bluuebunny/crossref_metadata_2025 huggingface dataset:
Carbohydrate metabolism during growth hormone treatment and after discontinuation of growth hormone treatment in girls with Turner syndrome treated with once or twice daily growth hormone injections
Authors: Sas Theo , De Muinck Keizer‐Schrama Sabine , Aanstoot Henk‐Jan , Stijnen Theo , Drop Stenvert ,   the Dutch Advisory Group on Growth Hormone
Published: March 2003

OBJECTIVE

To assess possible side‐effects of treatment with supraphysiological GH dosages on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during GH treatment until adult height is reached as well as after discontinuation of GH treatment.

DESIGN

In a prospective, randomized injection frequency‐response study, the effect of GH treatment in combination with low dose ethinyl oestradiol on CH metabolism was evaluated, comparing twice daily (BID) with once daily (OD) injections of a total GH dose of 6 U/m2/day until adult height was reached.

PATIENTS

Nineteen untreated girls with TS, mean (SD) pretreatment age 13.3 (1.7) (range 11.0–17.6) year.

MEASUREMENTS

Glucose and insulin concentrations during oral glucose tolerance tests (OGTT) were measured before and during GH treatment, as well as at 6 months after discontinuation of GH treatment.

RESULTS

GH treatment was discontinued after a mean of 43 (range 27–57) months. In one of the 19 girls, a different girl at each time point before, during and after discontinuation of GH treatment, the glucose response to OGTT after 120 minutes was above 7.8 mmol/l but below 11.1 mmol/l, indicating impaired glucose tolerance. None of the girls developed diabetes mellitus. Fasting glucose levels did not significantly change during, or after discontinuation of GH treatment. The 3 h area under the curve for time–concentration adjusted for fasting levels during the OGTT for glucose showed a significant decrease during GH treatment. In contrast to the glucose levels, GH treatment induced considerably higher insulin levels compared to pretreatment values. After discontinuation of GH insulin levels decreased to values comparable with pretreatment levels. None of these observed changes were different between the GH injection frequency groups. The changes in CH variables during and after discontinuation of GH were not related to changes in body mass index.

CONCLUSIONS

GH treatment with 6 U/m2/day in combination with low dose ethinyl oestradiol in girls with Turner syndrome aged ≥ 11 years did not negatively influence glucose levels, but induced higher levels of insulin indicating relative insulin resistance. These changes in insulin levels were independent of the frequency of the GH injections (once vs. twice daily). After discontinuation of GH treatment, insulin values decreased to baseline levels.
Goitrogenesis during pregnancy and neonatal hypothyroxinaemia in a borderline iodine sufficient area
Authors: Kung A. W. C. , Lao T. T. , Chau M. T. , Tam S. C. F. , Low L. C. K.
Published: March 2003

Severe iodine deficiency disorders (IDDs) may have been eradicated in many parts of the world, but milder forms still exist and may escape detection. We evaluated the impact of pregnancy on the maternal and fetal thyroid axis in Hong Kong, a coastal city in southern China with borderline iodine intake.

A prospective study performed in a maternity hospital.

Two hundred and thirty pregnant women were prospectively studied and their neonates assessed at birth.

Urine iodine concentration, thyroid function tests and thyroid volume (TV) by ultrasound were determined in the mothers during pregnancy and up to 3 months postpartum and in the neonates.

Increased urinary iodine concentration was seen from first trimester onwards and the proportion of women having urine iodine concentration of < 0·4 µmol/l decreased from 11·3% in the first trimester to 4·7% in the third trimester. There was progressive reduction in circulating fT4 and fT3 concentrations and free thyroxine index (FTI) with increasing gestation and the percentage of women having subnormal levels at term were 53·2%, 61·1% and 4·8%, respectively. The serum TSH concentration during pregnancy doubled towards term. In the first trimester, multiparous women had significantly larger TV than the nulliparous women (P < 0·001). By the third trimester, TV had increased by 30% (range 3–230%) so that the goitre incidence was 14·1%, 21·8%, 25·9% during the three trimesters of pregnancy, and 24·3% and 21·9% at 6 weeks and 3 months postpartum (ANOVA, P < 0·05). The change in thyroid volume during pregnancy correlated positively with the change in thyroglobulin (r = 0·225, P < 0·002) and negatively with urinary iodine concentration (r = − 0·149, P < 0·02).

Fourteen women with excessive thyroidal stimulation in the second trimester (defined as those with thyroglobulin (Tg) concentrations in the highest tertile and FTI in the lowest tertile) were found to have lower urine iodine concentrations and larger TV (both P < 0·005) throughout pregnancy, and their neonates had higher cord TSH (P < 0·05), Tg (P < 0·05) and slightly larger TV (P = 0·06) as compared to the findings in 216 pregnant women without evidence of thyroid stimulation. Seven neonates (50%) born to these women had subnormal fT4 levels at birth.

In a borderline iodine sufficient area, pregnancy posed an important stress resulting in higher rates of maternal goitrogenesis as well as neonatal hypothyroxinaemia and hyperthyro‐ trophinaemia. An adequate iodization program is necessary to eliminate iodine deficiency disorders during pregnancy.
Congenital thyrotoxicosis in premature infants
Authors: Smith Christopher , Thomsett Michael , Choong Catherine , Rodda Christine , McIntyre H. David , Cotterill Andrew M.
Published: March 2003

Graves' disease (GD) complicates 0·1% to 0·2% of pregnancies, but congenital thyrotoxicosis is rare occurring in one in 70 of these pregnancies independent of maternal disease status. Antenatal prediction of affected infants is imprecise; however, maternal history, coupled with a high maternal serum TSH receptor binding immunoglobulin index (TBII) predict adverse neonatal outcome. Mortality is reported to be as high as 25% in affected infants and would therefore be expected to be higher in premature infants. This study illustrates that in sick, premature, extreme low birth weight (ELBW) or intrauterine growth retarded (IUGR) infants, the diagnosis maybe overlooked especially in the absence of antenatal risk assessment and management of thyrotoxicosis in this setting is complex.

