bluuebunny/crossref_metadata_2025 huggingface dataset:
One size does not fit all: how the tobacco industry has altered cigarette design to target consumer groups with specific psychological and psychosocial needs
Authors: Cook Benjamin Lê , Wayne Geoffrey Ferris , Keithly Lois , Connolly Gregory
Published: October 2003

Aims To identify whether the tobacco industry has targeted cigarette product design towards individuals with varying psychological/psychosocial needs.

Design Internal industry documents were identified through searches of an online archival document research tool database using relevancy criteria of consumer segmentation and needs assessment.

Findings The industry segmented consumer markets based on psychological needs (stress relief, behavioral arousal, performance enhancement, obesity reduction) and psychosocial needs (social acceptance, personal image). Associations between these segments and smoking behaviors, brand and design preferences were used to create cigarette brands targeting individuals with these needs.

Conclusions Cigarette brands created to address the psychological/psychosocial needs of smokers may increase the likelihood of smoking initiation and addiction. Awareness of targeted product development will improve smoking cessation and prevention efforts.
Effects of treatment with Sandostatin®LAR®on small dense LDL and remnant‐like lipoproteins in patients with acromegaly
Authors: Tan K. C. B. , Pang R. W. C. , Tiu S. C. , Lam K. S. L.
Published: October 2003

objective Acromegalic patients have been shown to have an increase in the concentrations of small dense low‐density lipoprotein (LDL) and remnant‐like lipoprotein particles (RLP). These lipoproteins are atherogenic and may contribute to the cardiovascular risk of these patients. The aim of this study was to determine whether treatment of acromegaly using Sandostatin®LAR®could lower these atherogenic lipoproteins.

methods Fourteen patients with active acromegaly were recruited and Sandostatin®LAR®, a long‐acting somatostatin analogue, was given every 4 weeks by intramuscular injection for 6 months. Fasting lipids, lipoproteins, lipolytic enzymes were determined at baseline, 12 and 24 weeks after treatment. Small dense LDL was measured using density gradient ultracentrifugation and RLP‐cholesterol (RLP‐C) by an immunoseparation assay.

results There was already a marked reduction in GH and IGF‐1 by week 8 and, in all subjects, IGF‐1 levels within their respective age‐specific normal range were achieved. At week 12, plasma triglyceride significantly decreased (P < 0·01) and both HDL2(P < 0·01) and HDL3(P < 0·01) subfractions increased. A reduction was seen in small dense LDL concentration (P < 0·05) and RLP‐C (P < 0·05). Lipoprotein lipase (LPL) activity increased (P < 0·01) and the magnitude of the increase in LPL activity correlated with the increase in HDL at 3 months (r = 0·55,P< 0·05) but not with the changes in plasma triglyceride, small dense LDL or RLP‐C. The improvement in plasma lipids and lipoproteins persisted until the end of the study.

conclusion Sandostatin®LAR®is effective in the treatment of acromegaly and is associated with favourable changes in plasma lipids and a reduction in small dense LDL and RLP‐C.
SPECT/CT hybrid imaging with 111In‐pentetreotide in assessment of neuroendocrine tumours
Authors: Krausz Yodphat , Keidar Zohar , Kogan Igor , Even‐Sapir Einat , Bar‐Shalom Rachel , Engel Ahuva , Rubinstein Rina , Sachs Jonathan , Bocher Moshe , Agranovicz Svetlana , Chisin Roland , Israel Ora
Published: October 2003

objective  Somatostatin receptor scintigraphy (SRS) of neuroendocrine (NE) tumours is often challenging because of minute lesion size and poor anatomic delineation. This study evaluates the impact of sequentially performed single‐photon emission computed tomography (SPECT)/CT fusion on SRS study interpretation and clinical management of these tumours.

patients and design  Seventy‐two patients were studied with routine SRS and SPECT/CT at 4, 24 and optionally 48 h after injection of 222 MBq 111In‐pentetreotide. Forty‐five patients were evaluated for carcinoid, 15 for islet cell tumour, seven for metastatic NE tumour, four for medullary thyroid carcinoma, and one patient had ophthalmopathy. SPECT/CT induced improvement in the interpretation of SPECT and conventional CT and resultant clinical management changes were recorded.

results  SRS was negative in 28 patients and positive in 44 patients. SPECT/CT provided no additional information in 48 patients, including all 28 negative studies. SPECT/CT improved localization of the SPECT‐detected lesions in 23 of the 44 positive studies. It defined the extent of disease in 17, showed unsuspected bone involvement in three, and differentiated physiological from tumour uptake in three studies. SPECT/CT affected the clinical management in 10 patients, altered the surgical approach in six, spared unnecessary surgery in two, and modified the therapeutic modality in two patients.

conclusions  SPECT/CT affected the diagnostic interpretation of SRS in 32% of the patients and induced changes in management in 14% of the patients.
Eating pattern and the effect of oral glucose on ghrelin and insulin secretion in patients with anorexia nervosa
Authors: Tanaka Muneki , Tatebe Yoshiki , Nakahara Toshihiro , Yasuhara Daisuke , Sagiyama Ken‐ichiro , Muranaga Tetsuro , Ueno Hiroaki , Nakazato Masamitsu , Nozoe Shin‐ichi , Naruo Tetsuro
Published: October 2003

objective  Ghrelin is thought to be involved in the regulation of eating behaviour and energy metabolism in acute and chronic feeding states. Circulating plasma ghrelin levels in healthy humans have been found to decrease significantly after oral glucose administration. Because it is suggested that eating behaviour may influence the secretion of ghrelin and insulin in anorexia nervosa (AN), we examined the effect of oral glucose on ghrelin and insulin secretion in subtypes of AN patients.

