent fashion, but pretreatment of serum with 10% polyethylene glycol restored TSH activity. The iodide uptake response was compared to the stimulation of cAMP production in the measurement of serum TSH bioactivity from human samples after immunoaffinity purification. In the cAMP production bioassay, immunoaffinity-purified serum TSH showed increased bioactivity in patients with primary hypothyroidism and TSH-secreting pituitary tumor compared to that in normal subjects, while in the iodide uptake bioassay minimal differences were detected among the different groups. To investigate further structure-function relationships of TSH in FRTL-5 cells we studied the effects of deglycosylated purified pituitary bovine and human TSH on both bioassays. Using two new enzymes, peptide-N-glycosidase and endo-beta-N-acetylglucosaminidase F, we removed one carbohydrate chain from TSH alpha and all three chains from TSH, respectively. In the iodide uptake bioassay both enzymes induced a 2-fold decrease in TSH biopotency, while in the cAMP production bioassay this decrease was only present with peptide-N-glycosidase-treated TSH. In summary, 1) the iodide uptake bioassay system in FRTL-5 cells represents a valid and sensitive method for the measurement of TSH bioactivity from different sources and can be applied to serum samples with elevated TSH concentrations by simple pretreatment with polyethylene glycol without immunoaffinity purification; 2) the enzymatic removal of one carbohydrate chain from both bovine and human TSH significantly decrease their biological activity, assessed as cAMP production and iodide uptake response in FRTL-5 cells, while the removal of three carbohydrate chains induces a significant decrease only in the iodide uptake bioassay: and 3) the disparate results for cAMP and iodide uptake in both human samples and deglycosylated pituitary TSH suggest that in addition to cAMP, other second messengers may play a role in TSH action.

Intrinsic bioactivity of thyrotropin in human serum is inversely correlated with thyroid hormone concentrations. Application of a new bioassay using the FRTL-5 rat thyroid cell strain.

We have developed a new bioassay for thyrotropin (TSH) in human serum to evaluate bioactivity in normal individuals and patients with different degrees of primary hypothyroidism. Unpurified TSH in serum showed no stimulation of cyclic AMP production in cultured FRTL-5 rat thyroid cells, but after immunopurification showed potent stimulatory activity. Immunoaffinity purification permitted up to 400-fold concentration of serum TSH, allowing bioactivity measurements even in certain normal sera. The limit of detection in the FRTL-5 bioassay was 10 microU of human TSH per 0.5 ml incubate, and half-maximal responses for standard human TSH was 102 +/- 26 (+/- SE) microU/0.5 ml. Immunoaffinity-purified serum TSH varied in bioactivity-to-immunoactivity (B/I) ratios from less than 0.25 to 1.21 among four euthyroid subjects and eight primary hypothyroid patients. An inverse correlation was found between B/I ratios of immunopurified basal TSH and the serum-free T4 (r = -0.7237, P less than 0.01), T4 (r = -0.6650, P less than 0.05), and T3 (r = -0.6382, P less than 0.05). B/I ratios of immunopurified TSH from three hypothyroid patients before and after acute stimulation by thyrotropin-releasing hormone showed no significant change, despite major changes in serum TSH. In summary, the present study shows an inverse relationship between the metabolic status of an individual and the intrinsic bioactivity of TSH.

Endocrine, biochemical, and morphological studies of a pituitary adenoma secreting growth hormone, thyrotropin (TSH), and alpha-subunit: evidence for secretion of TSH with increased bioactivity.

A 40-yr-old man who had acromegaly and hyperthyroidism due to a GH/TSH-secreting pituitary adenoma is described. Serum free T4 was 2.8 ng/dl, free T3 was 1.1 ng/dl, and TSH was 1.2-1.5 microU/ml; the latter was measured in an immunoradiometric assay with a sensitivity of 0.07 microU/ml. Serum TSH was immunologically identical to standard TSH and did not decrease during a T3 suppression test. Serum free alpha-subunit and the molar alpha-subunit to TSH ratio were high (6.1 ng/ml and 31.2, respectively). TRH administration induced significant increases in both GH (+129%) and alpha-subunit (+156%) levels. Conversely, dopamine infusion resulted in a decrease in serum GH (-66%) and alpha-subunit (-43%) levels, and subsequent administration of the dopamine antagonist sulpiride induced significant increases in both GH and alpha-subunit (+393% and +106%, respectively). Similarly, somatostatin infusion inhibited GH (-43%) and alpha-subunit (-61%) secretion. Serum TSH levels were not affected by TRH, dopamine, or somatostatin. The biological to immunological activity ratio of serum TSH purified by immunoaffinity chromatography and measured in an adenylate cyclase assay was significantly increased compared to that in serum from hypothyroid or euthyroid subjects [biological to immunological activity ratio, 6.9 +/- 0.2 (+/- SD) vs. 4.4 +/- 1.1; P less than 0.001]. In gel chromatography, the apparent mol wt of the patient's TSH was smaller than that of the controls. After adenomectomy, all of the altered parameters of pituitary function became normal. Double gold particle immunostaining of the adenomatous tissue showed that all of the cells contained secretory granules positive for GH and alpha-subunit, while very few cells were positive for TSH beta as well as GH and alpha-subunit. These data indicate that in this patient serum TSH had an apparent mol wt smaller than that of normal TSH and an increased biological activity which, along with the autonomous TSH secretion, account for hyperthyroidism in the presence of low normal TSH levels; alpha-subunit originated from the same adenomatous cells that secreted GH but not TSH, thus explaining the in vivo observation that alpha-subunit responses to several agents were dissociated from TSH responses and parallel to GH responses; and TSH and GH were colocalized in a minority of the neoplastic cells.