The records of premature neonates born at the three main maternity units in Brisbane, between January 1996 and July 1998 diagnosed with congenital thyrotoxicosis were reviewed. Data were recorded on gestational age, birth weight (B Wt), maternal thyroid history and current status, and neonatal course. Thyroid function and TBII status was assessed using standard biochemical assays.

Seven neonates from five pregnancies were identified (four female, three male). Mean gestational age was 30 week (25–36 week) and median B Wt was 1·96 kg (0·50–2·62 kg). Only one mother received formal antenatal counselling by a paediatric endocrine service and had a TBII (54%) measured prior to delivery. Three of five mothers had elevated TBII measured after diagnosis in their offspring (57%, 65%, 83%) and in one mother, a TBII was not performed. All mothers were biochemically euthyroid at delivery. Mean age at diagnosis was 9 days (1–16 days) and mean age at commencement of treatment was 12 days (7–26 days). Two infants received propylthiouracil and five received a combination of carbimazole and pro‐pranolol. Four became biochemically hypothyroid, in three this resolved with cessation of the antithyroid drug (ATD), and one required ongoing T4 supple‐mentation. Only one infant required treatment for cardiac failure and there were no deaths in this cohort.

This is a large series of extremely small and premature infants with neonatal thyro‐toxicosis. Presentation was nonspecific. The diag‐nosis was delayed because of low birth weight, prematurity, multiple birth and/or an unrecognized maternal history of Graves' disease. The treatment of neonatal thyrotoxicosis was difficult in these extreme low birth weight infants yet no infant died and significant morbidity was confined to high output cardiac failure in one infant. With antenatal recog‐nition of past or active Graves' disease, assessment of maternal TSH receptor binding immunoglobulin index prior to delivery and postnatal monitoring of cord TSH and venous fT4 and TSH on days 4 and 7 rapid treatment of affected infants may have further reduced neonatal morbidity.
The exon 3‐retaining and the exon 3‐deleted forms of the growth hormone‐binding protein (GHBP) in human serum are regulated differently
Authors: Kratzsch J. , Wu Z. , Kiess W. , Dehmel B. , Bosse‐Henck A. , Reuter W. , Pflaum C. D. , Strasburger C. J.
Published: March 2003

Recently, two isoforms of the growth hormone‐binding protein (GHBP), which is identical with the extracellular domain of the growth hormone receptor (GHR), have been described. One isoform contains the exon 3 (E3(+)GHBP) and one excludes the exon 3 (E3(–)GHBP). The distribution of both isoforms in peripheral blood and their functional relevance is so far unknown.

To study the molecular distribution of both species we have analysed sera of 141 subjects with average weight, overweight and obesity by newly developed immunoassays. The relationship between the different molecular forms of GHBP and specific parameters of body composition as well as risk factors of metabolic disturbances, were then examined.

The extracellular domain of the exon 3‐retaining and ‐deleted isoforms of the GHR are released as E3(+)GHBP and E3(–)GHBP into the peripheral circulation. Furthermore, both molecular species do not show any correlation to each other (r = 0·67) and their relative proportion in blood is gender‐dependent with a higher E3(–)GHBP proportion in females (P < 0·01). E3(+)GHBP appears to have a considerably stronger correlation to indicators (BMI, fat mass, waist circumference) and metabolic risk factors (fasting insulin, uric acid, triglycerides, apolipoprotein B, diastolic blood pressure) of adiposity than E3(–)GHBP, indicating differences in their functional significance.

The availability of assays for the determination of GHBP isoforms may be very important for the study of the GH receptor and its soluble extracellular domain, GHBP.
Effect of Sandostatin® LAR® on serum leptin levels in patients with acromegaly
Authors: Tan K. C. B. , Tso A. W. K. , Lam K. S. L.
Published: March 2003

Serum leptin levels are decreased in patients with acromegaly and rise after GH is normalized by surgical treatment. We have evaluated the effect of Sandostatin® LAR® on leptin levels in acromegalic patients since there are recent data to suggest that somatostatin, in addition to its GH lowering effect, also reduces serum leptin levels in humans.

Nineteen patients with active acromegaly were studied. Eleven patients received monthly injection of Sandostatin® LAR® and eight patients underwent transsphenoidal surgery. Serum concen‐trations of leptin, GH, IGF‐1 and insulin were measured before and after treatment.

Serum leptin concentrations were lower in patients with active acromegaly than controls matched for age, sex and body mass index (BMI) [2·79 µg/l (2·60) vs. 4·41 µg/l (5·07); median (inter‐quartile range); P < 0·01]. A positive correlation between serum leptin concentrations and BMI was observed in the controls (r = 0·46, P < 0·05) but not in the acromegalic patients before treatment (r = 0·32, ns). In the group of patients treated with Sandostatin® LAR®, a marked reduction in GH and IGF‐1 was achieved by week 8 and GH and IGF‐1 remained suppressed throughout the 6 months of treatment. There was no change in BMI. A significant increase in leptin levels only became evident after 6 months of treatment [2·99 µg/l (2·60) vs. 4·21 µg/l (3·84), P < 0·05]. Leptin levels also significantly increased after transsphenoidal surgery [3·05 µg/l (5·73) vs. 5·19 µg/l (4·93), P < 0·05]. The positive correlation between serum leptin concentrations and BMI was restored in acromegalic patients both after treatment with Sandostatin® LAR® (r = 0·62, P < 0·05) and after surgery (r = 0·81, P < 0·05).