design and patients  Twenty female AN patients and 10 age‐matched female controls were subjects. The patients were subdivided into two subtypes based on eating behaviour as follows: 11 restricting type (AN‐R), nine binge‐eating and purging type (AN‐BP). Subjects underwent an oral glucose tolerance test at 08·00 h. Blood was collected 0, 30, 60, 120 and 180 min after the glucose load.

results  Both AN‐R and AN‐BP had a significant increased basal ghrelin level (P < 0·01) and a significantly decreased basal insulin level (P < 0·05) as compared to controls. The time of the nadir of mean ghrelin in AN‐BP (120 min, 58·1% of basal level, 204·9 ± 34·3 pmol/l, mean ± SEM) was delayed compared to controls (60 min, 60·2%, 74·3 ± 7·9 pmol/l), and in the AN‐R group it kept decreasing for 180 min (80·0%, 182·4 ± 31·5 pmol/l). The peaks insulin levels in AN‐BP (120 min, 319·3 ± 88·8 pmol/l) and AN‐R (180 min, 418·9 ± 68·4 pmol/l) were also delayed as compared to controls (60 min, 509·2 ± 88·8 pmol/l). The glucose level at 180 min in AN‐R was significantly (P < 0·05) higher than in controls.

conclusions  These findings suggest that differences in eating behaviour in AN may induce alterations in both ghrelin and insulin metabolism in the acute feeding state. Furthermore, metabolic changes in the restrictive eating pattern may be related to the pathophysiology of small quantitative meal intake in AN‐R patients.
The TSH response to domperidone reflects the biological activity of prolactin in macroprolactinaemia and hyperprolactinaemia
Authors: Pinto L. P. , Hanna F. W. F. , Evans L. M. , Davies J. S. , John R. , Scanlon M. F.
Published: October 2003

objective  To test the hypothesis that patients with hyperprolactinaemia due to biologically inactive macroprolactin will not show the characteristically increased dopaminergic inhibition of TSH release seen in patients with microprolactinomas secreting biologically active monomeric PRL.

design  Comparison of the TSH and PRL responses to dopamine antagonism with domperidone (10 mg i.v.) in patients with hyperprolactinaemia due to macroprolactinaemia or microprolactinomas.

patients  Twenty‐two patients referred for the investigation of their hyperprolactinaemia were studied: 11 patients with macroprolactinaemia and 11 patients with hyperprolactinaemia due to microprolactinoma.

measurements  TSH and PRL levels were measured at baseline and 30 min following domperidone in both groups.

results  Patients with macroprolactinaemia showed normal TSH and PRL responses to dopamine antagonism whereas patients with microprolactinomas showed exaggerated TSH responses and reduced PRL responses. Although there was considerable overlap between the PRL responses in the two groups, there was very clear separation between the PRL/TSH response ratios (normal > 1·0) of 4·0 ± 1·8 for the macroprolactinaemia group and 0·4 ± 0·2 for the microprolactinoma group (P < 0·0001).

conclusions  These data support the hypothesis that elevated circulating levels of macroprolactin, as opposed to biologically active monomeric PRL, do not exert increased positive feedback on the hypothalamic dopaminergic inhibition of TSH release.
Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index
Authors: Van Rossum Elisabeth F. C. , Koper Jan W. , Van Den Beld Annewieke W. , Uitterlinden André G. , Arp Pascal , Ester Wietske , Janssen Joop A. M. J. L. , Brinkmann Albert O. , De Jong Frank H. , Grobbee Diederick E. , Pols Huibert A. P. , J. Lamberts Steven W.
Published: October 2003

objective  Sensitivity to glucocorticoids differs between individuals, partially due to genetic variation in the glucocorticoid receptor (GR) gene. We studied the sequence alteration of a previously described intronic BclI polymorphism of the GR gene, and investigated whether there was an association with sensitivity to glucocorticoids and anthropometric parameters in a group of healthy elderly individuals.

design and measurements  In study group 1, two overnight dexamethasone suppression tests (DSTs) were performed: with 1 mg dexamethasone, and 2·5 years later with 0·25 mg dexamethasone. Anthropometric parameters were measured in a larger population (study group 2), as well as in a third study group, in which we also measured body composition by dual‐energy X‐ray absorbtiometry (DEXA) scans.

subjects  Groups 1 and 2, respectively, 191 and 1963 male and female participants of the Rotterdam study, a population‐based study in Dutch elderly. Study group 3: 370 elderly males (mean age 77·8 ± 0·2 years) from Zoetermeer, the Netherlands.

results  We identified the BclI restriction site polymorphism as a C/G substitution in intron 2, 646 nucleotides downstream from exon 2. After both 1 mg and 0·25 mg DST, heterozygous (CG) and homozygous G‐allele carriers (GG) had lower cortisol levels than CC‐carriers (P = 0·01 and P = 0·02, respectively). In study group 2, we found a lower body mass index (BMI; P = 0·006) and waist–hip ratio (WHR; P = 0·02) in G‐allele carriers. In study group 3, again we found a lower BMI (P = 0·05) in G‐allele carriers. No differences were found in fat mass. However, lean mass tended to be lower in G‐allele carriers (P = 0·07).

conclusions  We characterized a BclI‐RFLP (restriction fragment length polymorphism) of the GR gene as a C/G polymorphism in intron 2 of which the G‐allele was associated with hypersensitivity to glucocorticoids. This resulted in a lower BMI in older individuals in general, while our study in elderly males suggests that the lower BMI is probably due to a greater loss of lean mass during the ageing process.
Prevalence of adrenal antibodies in Addison's disease among north Indian Caucasians
Authors: Nigam R. , Bhatia E. , Miao D. , Yu L. , Brozzetti A. , Eisenbarth G. S. , Falorni A.
Published: October 2003

objective  The prevalence of antibodies in different organ‐specific autoimmune diseases can vary depending on the racial group studied. Data on the prevalence of antibodies against steroidogenic enzymes in Addison's disease is available only for white Caucasians. We have evaluated the frequency of antibodies against adrenal cytoplasm, 21‐hydroxylase, 17‐α‐hydroxylase and side‐chain cleavage enzyme in a cohort of Indian patients with Addison's disease of idiopathic and granulomatous aetiology.