Bromocriptine treatment of microprolactinomas: evidence of stable prolactin decrease after drug withdrawal.

Thirty-six women with PRL-secreting pituitary microadenomas [mean PRL, 114 +/- 12.5 (+/- SE) ng/ml] were treated with bromocriptine (BRC; 2.5-10 mg/day) for 12 months. During BRC treatment, serum PRL decreased in all patients. After termination of treatment, mean serum PRL levels, evaluated at 15, 30, and 45 days, were significantly decreased (-41.6%, -43.0%, and -40.2%, respectively) compared to pretreatment values. The patients were arbitrarily divided into 3 groups: 12 responders, in whom the PRL persistent posttreatment decrease was greater than 50%, 8 hyporesponders, in whom the PRL decrease was between 30% and 50%, and 16 nonresponders with absent or negligible PRL decrease. Four patients had normal PRL levels and clinical remission for 14-30 months after BRC withdrawal. In 18 women, BRC treatment was repeated for another 12 months. After termination of treatment, 11 patients were responders, 1 was a hyporesponder, and 6 were nonresponders. Four of these 18 patients still had normal PRL levels 8-28 months after drug discontinuation. The responses of PRL to TRH and domperidone were compared before and after termination of treatment at 30 and 45 days, respectively. Both mean peak values of PRL and absolute increases after TRH treatment were similar before and after BRC administration; however, a PRL response to TRH was present in 15% of 26 patients before treatment and in 42% after treatment. The mean peak values after domperidone were similar before and after BRC treatment, but the absolute increase over the basal value was much higher after BRC; PRL response to domperidone was present in 16% of 19 patients before BRC treatment and in 74% after BRC. These data suggest that BRC is effective in the treatment of some microprolactinomas; BRC effectiveness improves after prolonged periods of administration. The variations in PRL responses to TRH and domperidone suggest profound modification of PRL secretion after BRC treatment.

Effect of bromocriptine and metergoline in the treatment of hyperprolactinaemic states.

The effects of bromocriptine or metergoline treatment were evaluated in 80 hyperprolactinaemic patients (62 women and 18 men). The patients were subdivided into 4 groups: group A) 16 women with idiopathic hyperprolactinaemia; group B) 19 women with untreated Prl-secreting microadenomas; group C) 27 women with unsuccessfully operated prolactinomas; group D) 18 men with unsuccessfully treated macroprolactinomas. Sixty-eight patients were given bromocriptine (2.5-20 mg/day) for 3-58 months and 33 patients were given metergoline (4-16 mg/day) for 3-19 months. Bromocriptine and metergoline were equally effective in the treatment of functional hyperprolactinaemia and of untreated microadenomas, while bromocriptine showed a more potent Prl-lowering effect than metergoline in patients with higher Prl levels and large prolactinomas; both drugs restored the gonadal function to a similar extent, though metergoline was effective in some cases, even in the absence of full Prl suppression. Bromocriptine seems to exert an antitumoral effect, as documented by CT scan in some patients with macroadenomas, but the precise role of both drugs with respect to dose, length of treatment and effectiveness after withdrawal needs to be evaluated further.

Evaluation of two inhibitory tests (nomifensine and L-dopa + carbidopa) for the diagnosis of hyperprolactinaemic states.

It has been reported that administration of nomifensine (Nom) or of L-dopa + carbidopa (L-dopa + Carb) potentiates central dopaminergic tonus, resulting in decreased prolactin (PRL) secretion. It has been proposed that these drugs would help to discriminate patients with PRL-secreting pituitary tumours from those with so-called 'functional' hyperprolactinaemia. In this study, oral Nom (200 mg) was given to forty-three hyperprolactinaemic patients and L-dopa + Carb (50 mg Carb every 6 h for four doses followed by L-dopa 100 mg and Carb 35 mg) to thirty of them and both treatment to ten normal subjects. The hyperprolactinaemic patients were divided into four clinical groups. Group A, twenty patients with proven PRL-secreting pituitary tumours; Group B, thirteen women with elevated PRL levels (less than 100 ng/ml) without any radiological evidence of a pituitary tumour (hyperprolactinaemia of unknown aetiology or 'functional' hyperprolactinaemia); Group C, four women with polycystic ovarian disease and mildly elevated serum PRL; Group D, six patients with various other disorders associated with hyperprolactinaemia. PRL levels decreased in the normal controls below the basal values by 61.3% +/- 6.2 (SEM) after Nom and 77.6% +/- 4.2 after L-dopa + Carb. Decreases in serum PRL of at least 50% (in three consecutive determinations) were found in group A in 20% of patients after Nom and in 25% after L-dopa + Carb; in group B in 15% and 40% of cases; in most of the hyperprolactinaemic women in group C; and some in group D. In conclusion, these two treatments did not discriminate between tumorous and non-tumorous cases of PRL hypersecretion.