Leptin concentrations were decreased in patients with active acromegaly and lowering GH by either Sandostatin® LAR® or transsphenoidal surgery led to an increase in leptin concentrations.
Autoimmune polyendocrine syndrome type 1 (APS I) in Norway
Authors: Myhre Anne Grethe , Halonen Maria , Eskelin Petra , Ekwall Olov , Hedstrand Håkan , Rorsman Fredrik , Kämpe Olle , Husebye Eystein S.
Published: March 2003

OBJECTIVE

The aim of the present study was to investigate Norwegian patients with autoimmune polyendocrine syndrome type I (APS I), with respect to occurrence and clinical presentation, reactivity towards different autoantigenes and mutations in the autoimmune regulator (AIRE) gene.

PATIENTS

Twenty Norwegian patients from 15 families with APS I (11 males, nine females; mean age 26 years, range 4–54) were included by contacting all major hospitals in Norway.

METHODS

Clinical data was collected from both patients and their physicians by the use of questionnaires and patient records. Autoantibodies were analysed using radioimmunoassays based on antigen synthesized by in vitro transcription and translation. AIRE mutations were determined by DNA sequence analysis.

RESULTS

The prevalence of APS I in Norway was estimated to be about 1 : 80 000 individuals. We found about the same distribution of disease characteristics as has been reported in Finnish patients. The diagnosis was delayed in many individuals. In two thirds of the cases, the patients were admitted in Hospital with acute adrenal insufficiency or hypocalcaemic crisis. Forty percent of these patients already had one of the main disease manifestations. Four different mutations in the AIRE gene were found in the Norwegian cohort. A 13‐bp deletion in exon 8 (1085–1097del) was the most frequent mutation, present in 22/40 (55%) of the alleles. Eighty‐five percent of the patients had either autoantibodies against 21 hydroxylase or aromatic l‐amino acid decarboxylase. Five of eight women (age > 13 years) had ovarian failure, and all of these had antibodies against side‐chain cleavage enzyme (P = 0·0002).

CONCLUSION

Norwegian patients with APS I clinically resemble patients from Finland and other European countries. The diagnosis APS I must be considered in children and adolescents with chronic mucocutaneous candidiasis, autoimmune adrenocortical failure or hypoparathyroidism in order to avoid fatal complications. Analysis of autoantibodies and mutational analysis of the AIRE gene are valuable diagnostic tools, especially in the early stages of the disease.
A comparison between low‐dose (1 µg), standard‐dose (250 µg) ACTH stimulation tests and insulin tolerance test in the evaluation of hypothalamo–pituitary–adrenal axis in primary fibromyalgia syndrome
Authors: Kırnap M. , Çolak R. , Eser C. , Özsoy O. , Tutus A. , Kelestimur F.
Published: March 2003

OBJECTIVE Primary fibromyalgia syndrome (PFS) is a nonarticular rheumatological syndrome characterized by disturbances in the hypothalamo–pituitary–adrenal (HPA) axis. The site of the defect in the HPA axis is a matter of debate. Our aim was to evaluate the HPA axis by the insulin‐tolerance test (ITT), standard dose (250 µg) ACTH test (SDT) and low dose (1 µg) ACTH test (LDT) in patients with PFS.

DESIGN AND PATIENTS Sixteen patients (13 female, three male) with PFS were included in the study. Sixteen healthy subjects (12 female, four male) served as matched controls. ACTH stimulation tests were carried out by using 1 µg and 250 µg intravenous (i.v.) ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0, 30 and 60 min. The ITT was performed by using i.v. soluble insulin, and serum glucose and cortisol levels were measured before and after 30, 60, 90 and 120 min. The 1 µg and 250 µg ACTH stimulation tests and the ITT were performed consecutively.

RESULTS Peak cortisol responses to both the low dose test (LDT) and standard dose test (SDT) (589 ± 100 nmol/l; 777 ± 119 nmol/l, respectively) were lower in the PFS group than in the control group (1001 ± 370 nmol/l; 1205 ± 386 nmol/l, respectively) (P < 0·0001). Peak cortisol responses to ITT (730 ± 81 nmol/l) in the PFS group were lower than in the control group (1219 ± 412 nmol/l) (P < 0·0001). Six of the 16 patients with PFS had peak cortisol responses to LDT lower than the lowest peak cortisol response of 555 nmol/l obtained in healthy subjects after LDT. There was a significant difference between the peak cortisol responses to LDT (589 ± 100 nmol/l) and peak cortisol responses to ITT (730 ± 81 nmol/l) in the PFS group (P < 0.0001). Peak cortisol responses to SDT (777 ± 119 nmol/l) were similar to peak cortisol responses to ITT (730 ± 81 nmol/l) in the PFS group.

CONCLUSION We conclude that the perturbation of the HPA axis in PFS is characterized by underactivation of the HPA axis. Some patients with PFS may have subnormal adrenocortical function. LDT is more sensitive than SDT or ITT in the investigation of the HPA axis to determine the subnormal adrenocortical function in patients with PFS.
The contribution of IGF‐I to skeletal integrity in postmenopausal women
Authors: Muñoz‐Torres Manuel , Mezquita‐Raya Pedro , Lopez‐Rodriguez Francisca , Torres‐Vela Elena , De Dios Luna Juan , Escobar‐Jimenez Fernando
Published: March 2003

OBJECTIVES The pathogenic role of the decline in serum concentrations of IGF‐I in postmenopausal osteoporosis is not fully elucidated. We investigated the associations among IGF‐I, bone mineral density (BMD), ultrasound parameters and prevalence of vertebral fractures in postmenopausal women.

DESIGN A cross‐sectional study.

PATIENTS One hundred and fifty‐four ambulatory postmenopausal women (61 ± 7 years) referred for osteoporosis screening.