design  Study of all patients with Addison's disease on whom serum samples were available (84% of total), presenting to the Endocrinology Department in a teaching hospital in India, between 1990 and 1999.

patients  Thirty‐eight patients with Addison's disease (19 idiopathic, 19 granulomatous).

methods  A radiobinding assay using in vitro transcribed and translated recombinant human 35S‐labelled 21‐hydroxylase, 17‐α‐hydroxylase and side‐chain cleavage enzymes was utilized to detect the respective antibodies. Adrenal cytoplasmic antibodies were measured by indirect immunofluorescence on cryostatic sections of human adrenal cortex.

results  Of the 19 patients with idiopathic Addison's disease, adrenal cytoplasmic antibodies were present in five (26%) patients, while 21‐hydroxylase antibodies were present in four (21%) subjects. The frequency of 21‐hydroxylase antibodies was similar among patients with isolated idiopathic Addison's disease (3/13, 23%), and those associated with other organ‐specific autoimmune diseases (1/6, 17%). 17‐α‐hydroxylase and side‐chain cleavage antibodies were present in four (21%) and three (16%) patients, respectively. Overall, at least one of the three antibodies was present in eight (42%) subjects. All four female patients with premature ovarian failure had antibodies against 17‐α‐hydroxylase and/or side‐chain cleavage enzyme. Two (11%) patients with granulomatous Addison's disease had adrenal antibodies. Of these, one patient with enlarged and calcified adrenal gland secondary to tuberculosis had a high titre of antibodies against all three steroidogenic enzymes.

conclusions  Antibodies to 21‐hydroxylase enzyme are less frequent in idiopathic Addison's disease in north Indians, when compared with other Caucasians. In contrast, the prevalence of 17‐α‐hydroxylase and side‐chain cleavage enzyme antibodies is similar to those reported. High titre antibodies against steroidogenic enzymes may occasionally be present in patients with clinical evidence of tuberculous Addison's disease.
Insulin gene VNTR genotype is associated with insulin sensitivity and secretion in infancy
Authors: Bazaes R. A. , Petry C. J. , Ong K. K. , Ávila A. , Dunger D. B. , Mericq M. V.
Published: October 2003

aims  We have previously demonstrated that insulin sensitivity and secretion at age 1 year was in part related to variation in weight and height gain during infancy. In order to determine whether genetic variation at the insulin gene could also influence these associations, we have studied the relationship between insulin gene variable number of tandem repeat (INS VNTR) genotypes, insulin secretion and early postnatal growth.

methods  We assessed fasting and dynamic insulin secretion in 99 healthy infants at age 1 year, using a short intravenous glucose tolerance test (sIVGTT). Infants were genotyped at the –23 HphI locus, as a surrogate marker for INS VNTR allele classes I and III. Anthropometric data were recorded at birth and at 1 year. Data are shown as median (interquartile range).

results  Fasting insulin levels were higher in III/III infants (n = 9) than in I/I infants [n = 55; 27·4 (17·6–75·6) pmol/l vs. 18·1 (10·3–25·2) pmol/l; P < 0·05]. Insulin secretion during the sIVGTT, as estimated by the serum insulin area under the curve, was also higher in III/III infants [2417 (891–4041) pmol min/l vs. 1208 (592–2284) pmol min/l; P < 0·05]. Fasting and postload plasma glucose levels were similar in both groups. Analysis of covariance showed that genotype differences in fasting insulin sensitivity and insulin secretion were independent of size at birth, postnatal growth velocity and current body mass index.

conclusions  Significant associations between INS VNTR genotype and both insulin sensitivity and secretion were apparent in infancy; these might interact with childhood appetite and nutrition to impact the development of childhood obesity and insulin resistance.
Impaired GH secretion to provocative stimuli in two families with hypocalciuric hypercalcaemia
Authors: Cecconi Elisabetta , Bogazzi Fausto , Cetani Filomena , Grasso Lucia , Marcocci Claudio , Genovesi Maura , Procopio Massimo , Gasperi Maurizio , Pinchera Aldo , Ghigo Ezio , Martino Enio
Published: October 2003

objective  To determine whether hypercalcemia per se might be responsible for an impairment in GH secretion.

design  Prospective study.

patients  Six subjects of two unrelated families with familial hypocalciuric hypercalcaemia (FHH), an autosomal dominant disorder due to inactivating mutations in the calcium receptor gene, leading to an increase in serum calcium levels and inappropriately normal serum PTH concentrations. Forty normal subjects, matched for sex and age served as controls.

measurements  Serum GH concentrations were measured after GHRH‐Arginine (GHRH‐Arg) stimulation test; serum IGF‐I, ACTH, cortisol, FT4, FT3, TSH, PRL, LH, FSH levels were measured under basal conditions.

results  All subjects (two male, four female, age range 24–74 years) had increased serum ionized calcium levels (range 1·36–1·56 mmol/l) and five of six patients had normal PTH levels (range for all patients was 14–68 ng/l). Basal serum GH concentrations ranged from 0·1 to 7·0 µg/l. Mean serum GH secretory peak after GHRH‐Arg stimulation test was reduced in five subjects (mean 9·3 ± 3·6 µg/l, P < 0·006 vs. Controls, mean 67·0 ± 44·0 µg/l, cut‐off, 16·0 µg/l) and normal in one subject (38·7 µg/l). However, serum IGF‐I levels were reduced only in two patients (29 and 57 µg/l) and normal in four subjects (range 127–208 µg/l). The basal secretion of the other anterior pituitary hormones was within their normal ranges.