MEASUREMENTS IGF‐I was measured by radioimmunoassay and BMD using dual‐energy X‐ray absorptiometry. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) at calcaneus were measured by a quantitative ultrasound system.

RESULTS IGF‐I was significantly lower in osteoporotic subjects and correlated positively with BMD, BUA and SOS. After adjusting for age, years since menopause and body mass index, IGF‐I accounted for 8·5% of the variance at lumbar spine BMD, 4·6% at femoral neck and 7·1% at calcaneal BUA. BUA was associated with IGF‐I independently of BMD. IGF‐I was lower in women with vertebral fractures (91 ± 39 µg/l vs. 114 ± 44 µg/l; P = 0·003). The osteoporosis densitometric criteria (t‐score ≤ −2·5 SD) was the most strongly independent associated variable with prevalent vertebral fractures [odds ratio (OR): 3·3 (1·4–7·6)], followed by IGF‐I levels below 75th percentile [OR: 3 (1–8·8)].

CONCLUSIONS Our study shows that IGF‐I is strongly associated with bone mineral density and reflects aspects of bone quality. The contribution of IGF‐I to skeletal integrity in postmenopausal women is clinically relevant.
Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults
Authors: Gómez José Manuel , Espadero Rosa María , Escobar‐Jiménez Fernando , Hawkins Federico , Picó Antonio , Herrera‐Pombo José Luis , Vilardell Enric , Durán Alejandra , Mesa Jordi , Faure Eduardo , Sanmartí Anna
Published: March 2003

objective To investigate the GH response to glucagon in adult patients with GH deficiency and in controls compared with the GH response to the insulin tolerance test (ITT) in patients with GH deficiency and to determine whether the use of glucagon results in a diagnostic utility test.

patients and design Seventy‐three patients with adult GH deficiency and organic hypothalamic‐pituitary disease were recruited, along with 46 controls. The patients were divided into five groups according to the number of associated hormone deficiencies present.

measurements Hypopituitary subjects underwent assessment of GH secretory status by the ITT, the glucagon test and measurement of serum IGF‐I concentration. Controls underwent the glucagon test. After the ITT, glucose and GH levels were measured at baseline, 30, 60 and 90 minutes, and after glucagon at baseline, 90, 120, 150, 180, 210 and 240 minutes.

results The highest GH value after the ITT in the patient group was 3 µg/l (0·76 ± 0·82 µg/l), and after the glucagon test the highest GH peak value was 2·9 µg/l (0·64 ± 0·79 µg/l). A correlation was found between the GH peak and the progressive number of hormone deficiencies. After the glucagon test, the GH peak obtained in the controls at 180 minutes was 9·8 ± 4·6 µg/l and, on an individual basis, none of the 46 controls failed to achieve peak GH levels higher than 3 µg/l. In the controls, a negative correlation was observed between the GH response to glucagon and age (r = –0·389, P = 0·0075) and body mass index (r = –0·329, P = 0·0254). The accuracy of the glucagon test for differentiating patients from controls, estimated by receiver operating characteristics (ROC) curve methodology, showed that the cut‐off of 3 µg/l for the GH peak provides 100% sensitivity and 100% specificity and is a reliable decision threshold.

conclusions The glucagon GH test is reliable and provides a clear separation between GH‐deficient and normal adults. A single glucagon test with a cut‐off of 3 µg/l for the GH peak is diagnostic of GH deficiency in adults and could be considered and studied as an alternative to the ITT.
Confirmation of severe GH deficiency after final height in patients diagnosed as GH deficient during childhood
Authors: Attanasio Andrea F. , Howell Simon , Bates Peter C. , Blum Werner F. , Frewer Paul , Quigley Charmian , Shalet Stephen M.
Published: March 2003

objective Human GH treatment of patients with childhood‐onset (CO) growth hormone deficiency (GHD) ceases when they reach final height; this provides an opportunity to retest GH status in all patients before determining whether GH therapy will be required in adult life. At present, the diagnostic approach to these patients is not fully standardized. This study aimed to characterize a large group of previously GH‐treated CO GHD patients and establish their GH status.

patients and methods The multinational study included 167 patients diagnosed as GH deficient and treated with hGH to final height during childhood. Mean age was 19·2 years and mean height standard deviation score (SDS) was –1·08. Peak serum GH concentrations were determined in standard GH stimulation tests. IGF‐I and IGFBP‐3 concentrations were determined at a central laboratory and converted to SDS values by reference to a normal population.

results Using only a peak GH value of less than 3 µg/l (1 mg = 3 U) in stimulation tests as the cut‐off, 133 (79·6%) patients would be classed as GH deficient. Using only an IGF‐I value less than –2 SDS as the cut‐off, 134 (80·2%) patients would be classed as GH deficient. However, by using both criteria there were 120 (71·9%) patients who were definitely severely GH deficient (group 1) and 20 (12·0%) who were not GH deficient (group 2), leaving 14 (8·4%) classed as GH deficient from IGF‐I SDS only (group 3) and 13 (7·8%) classed as GH deficient from stimulation test only (group 4). There was no difference between the groups in height SDS or body mass index (BMI), but the GH‐deficient patients tended to have been diagnosed at a younger age (group 1, 8·2 ± 3·9; group 2, 10·0 ± 4·0; P = 0·052). For patients classed as GH deficient compared with those not GH deficient, the percentage of males was lower (group 1, 64·2%; group 2, 90·0%; P = 0·022) and the percentage with multiple pituitary hormone deficiencies was higher (group 1, 81·7%; group 2, 20·0%; P < 0·001), with the other two groups being intermediate in each case. Only the group classed as GH deficient by both criteria had a mean IGFBP‐3 less than –2 SDS and both IGF‐I SDS and IGFBP‐3 SDS increased steadily across the four groups.

conclusions A high percentage (71·9%) of these childhood‐onset GH‐deficient patients were still GH deficient in adult life and are likely to require further hGH treatment. While 12·0% could be classed as definitely no longer GH deficient, there are some patients who are intermediate (16·2%) and may be classed as GH deficient by one criterion but not the other. When GH stimulation test results and IGF‐I concentration are discordant, the IGFBP‐3 level does not establish diagnosis and the hGH treatment requirement of such patients remains a dilemma.
The treatment of a thyrotropin‐secreting pituitary macroadenoma with octreotide in twin pregnancy
Authors: Blackhurst G. , Strachan M. W. , Collie D. , Gregor A. , Statham P. F. X. , Seckl J. E. R.
Published: March 2003

TSH‐secreting pituitary tumours are rare but difficult to treat due to a combination of refractory hyperthyroidism and low surgical cure rates. We describe the case of a 21‐year‐old woman who, despite twin pregnancy, became euthyroid and had dramatic tumour shrinkage on octreotide treatment. To our knowledge, this is the first description of the use of octreotide for a TSH‐secreting pituitary adenoma throughout pregnancy.
Cerebrovascular mortality in patients with pituitary adenoma
Authors: Brada M. , Ashley S. , Ford D. , Traish D. , Burchell L. , Rajan B.
Published: March 2003

Objective To assess cerebrovascular mortality in a UK cohort of patients with pituitary adenoma known to have increased incidence of cerebrovascular accidents (CVA).

Methods A total of 334 patients treated at the Royal Marsden Hospital (RMH) between 1962 and 1986 with surgery and postoperative radiotherapy were followed up via the NHS Central Register (NHSCR) to identify deaths and emigrations. The causes of death were assessed by NHSCR‐based death certificates and coded according to the 9th revision of ICD. Follow‐up was censored at age 85, on emigration or cancellation of NHSCR. Thirteen patients could not be traced. A total of 4982 person‐years was accumulated in the cohort. Expected numbers of deaths were computed from the national age‐, sex‐ and period‐specific mortality rates for England and Wales.

Results In the pituitary adenoma cohort, 128 deaths were observed compared to 80·9 expected [relative risk (RR) of death 1·58 (95% CI: 1·32–1·90)]. There were 33 cerebrovascular deaths compared with 8·04 expected (RR 4·11, 95% CI 2·84–5·75). Three deaths were from subarachnoid haemorrhage compared to 0·54 expected (RR 5·51, 95% CI 1·14–16·09). There was an increased cerebrovascular mortality in women (RR 6·93, 95% CI 4·29–10·60) compared to men (RR 2·4, 95% CI 1·24–4·20; P = 0·002) and in patients having debulking surgery (RR 5·19, 95% CI 3·50–7·42) compared to biopsy/no surgery (RR 1·33, 95% CI 0·27–3·88; P = 0·02). The RR in patients with nonsecretory tumours was 3·65 (95% CI 2·26–5·58), compared with 5·23 (95% CI 2·25–10·30) in secretory tumours (P = 0·4). The effect of age at radiotherapy was not significant (P = 0·4).

Conclusion Patients with pituitary adenoma treated with surgery and radiotherapy have an increased risk of cerebrovascular mortality compared to the general population, which mirrors the increased incidence of CVA. The possible risk factors include hypopituitarism, radiotherapy and extent of surgery but none are at present proven causes. The evaluation of new treatment strategies should not only assess intermediate end‐points of tumour and endocrine control but should concentrate on long‐term survival with particular emphasis on CVA incidence and mortality.
Size at birth, gestational age and cortisol secretion in adult life: foetal programming of both hyper‐ and hypocortisolism?
Authors: Kajantie Eero , Phillips David I. W. , Andersson Sture , Barker David J. P. , Dunkel Leo , Forsén Tom , Osmond Clive , Tuominen Juha , Wood Peter J. , Eriksson Johan
Published: March 2003

objective Recent studies have suggested that lifelong programming of the hypothalamic–pituitary–adrenal (HPA) axis in utero is an important mechanism in explaining the link between small size at birth and adult cardiovascular disease. However, direct evidence from human birth cohorts has so far been contradictory. We set out to study reasons for this discrepancy by examining the relationship between adult HPA axis function and birthweight and body proportions at birth in a group of elderly subjects with detailed birth records.

design Birth cohort study.

subjects Four hundred and twenty‐one men and women (mean age 69·5 years, range 65·1–75·8 years) born at term in Helsinki, Finland, during 1924–33, with body size and gestational age at birth recorded.

measurements Fasting serum cortisol and cortisol‐binding globulin concentrations. The concentration of free cortisol was estimated by their ratio.

results There was no significant correlation between fasting cortisol concentrations and birthweight in either men or women. However, there was a weak inverse association between fasting cortisol and length at birth in women but not in men. There was also a significant positive association between cortisol and ponderal index in both genders. We found that the association between foetal growth on fasting total and free cortisol concentrations differed in subjects born at different gestational ages. In subjects born before 39 weeks of gestation, both total and free cortisol showed inverse correlations with birthweight (P = 0·02 and P = 0·09, respectively) and length at birth (P = 0·001 and P = 0·02), whereas in subjects born after 40 weeks of gestation there were positive correlations with birthweight (P = 0·06 and P = 0·002) and ponderal index at birth (P = 0·003 and P = 0·003). The interactions between birthweight and gestational age were statistically significant (P = 0·01 for total and P = 0·003 for free cortisol).

conclusions These data suggest that the relationship between size at birth and cortisol concentrations in adult life is different in subjects born at different gestational ages: both hyper‐ and hypocortisolism may arise as a consequence of foetal programming of the hypothalamic–pituitary–adrenal axis during intrauterine life.
The C‐terminal fragment of big endothelin‐1 does not potentiate the vasoactive effects of endothelin‐1
Authors: Ottosson‐Seeberger  , Hemsén  , Lundberg  , Ahlborg
Published: March 2003