conclusions  The results of the present study support the concept that elevated serum calcium levels impair GH secretion. However, the clinical relevance of GH deficiency in FHH remains to be elucidated.
Decrease in carotid intima‐media thickness in hypothyroid patients after normalization of thyroid function
Authors: Nagasaki Toshiki , Inaba Masaaki , Henmi Yasuko , Kumeda Yasuro , Ueda Misako , Tahara Hideki , Sugiguchi Shigeru , Fujiwara Shigehiko , Emoto Masanori , Ishimura Eiji , Onoda Naoyoshi , Ishikawa Tetsuro , Nishizawa Yoshiki
Published: October 2003

objective  This case–control study was carried out to assess whether levothyroxine (L‐T4) replacement might cause regression of the enhanced atherosclerosis seen in hypothyroid patients.

patients and methods  Intima‐media thickness (IMT) in the common carotid artery (CCA) was measured from digitalized still images taken during scanning by high‐resolution ultrasonography as an indicator of early atherosclerosis. Thirty‐five hypothyroid patients were examined for their CCA IMT before and 1 year after normalization of thyroid function by L‐T4 replacement. As control, 35 healthy subjects were enrolled from among the participants in a local health‐check programme conducted at the Osaka City University Hospital.

results  Basal CCA IMT was significantly higher in hypothyroid patients [0·635 ± 0·018 (mean ± SE) mm] than in control subjects (0·559 ± 0·021 mm, P < 0·005). After 1 year of euthyroidism, 34 out of 35 patients showed a significant decrease of CCA IMT, to 0·552 ± 0·015 mm (P < 0·0001), a level comparable to normal controls. CCA IMT change was closely associated with basal levels of total cholesterol (r = −0·472, P= 0·0031), low‐density lipoprotein (LDL) cholesterol (r = −0·441, P= 0·0076) and the total/HDL cholesterol ratio (r =−0·435, P= 0·0057), but not with any of the other variables measured except for age (r = −0·353, P= 0·0296).

conclusions  This study demonstrated that L‐T4 treatment might have the potential to reverse the progression of atherosclerosis in hypothyroid patients. Furthermore, it suggests that increased levels of LDL cholesterol and the total/HDL cholesterol ratio have an important role in the increased common carotid intima‐media thickness in hypothyroid patients.
The effects of growth hormone deficiency and replacement on glucocorticoid exposure in hypopituitary patients on cortisone acetate and hydrocortisone replacement
Authors: Swords F. M. , Carroll P. V. , Kisalu J. , Wood P. J. , Taylor N. F. , Monson J. P.
Published: October 2003

objective  11β‐hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone to active cortisol. 11βHSD1 activity is increased in GH deficiency and inhibited by GH and IGF‐I in acromegaly. However it is not known whether these changes in cortisol metabolism exert significant effects during hydrocortisone therapy, and the effect has not been studied in patients taking cortisone acetate. We have studied the effect of GH induced 11βHSD1 inhibition in hypopituitary adults with severe GH deficiency to determine whether this inhibition has a different magnitude of effect when patients are taking different forms of glucocorticoid replacement therapy.

design, patients and measurements  We have taken the ratio of 11‐hydroxy/11‐oxo cortisol metabolites (Fm/Em), an established measure of net 11βHSD activity to reflect the likely balance of cortisol to cortisone exposure in tissues expressing 11βHSD1, principally the liver and adipose tissue. We recruited 10 hypopituitary adults all on established glucocorticoid replacement therapy, but who were not receiving GH. Patients were treated with their standard hydrocortisone therapy for one week and an equivalent dose of cortisone acetate in its place for one week in random order. Serial serum cortisol assessments and urine steroid profiles were performed on each treatment. All patients were then established on GH therapy for at least three months before the two‐week cycle was repeated. Fm/Em was also measured in a control population (20F, 20M).

results  Prior to GH, the ratio Fm/Em was greater with hydrocortisone compared with cortisone acetate replacement (1·17 ± 0·28 and 0·52 ± 0·09 respectively, P < 0·001) or with normal subjects (normal males: 0·81 ± 0·24, females 0·66 ± 0·14). Following GH replacement Fm/Em fell in patients on hydrocortisone and cortisone acetate (Pre‐GH: 0·84 ± 0·40, Post‐GH: 0·70 ± 0·34, P < 0·05) confirming the inhibition of 11βHSD1 by GH/IGF‐I. Conversely, the ratio of urinary free cortisol/cortisone did not change indicating unchanged 11βHSD2 activity. Mean circulating cortisol also fell in all subjects after GH. This effect was greater during cortisone acetate treatment (−18·7%, P < 0·0001), than during hydrocortisone replacement (−10·9%, P < 0·05).

conclusions  Our data suggest that tissue exposure to glucocorticoid is supra‐physiological in hypopituitary patients with untreated GH deficiency taking hydrocortisone replacement therapy. This situation is ameliorated by GH replacement therapy. However, local and circulating cortisol concentrations are more vulnerable to the inhibitory effect of GH on 11βHSD1 in patients taking cortisone acetate, such that serum cortisol assessments should be made in patients taking cortisone acetate after GH therapy to ensure that glucocorticoid replacement remains adequate.
Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism before and after control of thyroid function
Authors: Iglesias Pedro , Alvarez Fidalgo Pilar , Codoceo Rosa , Díez Juan J.
Published: October 2003

objective  Adipose tissue is a hormonally active system that produces and releases different bioactive substances. Leptin, adiponectin and resistin are some of the recently discovered adipocytokines that participate in the regulation of intermediate metabolism. The aim of this study was to evaluate the circulating levels of leptin, adiponectin and resistin in patients with thyroid dysfunction before and after normalization of thyroid function with appropriate therapy.