The aim was to study the cardiovascular effects of the C‐terminal (22–38) fragment of big endothelin‐1, which is produced by the cleavage of big endothelin‐1 (big ET‐1) to endothelin‐1 (ET‐1). An intravenous infusion of the (22–38) fragment (4, 8 and 12 pmol kg−1 min−1, each dose for 10 min) was given to 10 healthy subjects. Four control subjects received 0·9% saline. Two additional subjects received ET‐1 (0·2 and 4 pmol kg−1 min−1, each dose for 20 min) alone or combined with an equimolar infusion of the (22–38) fragment on two separate occasions. The fragment infusion did not alter heart rate, mean arterial blood pressure, cardiac output, systemic or pulmonary vascular resistance, splanchnic, cerebral or forearm blood flow. Renal blood flow showed a slight fall (11%, P<0·001) in the fragment group of the same magnitude as in a previous control study. After the fragment infusion, a decrease in mean pulmonary arterial pressure (MPAP) by 12% (P<0·01) and in pulmonary capillary wedge pressure (PCWP) by 31% (P<0·001) was noted, which did not differ from the pulmonary pressures in the saline‐infused control group. The (22–38) fragment, when combined with ET‐1, was not able to modify the effects of ET‐1 on heart rate, mean arterial blood pressure, splanchnic and renal blood flow. Consequently, the exogenous (22–38) fragment does not seem to cause any significant cardiovascular effects in healthy humans.
Cholinergic blockade and the mesenteric artery response to head‐up tilt‐induced central hypovolaemia
Authors: Perko  , Madsen  , Perko  , Secher
Published: March 2003

The influence of muscarinic blockade on the superior mesenteric artery (SMA) response to head‐up tilt (HUT) was assessed by Doppler ultrasound in eight healthy adults pretreated with i.v. glycopyrron. During supine rest, cholinergic blockade increased heart rate from 58 ± 3 to 106 ± 6 beats min−1 (mean ± SE) and mean arterial pressure from 81 ± 3 to 97 ± 4 mmHg (P<0·01) and it reduced the cardiac stroke volume from 89 ± 6 to 59 ± 7 ml (P<0·01) with no significant effect on the SMA diameter and blood flow velocities. HUT provoked a further increase in heart rate to 134 ± 5 beats min−1(P<0·01) and a reduction in stroke volume to 45 ± 4 ml (P<0·01). The early diastolic velocity increased from −51 ± 4 to 6 ± 8 cm s−1 during the normotensive stage of HUT and further to 21 ± 9 cm s−1 during the hypotensive stage with a reduction in mean arterial pressure from 97 ± 4 to 73 ± 7 mmHg (P<0·01) but, in contrast to control HUT (without cholinergic blockade), the end‐diastolic velocity did not change significantly. Maintenance of blood velocity and diameter in spite of an increase in arterial pressure at rest indicates increased SMA impedance. Likewise, during hypovolaemia, a glycopyrron‐induced inhibition in diastolic velocity supports an increase in SMA impedance. The results indicate cholinergic vasorelaxing influence on the superior mesenteric artery both at rest and during normotensive central hypovolaemia.
Altered cardiovascular autonomic regulation after salmeterol treatment in asthmatic children
Authors: Jartti Tuomas T. , Kaila Timo J. , Tahvanainen Kari U. O. , Kuusela Tom A. , Vanto Timo T. , Välimäki Ilkka A. T.
Published: March 2003

The effects of therapeutic 4 weeks' inhaled salmeterol treatment on the cardiovascular and respiratory autonomic nervous regulation was studied in 11 asthmatic children using inhaled corticosteroid medication. The study followed a randomized, double‐blind, placebo‐controlled cross‐over design. The salmeterol dose was 50 μg twice daily. The 4‐week salmeterol treatment increased baseline heart rate, low‐frequency/high‐frequency (LF/HF) variability ratio of R–R intervals, LF variability of systolic arterial pressure (SAP) and maximum tidal volume during the deep breathing test, as well as morning and evening peak expiratory flow (PEF) values. The 4‐week salmeterol treatment decreased baseline HF variability of R–R intervals. As a response to the acute 600 μg of salbutamol, the changes in heart rate, HF variability of R–R intervals and diastolic blood pressure were significantly smaller after 4 weeks' salmeterol treatment. In conclusion, 4 weeks' therapeutic salmeterol treatment decreases basal cardiovagal reactivity, increases sympathetic dominance in the cardiovascular autonomic balance and improves pulmonary function. A tolerance develops in the cardiovascular response but not in the bronchodilatory response.
Properties of spiral waves in a piece of isotropic myocardium
Authors: Wohlfart  , Ohlén
Published: March 2003

Tachyarrhythmias of the heart can be due to the presence of one or more spiral waves of electrical activity. Spiral waves were simulated using a previously described ionic model of cardiac action potentials in a 75 × 75 network of compartments. The compartments were connected by means of resistors and made isotropic in order to catch basic properties of spiral waves. The cross‐field stimulation technique was used to generate single or double spiral waves. The analysis showed that a spiral wave was created when the second excitation front became critically curved, in the wake of the preceding wave, so that decremental propagation occurred. A spiral wave could also be generated from a wave circulating around an obstacle when the obstacle size was suddenly reduced. The spiral waves steadily circled around an area with excitable but unexcited cells. An undisturbed spiral wave in the isotropic medium circled around in a stable pathway, but drifted along the borders of cells made non‐excitable. An excitation within an existing spiral wave could generate new spiral waves that interacted with each other and formed complex excitation patterns. A sudden prolongation of the refractory period reduced the central area with unexcited cells in the spiral pathway but only slightly prolonged the revolution time. A further prolongation of the refractory period extinguished the spiral wave when the tip of the spiral wave invaded refractory areas. The described ionic compartment model could accurately produce spiral waves with properties in line with experimental results reported by others.
Reproducibility of the alterations in circulation and cerebral oxygenation from supine rest to head‐up tilt
Authors: Houtman  , Colier  , Hopman  , Oeseburg
Published: March 2003

Cardiovascular stability, as affected by several diseases, may be assessed by head‐up tilt testing. Follow‐up studies are essential in both evaluating interventions and assessing progression. However, data on the reproducibility of the changes in circulatory status and cerebral oxygenation provoked by head‐up tilt testing are fundamental to follow‐up studies. The aim of this study was, therefore, to assess the reproducibility of the alterations in stroke volume (SV), mean arterial pressure (MAP), as well as oxygenated ([O2Hb]) and deoxygenated haemoglobin ([HHb]) concentration in cerebral tissue from supine rest (SUP) to head‐up tilt (HUT). SV was calculated by Modelflow, a pulse contour method, from the finger arterial pressure wave measured by Portapres, the portable version of Finapres. [O2Hb] and [HHb] were measured using near‐infrared spectroscopy (NIRS). Ten healthy individuals visited the laboratory on two different days. On both days, they underwent 10 min SUP followed by 10 min 70° HUT twice. SV decreased, which was (in part) compensated for by an increased heart rate, while MAP increased slightly during HUT compared with SUP. Although [HHb] increased during HUT, no presyncope symptoms were experienced. The circulatory variables (SV, HR and MAP) as well as [HHb] showed an acceptably small systematic and random error as well as reproducibility error compared with the observed difference between HUT and SUP and were similar between and within visits. Therefore, it is concluded that MAP measured by Portapres and SV calculated by Modelflow as well as HHb measured by NIRS seem to be reproducible and may therefore be used in follow‐up studies.
Determination of baroreflex gain using auto‐regressive moving‐average analysis during spontaneous breathing
Authors: O’Leary  , Lin  , Hughson
Published: March 2003

The heart rate component of the arterial baroreflex gain (BRG) was determined with auto‐regressive moving‐average (ARMA) analysis during each of spontaneous (SB) and random breathing (RB) protocols. Ten healthy subjects completed each breathing pattern on two different days in each of two different body positions, supine (SUP) and head‐up tilt (HUT). The R–R interval, systolic arterial pressure (SAP) and instantaneous lung volume were recorded continuously. BRG was estimated from the ARMA impulse response relationship of R–R interval to SAP and from the spontaneous sequence method. The results indicated that both the ARMA and spontaneous sequence methods were reproducible (r=0·76 and r=0·85, respectively). As expected, BRG was significantly less in the HUT compared to SUP position for both ARMA (mean ± SEM; 3·5 ± 0·3 versus 11·2 ± 1·4 ms mmHg–1; P<0·01) and spontaneous sequence analysis (10·3 ± 0·8 versus 31·5 ± 2·3 ms mmHg–1; P<0·001). However, no significant difference was found between BRG during RB and SB protocols for either ARMA (7·9 ± 1·4 versus 6·7 ± 0·8 ms mmHg–1; P=0·27) or spontaneous sequence methods (21·8 ± 2·7 versus 20·0 ± 2·1 ms mmHg–1; P=0·24). BRG was correlated during RB and SB protocols (r=0·80; P<0·0001). ARMA and spontaneous BRG estimates were correlated (r=0·79; P<0·0001), with spontaneous sequence values being consistently larger (P<0·0001). In conclusion, we have shown that ARMA‐derived BRG values are reproducible and that they can be determined during SB conditions, making the ARMA method appropriate for use in a wider range of patients.
An 18oxygen inhalation method for determination of total body formation of nitric oxide in humans
Authors: Sakinis Augustinas , Jungersten Lennart , Wennmalm Åke
Published: March 2003

The formation of nitric oxide (NO) and the subsequent conversion of the NO formed into nitrate require molecular oxygen. Based on this fact, we have recently developed a method using inhalation of the stable oxygen isotope, i.e. 18O2, to determine total formation of NO in small laboratory animals. The method has now been further developed to be applicable also in humans. Five healthy awake male subjects inhaled a gas mixture of unlabelled and 18‐labelled oxygen (approximate ratio 4:1) in nitrogen from a closed breathing system equipped with eliminators for carbon dioxide and water vapour. The ratio of unlabelled to 18‐labelled oxygen, as well as the total oxygen concentration during the inhalation, were monitored. Venous blood samples were taken before and after the inhalation for analysis of unlabelled and 18O‐labelled nitrate by gas chromatography/mass spectrometry. The procedure was repeated with the same protocol on a later occasion, during ongoing treatment with the NO synthesis inhibitor NG‐monomethyl‐
L‐arginine (
L‐NMMA). The average nitrate level in plasma in the absence of
L‐NMMA was 26 μmol l–1. The rate of total synthesis of NO was estimated to be 0·38 ± 0·06 μmol kg–1 h–1, corresponding to a total body formation of 600–700 μmol/24 h in an adult male. Infusion of
L‐NMMA caused an increase in mean arterial blood pressure from 86 ± 4 to 99 ± 5 mmHg (P<0·05). The average plasma level of nitrate during infusion of
L‐NMMA was 24 μmol l–1. NO formation during infusion of
L‐NMMA was 0·17 ± 0·03 μmol kg–1 h–1, i.e. significantly (P<0·05) lower than in the absence of
L‐NMMA. We suggest that the described method allows direct determination of total NO formation in man. The method may be useful in the study of various experimental and pathophysiological conditions affecting NO formation.
Changes in transfer factor of the lung in response to bronchodilatation
Authors: Åkesson Ulla , Dahlström Jan‐Anders , Wollmer Per
Published: March 2003