patients and measurements  We studied 20 patients with hyperthyroidism (16 women and 4 men; mean age 47·2 ± 3·9 years) and 20 patients with hypothyroidism (17 women and 3 men; 51·5 ± 4·1 years). A group of 20 euthyroid subjects served as control group. Patients were evaluated at the time of diagnosis and again after normalization of thyroid function with appropriate therapy. Serum concentrations of free T4 (FT4), total T3, TSH, insulin, leptin, adiponectin and resistin were measured in all subjects.

results  Hyperthyroid patients showed significantly decreased leptin levels in comparison with controls (11·0 ± 1·1 vs. 30·4 ± 5·0 µg/l, P < 0·001). No significant differences in adiponectin levels between hyperthyroid and control groups were found (27·8 ± 4·0 vs. 46·0 ± 12·0 mg/l, NS). Patients with hyperthyroidism exhibited reduced resistin levels in comparison with euthyroid subjects (6·4 ± 0·8 vs. 8·4 ± 0·7 µg/l, P < 0·05). Normalization of circulating thyroid hormone was accompanied by a nonsignificant increase in leptin levels (12·9 ± 1·7 µg/l, P < 0·01 vs. control) and no significant modification both in adiponectin (32·0 ± 7·1 mg/l, NS) and resistin (5·4 ± 0·7 µg/l, NS) levels. Adjustment of adipocytokine concentrations for body mass index (BMI) showed that treatment of hyperthyroidism induced a significant reduction in adjusted resistin concentrations (0·21 ± 0·03 vs. 0·28 ± 0·03 µg/l/BMI units, P < 0·05), with no changes in adjusted leptin and adiponectin. Hypothyroid patients showed significantly lower leptin levels compared with the controls (16·0 ± 3·5 vs. 30·4 ± 5·0 µg/l, P < 0·05). Adiponectin levels in patients with hypothyroidism (71·8 ± 16·0 mg/l) were similar to those in the control group and were not modified with therapy. Resistin levels were significantly reduced among hypothyroid patients (5·8 ± 1·0 µg/l, P < 0·05), and were not increased after levothyroxine therapy. A significant rise in BMI‐corrected leptin levels was observed after replacement therapy, with no changes in adiponectin‐ and resistin‐corrected values.

conclusions  The results suggest that (1) low serum leptin levels are present in both hyperthyroid and hypothyroid patients but are only increased after therapy in the latter; (2) resistin might be implicated in the insulin resistance state that accompanies thyrotoxicosis; and (3) inadequate secretion of adiponectin seems to have no role in metabolic changes associated with thyroid dysfunction.
Ghrelin mRNA and GH secretagogue receptor mRNA in human GH‐producing pituitary adenomas is affected by mutations in the α subunit of G protein
Authors: Kim Kyongsong , Sanno Naoko , Arai Keiko , Takano Koji , Yasufuku‐Takano Junko , Teramoto Akira , Shibasaki Tamotsu
Published: October 2003

objective  Ghrelin and its receptor, growth hormone secretagogue (GHS) receptor (GHSR), are expressed in the normal pituitary gland and various types of pituitary adenoma. Somatic mutations in the subunit of Gs α protein (gsp), which led to a constitutive activation of adenylyl cyclase, are reported in GH‐producing pituitary adenomas. We analysed the relationship between ghrelin mRNA and GHSR mRNA expression levels in gsp mutation‐positive and ‐negative GH‐producing pituitary adenomas.

patients  Pituitary adenoma tissue was obtained at surgery from 20 patients with acromegaly.

methods  The expression levels of human ghrelin mRNA and GHSR mRNA were quantified using a competitive RT–PCR method. To detect the gsp mutations, amplified Gs α subunit cDNA fragments were sequenced directly using RT–PCR method.

results  There was no significant difference in the expression of ghrelin mRNA between mutation‐positive and ‐negative adenomas. The expression of GHSR mRNA was significantly lower in gsp mutation‐positive than ‐negative adenomas. There was a significant negative correlation between the levels of ghrelin mRNA and GHSR mRNA expression in mutation‐negative adenomas; no such correlation was found in mutation‐positive adenomas.

conclusion  These results suggest that GHSR mRNA expression is downregulated by ghrelin in gsp mutation‐negative GH‐producing pituitary adenomas, and that changes in intracellular signalling pathways in gsp mutation‐positive GH‐producing pituitary adenomas affect the expression of G protein‐coupled receptors such as GHSR. The absence of negative correlation between ghrelin and GHSR expression might be induced by lowered GHSR expression in gsp mutation‐positive GH‐producing adenomas.
Increased prevalence of sublinical brain perfusion abnormalities in patients with autoimmune thyroiditis: evidence of Hashimoto's encephalitis?
Authors: Zettinig Georg , Asenbaum Susanne , Fueger Barbara J. , Hofmann Andrea , Diemling Markus , Mittlboeck Martina , Dudczak Robert
Published: October 2003

objectives  Hashimoto's encephalitis is a term which describes encephalopathy associated with autoimmune thyroiditis, but it is not based on evidence, whether Hashimoto's encephalitis is a distinct clinical entity by itself. In previously reported cases of Hashimoto's encephalitis, abnormal brain perfusion studies have been reported. The aim of this study was to evaluate the prevalence of brain perfusion abnormalities in euthyroid patients with autoimmune thyroiditis.

methods  99mTc Ethyl cystein dimer (ECD) single photon emission computed tomography (SPECT) studies were performed in a study group of 41 euthyroid patients with autoimmune thyroiditis and a matched control group of 35 healthy individuals. All study participants had a normal neurological investigation and a detailed neurological history taking. Individuals with known or suspected morphological brain abnormalities were excluded from the study. Zung's Self‐Rating Anxiety Scale (SAS) and Zung's Self‐Rating Depression Scale (SDS) were used to detect depression and mood disorders. Automatic quantification of perfusion was performed with both a voxel‐based analysis as well as a volume‐of‐interest (VOI) based analysis of 46 predefined cortical and subcortical regions. The findings from both groups were compared to a reference template.

results  In the voxel‐based analysis, there was a significant difference between patients and controls in the mean volume of perfusion defects deviating 2SD below the normal values (21·8 ml vs. 10·4 ml; P = 0·02). Hyperperfused areas, however, did not differ significantly between study patients and controls. A significant correlation of the perfusion defects with time since diagnosis of autoimmune thyroiditis was seen (r = 0·42). In the VOI‐based analysis, abnormal regions were more frequent in the study group when compared to controls (P < 0·01) However, no topographic pattern was apparent. Regarding neurological findings, no significant difference was found between study patients and controls. However, both the SAS and SDS scores differed significantly between the two groups, but there was neither a correlation between the two scores and perfusion abnormalities nor an association with depression in our study group.

conclusions  These findings of impaired brain perfusion in patients with autoimmune thyroiditis further strengthen the hypothesis of a possible cerebral involvement in autoimmune thyroiditis in individual cases. The presence of cerebral hypoperfusion suggests a cerebral vasculitis as the most likely pathogenetic model.
Chromogranin A as serum marker of pituitary adenomas
Authors: Gussi Ilinca‐Lucia , Young Jacques , Baudin Eric , Bidart Jean Michel , Chanson Philippe
Published: October 2003

objective  The diagnostic impact of chromogranin A (CgA) measurement has been studied in various neuroendocrine tumours (NET) such as pheochromocytomas, gastrinomas and neuroblastomas. Clinically nonfunctioning pituitary adenomas (NFPA) are generally diagnosed on tumoural symptoms or hypopituitarism and, except for gonadotrophins and their free subunits which may be increased in the case of gonadotrophinomas, markers of endocrine secretory activity are lacking not only for diagnostic purpose but also in the postoperative follow‐up of these patients. As the presence of CgA has been demonstrated by immunohistochemistry in pituitary adenomas, we performed this study to further assess the sensitivity of CgA measurement in sporadic pituitary adenomas using a new, specific, sandwich immunoassay.

subjects  We first completed a basal normative data set obtained using this assay by studying four healthy men (49 ± 13 years old), five healthy premenopausal women (35·8 ± 7·5 years old) and five healthy postmenopausal women (49·1 ± 4·6 years old) basally and after TRH administration. Twenty‐seven patients [12 men (64·2 ± 11·8 years), even premenopausal women (38·4 ± 5·7 years) and eight postmenopausal women (67·7 ± 10·3 years)] with NFPA, 15 acromegalic patients [nine men (45 ± 13·3 years), six women (52 ± 14·9 years)] and 19 patients with a prolactin‐secreting adenoma [four men (41·2 ± 18 years) and 15 women (31·2 ± 7·5 years), with a macroadenoma (n = 11) or a microadenoma (n = 8)] had basal and TRH‐stimulated measurement of CgA. A gonadotrophin‐releasing hormone (GnRH)‐stimulation test was also performed in two, four and four patients, respectively. All patients had sporadic pituitary adenomas.

measurements  Serum CgA was measured using a solid‐phase two‐site immunoradiometric assay based on monoclonal antibodies that bind to two distinct contiguous epitopes within the 145–245 region of CgA.

results  Mean basal CgA concentration in 14 normal subjects was 80·2 ng/ml (SD: 31·7; range 19–124). A cut‐off value for normal range was thus set at 125 ng/ml. TRH injection did not change significantly the CgA levels, peak values remaining less than 124 ng/ml. Three out of 27 subjects with NFPA (11%) had elevated basal CgA levels (576, 143, 241 ng/ml, respectively). Serum levels of CgA were not influenced by TRH in any of the NFPA subjects (including those three with increased basal levels). One out of 15 acromegalic patients (6·6%) and one out of 19 hyperprolactinemic patients (5·2%) had elevated serum basal CgA which did not significantly increase after TRH administration. In the remaining patients TRH‐tests did not modify CgA levels. GnRH administration did not modify CgA levels.

conclusions  CgA serum levels measurement, assessed with a novel assay, does not provide a helpful marker for the clinical management of functioning and NFPA.
Ghrelin concentrations in healthy children and adolescents
Authors: Whatmore A. J. , Hall C. M. , Jones J. , Westwood M. , Clayton P. E.
Published: October 2003

objective  In addition to its regulation by GH releasing hormone (GHRH) and somatostatin, release of GH from the pituitary is modulated by a third factor, ghrelin, which is expressed in high concentration in the stomach and is present in the circulation. Ghrelin has also been shown to cause weight gain by increasing food intake and decreasing fat utilization. Ghrelin is a potential candidate hormone to influence nutrient intake and growth. Its role through normal childhood and adolescence has not been fully defined.

design  Cross‐sectional study in 121 healthy children (65 male, 56 female) aged 5–18 years, in whom height, weight, body mass index (BMI), pubertal status and measurements of IGF‐I, IGFBP‐3, IGFBP‐1 and leptin were available.

methods  Serum ghrelin concentrations have been measured in radioimmunoassay (RIA; Phoenix, AZ, USA) that detects active and inactive human ghrelin. Relationships between ghrelin and anthropometric data and growth factors were assessed by correlation and regression analyses.

results  Ghrelin was detected in all samples, with a median concentration of 162 pg/ml, range 60–493 pg/ml. Prepubertal children had higher ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0·001], with significant negative correlations between ghrelin and age (rs = −0·39, P < 0·001) and pubertal stage (rs = −0·42, P < 0·001). The decrease in ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, ghrelin was negatively correlated to BMI SD (rs = −0·24, P = 0·006) and to weight SD (rs = −0·24, P = 0·008) but not height sds. Ghrelin was also negatively correlated to IGF‐I (rs = −0·48, P < 0·001), IGFBP‐3 (rs = −0·32, P < 0·001) and leptin (rs = −0·22, P = 0·02) but not IGF‐II. It was positively related to IGFBP‐1 (rs = +0·46, P < 0·001). In stepwise multiple regression, 30% of the variability in ghrelin through childhood could be accounted for by log IGF‐I (24%) and log IGFBP‐1 (6%).