Measurement of the transfer factor for carbon monoxide (TLCO) is a widely used clinical lung function test. Although it is frequently applied in patients with bronchial obstruction, there is little information on the effects of bronchodilatation on the test. We therefore measured TLCO in 40 patients before and after inhalation of terbutaline. TLCO was measured with the single‐breath technique in 20 patients and with the intra‐breath technique in 20 patients. TLCO was also measured in 20 healthy subjects with the single‐breath technique. Forced expiratory volume (FEV1) increased from 2·9 ± 1·1 to 3·2 ± 1·2 l in patients with bronchial obstruction in response to terbutaline inhalation. TLCO increased from 8·2 ± 2·6 to 8·6 ± 2·7 mmol min–1 kPa–1 (P< 0·001) and alveolar volume (VA) from 5·74 ± 1·21 to 5·90 ± 1·21 l (P<0·001). There was no difference between the single‐breath and the intra‐breath techniques. There was little change in FEV1 in the healthy subjects in response to terbutaline. TLCO increased from 10·2 ± 2·1 to 10·5 ± 2·2 mmol min–1 kPa–1 (P< 0·01), but there was no change in VA. The increase in TLCO in patients may partly be explained by improved distribution of the inhaled gas. In healthy subjects, terbutaline may increase pulmonary capillary volume. We conclude that bronchodilatation results in a small increase in TLCO in patients with light to moderate bronchoconstriction as well as in healthy subjects. The effect is small and should in most cases be simple to account for in the interpretation of pulmonary function tests, provided the patient’s treatment is known.
Lack of effect of acupuncture upon signs and symptoms of delayed onset muscle soreness
Authors: Barlas Panos , Robinson Judith , Allen Jim , Baxter G. David
Published: March 2003

The effect of acupuncture upon experimentally induced delayed onset muscle soreness (DOMS) was assessed in a placebo‐controlled study under blinded conditions. Volunteers (n=48; 24 M & 24 F) were randomly allocated to one of four groups: control (20 min rest), placebo (minimal needling at non‐acupuncture points), treatment group 1 (acupuncture at classic acupuncture points) and treatment group 2 (acupuncture at ‘tender’ points). DOMS was induced in the elbow flexors of the non‐dominant arm using a standardized eccentric exercise regime. Measurements of elbow range of movement (flexion, extension, relaxed angle), and pain as well as visual analogue scores (VAS), tenderness (using a pressure algometer) were employed as indices of treatment efficacy. Measurements of elbow range of movement and tenderness were made prior to DOMS induction on the first day, and repeated pre‐ and post‐treatment on subsequent days; pain was assessed using visual analogue scales post‐induction and post‐treatment on the first day, and pre‐ and post‐treatment thereafter. For all conditions, subjects rested supine for a period of 20 min, during which treatment was delivered according to group allocation. Repeated measures and one‐way analysis of variance (ANOVA) demonstrated no significant interactive (AB) effects, except for visual analogue scores (P=0·0483); one factor ANOVA on the second day of the experiment (pre‐treatment) indicated significant differences between the control and all other groups. However, such differences were not found on any other day of the experiment. It is concluded that acupuncture has little effect upon the cardinal signs and symptoms of DOMS, at least under the conditions of the current experiment.
Cardiovascular functioning during the menstrual cycle
Authors: Moran Victoria Hall , Leathard Helen L. , Coley John
Published: March 2003

Variations in cardiovascular functioning during the ‘normal’ menstrual cycle have been little researched. Resting‐blood pressures, resting‐heart rate, rate‐pressure product (RPP) and a derived index of fitness (Schneider Index) were monitored throughout natural, hormonally defined menstrual cycles. Volunteers were 26 women (20–48 years) who had regular (25–35 days) cycles. Their blood pressures and heart rate (at rest and according to Schneider’s protocol) were measured at the same time daily (Monday–Friday) for 5 weeks. Daily, early morning‐urine samples were assayed for sex hormones enabling accurate definition of cycle phase for each woman. Resting systolic‐blood pressure was significantly higher in the ovulatory phase (P<0·05) than in the follicular or luteal phases, but resting‐diastolic pressures did not differ significantly between phases. Resting‐heart rate was significantly higher in both ovulatory (P<0·01) and luteal (P<0·01) phases than in the menstrual and follicular phases. The Schneider Index was higher during the follicular phase than during the ovulatory (P<0·005) or luteal (P<0·01) phases, the RPP was higher during the ovulatory phase than during the bleeding (P<0·05) and follicular (P<0·005) phases. These findings provide a pattern of menstrual cycle‐related variation in cardiovascular functioning that can be related to established actions of the ovarian steroids.
Gastrointestinal mean transit times in young and middle‐aged healthy subjects
Authors: Graff J. , Brinch K. , Madsen J. L.
Published: March 2003

To investigate the effects of age and gender on gastric, small intestinal and colonic mean transit times, a study was conducted in 32 healthy volunteers: eight young women (22–30 years), eight young men (20–28 years), eight middle‐aged women (43–51 years) and eight middle‐aged men (38–53 years). After ingestion of a meal containing 111Indium‐labelled water and 99mTechnetium‐labelled omelette imaging of the abdomen was performed at intervals of 30 min until all radioactivity was located in the colon and henceforth at intervals of 24 h until all radioactivity had cleared from the colon. Gastric, small intestinal and colonic mean transit times were calculated. The gastric, small intestinal and colonic mean transit times were significantly longer in women. Ageing was shown to accelerate the gastric and small intestinal transit significantly. In the group of men the colonic mean transit time was unaffected by age, but middle‐aged women had a significantly slower colonic transit than young women. We therefore conclude that both age and gender have to be considered when reference values for gastric, small intestinal and colonic mean transit times have to be established.