conclusions  The fall in ghrelin over childhood and with puberty does not suggest that it is a direct growth‐promoting hormone. However in view of the negative relationship with IGF‐I and the positive relationship with IGFBP‐1, this fall in ghrelin could facilitate growth acceleration over puberty.
Update on genetic and clinical aspects of primary hyperparathyroidism
Authors: Miedlich S. , Krohn K. , Paschke R.
Published: October 2003

Primary hyperparathyroidism (pHPT) is a common endocrine disorder that predominantly affects postmenopausal women. It is mostly caused by solitary tumours within the parathyroid glands. Although the pathophysiology of pHPT is still incompletely understood, recent studies provide new clues on the development and cellular growth of tumours within the parathyroids associated with hypersecretion of parathyroid hormone and hypercalcaemia. The natural course of pHPT is rather benign. Nowadays, it has become an oligo‐ or asymptomatic disease often only detected by routine blood tests. These facts raise the question whether to perform parathyroidectomy on oligo‐ and asymptomatic patients with pHPT or whether it is possible to monitor these patients without surgery. The aim of this article is to review the literature as regards (i) the pathophysiological mechanisms that underlie parathyroid neoplasia and (ii) the defective calcium‐sensing in patients with pHPT (iii) environmental and/or genetic risk factors that predispose to or promote parathyroid neoplasia, as well as (iv) alternative approaches to treat oligo‐ and asymptomatic patients with pHPT medically.
Mechanisms of nitrate tolerance: potential roles of folate
Authors: Bellisarii F. Iachini , Gallina S. , Zimarino M. , De Caterina R.
Published: October 2003

More than 100 years since their introduction in cardiovascular therapy, nitrates continue to be widely used in ischaemic heart disease despite incomplete knowledge of their intimate mechanism of action. Particularly, the development of a progressive attenuation of their efficacy over prolonged use (tolerance) continues to be the subject of current investigation. Newer findings point to the role of increased intracellular oxidative stress as a mechanism for tolerance and to folic acid derivatives as pharmacologic means to attenuate its development. This paper reviews nitrate mechanism of action, the history of nitrate tolerance and newer findings related to the use of folate to prevent this phenomenon.
Increased skeletal muscle expression of PKC‐θ but not PKC‐α mRNA in type 2 diabetes: inverse relationship with in‐vivo insulin sensitivity
Authors: Gray S. , Idris I. , Davis K. R. , Donnelly R.
Published: October 2003

Background  Increases in PKC‐θ (the major isoenzymic form of PKC in skeletal muscle) protein and isozyme activity have been reported in skeletal muscle from patients with type 2 diabetes mellitus (T2DM) and dietary‐induced rodent models of insulin resistance, but the underlying biochemical mechanism is unclear and muscle PKC‐θ mRNA expression has not been previously reported in patients with T2DM or in relation to in‐vivo measurements of insulin sensitivity.

Methods  Diet‐only treated patients with T2DM (n = 7) and healthy nondiabetic controls (n = 7) of similar BMI attended the clinical research unit on two occasions, 1 week apart, for a skeletal muscle biopsy 2 h after a 75‐g oral glucose load and measurement of whole‐body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp.

Results  Type 2 DM patients were insulin resistant (M‐value 3·0 ± 0·4 vs. 8·6 ± 0·8 mg glucose kg−1 min−1) with fasting hyperinsulinaemia (306 ± 116 vs. 34 ± 9 pmol L−1, P < 0·001) and hypertriglyceridaemia (3·6 ± 0·7 vs. 1·3 ± 0·3 mmol L−1, P < 0·01) relative to controls. Semi‐quantitative RT‐PCR showed that expression of PKC‐θ mRNA (relative to GAPDH mRNA) was 6‐fold higher in T2DM subjects (0·63 + 0·25% vs. 0·09 + 0·07%, P < 0·001), whereas there was no difference in expression of PKC‐α mRNA between the two groups. Expression of PKC‐θ mRNA was inversely correlated with insulin sensitivity (M) and positively correlated with fasting serum insulin concentration (P < 0·02).

Conclusions  This is the first clinical study of PKC‐θ mRNA expression in human diabetic skeletal muscle. The results indicate that transcriptional up‐regulation of PKC‐θ may at least partly contribute to the increased muscle PKC‐θ signalling in T2DM, and that PKC‐θ mRNA may be inversely related to in‐vivo insulin sensitivity.
Acute haemodynamic effects of losartan in anaesthetized cirrhotic rats
Authors: Heller J. , Shiozawa T. , Trebicka J. , Hennenberg M. , Schepke M. , Neef M. , Sauerbruch T.
Published: October 2003

Background  Portal hypertension in cirrhosis is the result of increased intrahepatic vascular resistance to portal outflow as well as increased portal tributary blood flow. The angiotensin II type 1 receptor antagonist losartan has been suggested as a portal pressure‐lowering drug in patients with cirrhosis.

Aim  To investigate the systemic and splanchnic haemodynamic effects of different doses of losartan.

Methods  In 35 anaesthetized rats with secondary biliary cirrhosis, 3, 10 or 30 mg of losartan kg−1 or solvent were administered intravenously. Ten sham‐operated rats served as controls. Mean arterial pressure and portal pressure were measured by catheters in the femoral artery or portal vein. Systemic and splanchnic haemodynamics and mesenterico‐systemic shunt rate were determined by the coloured microsphere method.

Results  Losartan reduced portal pressure (sham: 9·1 ± 0·4. cirrhosis: 19·3 ± 1·1, after 3 mg kg−1 of losartan 16·4 ± 0·4, after 10 mg kg−1 of losartan 15·6 ± 0·6, after 30 mg kg−1 of losartan 14·9 ± 0·6 mmHg) without reducing portal sinusoidal resistance. However, in cirrhotic rats it reduced portal tributary blood flow (sham: 4·3 ± 0·6. cirrhosis: 8·6 ± 1·4, after 3 mg kg−1 of losartan 3·8 ± 0·7, after 10 mg kg−1 of losartan 4·7 ± 0·5, after 30 mg kg−1 of losartan 5·9 ± 0·9 mmHg). This was owing either to an increase in splanchnic vascular resistance at the 3 mg kg−1 dose or to a reduction in the splanchnic perfusion‐pressure gradient secondary to a reduction in mean arterial pressure at the 10 and 30 mg kg−1 doses (mean arterial pressure: sham: 109·7 ± 4·8. cirrhosis: 109·4 ± 2·8, after 3 mg kg−1 of losartan 99·7 ± 2·9, after 10 mg kg−1 of losartan 89·9 ± 3·4, after 30 mg kg−1 of losartan 81·0 ± 2·9 mmHg).

Conclusions  Low doses of losartan reduce portal hypertension by an increase in splanchnic vascular resistance without hypotensive side‐effects on arterial pressure.
COX‐2 inhibition and prostaglandin receptors in experimental nephritis
Authors: Waldner C. , Heise G. , Schrör K. , Heering P.
Published: October 2003

Background  Renal cyclooxygenases (COX) produce the prostaglandins (PG) E2, I2 and thromboxane (TxA2), which interact with distinct G protein‐coupled receptors. We investigated the expression of the three EP receptors EP2, EP3 and EP4 and the receptors for PGI2 (IP) and TxA2 (TP) in rats with passive Heymann nephritis (PHN). We studied their regulation by COX‐2 inhibition with celecoxib.

Materials and methods  Four groups of Wistar rats were studied: healthy rats (group A), healthy rats treated with celecoxib (group B), rats with PHN (group C), and rats with PHN receiving celecoxib (group D). Expression of the mRNA for all receptors in the renal cortex and for the EP3 receptor in cultured mesangial cells (MCs) was determined by semiquantitative reverse transcriptase polymerase chain reaction. Stable prostaglandin metabolites were measured in the urine by radioimmunoassay.

Results  Rats with PHN (group C) showed an 1·8‐fold increase of cortical EP3 receptor mRNA expression as compared with controls (group A). In celecoxib‐treated PHN rats (group D) the mRNA expression of the EP3 and EP4 receptors was significantly reduced to 1·0‐fold and 0·7‐fold induction, respectively. Furthermore, the excretion of bicyclo‐prostaglandin E2 (PGE2) was inhibited by celecoxib. No changes were observed in the expression of the other PG‐receptors. In cultured MC, PGE2 enhanced the EP3 mRNA expression.

Conclusions  These data suggest a predominant role of the EP3 receptor in the transduction of PGE2‐actions in PHN. It was concluded that COX‐2‐dependent PGE2 is able to potentiate its effects in the kidney by up‐regulating its own receptors.
Low concentrations of intravenous polygelines promote low‐molecular weight proteinuria
Authors: Veldman B. A. J. , Schepkens H. L. E. , Vervoort G. , Klasen I. , Wetzels J. F. M.
Published: October 2003

Background  Previously we observed that atrial natriuretic peptide (ANP)‐induced albuminuria was accompanied by an increase in urinary excretion of the low‐molecular weight protein (LMW protein) β2‐microglobulin (β2‐m), suggesting that the albuminuria may at least partly be the result of blockade of tubular protein reabsorption. However, in our experiments ANP was dissolved in the polygeline Haemaccel® (Hoechst, Behring‐Werke, Marburg Germany) to prevent adhesion of ANP to the infusion system. Anecdotal reports have shown that high dosages of polygelines such as Haemaccel® or Gelofusine® (Braun NPBI Oss, the Netherlands) may influence tubular protein handling. In the present study we have evaluated the effect of a low and high doses of the polygeline Haemaccel® on proteinuria. In addition, we have reassessed the effects of ANP.

Materials and methods  We measured urinary β2‐microglobulin (β2‐m) and albumin excretion in healthy volunteers after infusion of a high‐dose pure Haemaccel® (0·04 mL kg−1 min−1 for 60 min), a low‐dose Haemaccel® (0·01 mL kg−1 min−1 for 60 min followed by infusion of 0·02 mL kg−1 min−1 for 60 min) and a low‐dose Gelofusine® (dose comparable to the low‐dose Haemaccel®). In addition we performed similar studies using ANP dissolved in saline and Haemaccel®.

Results  Infusion of Haemaccel® caused a dose‐dependent increase in urinary excretion of β2‐m. There were no differences between Haemaccel® and Gelofusine®. After infusion of ANP dissolved in Haemaccel® urinary β2‐m excretion increased from 0·05 ± 0·03 µg min−1 to 27 ± 10 µg min−1 and urinary albumin excretion increased from 4·5 ± 1·1 µg min−1 to 9·7 ± 6·3 µg min−1 (P < 0·05). During ANP + saline infusion, urinary β2‐m excretion did not change, whereas the urinary albumin excretion increased from 5·3 ± 1·5 µg min−1 to 7·9 ± 2·4 µg min−1 (P < 0·05).

Conclusions  Our study demonstrates that even low doses of the polygelines Haemaccel® and Gelofusine® profoundly attenuate the tubular reabsorption of the low‐molecular weight protein β2‐m. Atrial natriuretic peptide does not affect tubular protein reabsorption. Therefore, the rise in albuminuria during ANP infusion most likely reflects alterations in glomerular permeability.