bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility*
Authors: Giwercman Yvonne Lundberg , Nikoshkov Andrej , Byström Birgitta , Pousette Åke , Arver Stefan , Wedell Anna
Published: March 2003

OBJECTIVE Resistance to androgens has been suggested as a possible cause of male infertility. This hypothesis is based mainly on binding studies in genital skin fibroblasts but the molecular evidence is sparse.

DESIGN Molecular studies of the androgen receptor gene were performed in 10 azoo‐ or oligozoospermic men, presenting with clinical signs of low androgen activity—poor virilization and high serum LH despite elevated testosterone levels, but without genital malformations.

PATIENTS Ten men with serum LH >10 IU/l and testosterone >30 nmol/l as well as a low sperm concentration < 20 × 106/ml.

MEASUREMENTS Genomic DNA was prepared from peripheral leucocytes and PCR‐amplification of the coding region of androgen receptor was performed, followed by direct sequencing. Identified mutations were reconstructed by site‐directed mutagenesis and the functional properties of the mutants were analysed, using transient expression in COS‐1 cells and subsequent transactivation assays. Hormone binding assays were performed in genital skin fibroblasts from the patients.

RESULTS Two of the 10 men were shown to have a mutation in the androgen receptor gene. Subject 1, who presented with azoospermia, serum testosterone (T) 50 nmol/l and LH 20 IU/l, had a mutation in exon 1, changing amino acid asparagine 233 to lysine (N233K). In fibroblasts cultured from genital skin, the receptor affinity for 5α‐dihydrotestosterone (DHT) was normal as compared to healthy controls, but the receptor–hormone complex was thermolabile at 42°C. Subject 2 exhibited severe oligozoospermia and a similar endocrine pattern (T = 50 nmol/l and LH = 25 IU/l). He had a mutation in exon 5 changing asparagine 756 to serine (N756S). The affinity for DHT in cultured genital fibroblasts from this patient was reduced. Transactivation was abnormal for both mutants, N233K reaching 46% and N756S 38% of wild type activity when stimulated with 10 nmol/l DHT.

CONCLUSIONS Androgen receptor mutations may affect sperm production without resulting in genital malformations. Thus, in infertile men with a clinical presentation of poor androgen activity and an endocrine profile compatible with androgen resistance, mutations in the androgen receptor should be taken into consideration.
Possible association but no linkage of the HSD11B2 gene encoding the kidney isozyme of 11β‐hydroxysteroid dehydrogenase to hypertension in Black people
Authors: White Perrin C. , Agarwal Anil K. , Li Airong , Nikkila Heli , Pratt J. Howard , Caulfield Mark , Clark Adrian , McTernan Claire , Stewart Paul M.
Published: March 2003

OBJECTIVE The HSD11B2 (HSD11K) gene encoding the kidney isozyme of 11β‐hydroxysteroid dehydrogenase is mutated in the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of salt‐sensitive hypertension. This gene is thus a logical candidate locus for risk of essential hypertension.

DESIGN AND METHODS Because hypertension in Black people tends to be of the low‐renin, salt sensitive type, we genotyped independent sets of hypertensives of Afro‐American (59 kindreds) and Afro‐Caribbean (66 kindreds) origin using a highly polymorphic (heterozygosity index 0·84) CA repeat polymorphism in the first intron of HSD11B2. Linkage was assessed by the affected pedigree member method.

RESULTS No linkage of hypertension to this locus could be demonstrated, but statistically significant allelic associations were noted.

CONCLUSIONS HSD11B2 does not have a strong influence on the development of essential hypertension in Black people, but weaker effects on blood pressure cannot be ruled out.
Germline sequence variant S836S in the RET proto‐oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population
Authors: Ruiz Agustín , Antiñolo Guillermo , Fernández Raquel M. , Eng Charis , Marcos Irene , Borrego Salud
Published: March 2003

OBJECTIVE The molecular basis of sporadic medullary thyroid carcinoma (MTC) remains elusive. While germline gain‐of‐function mutations in the RET proto‐oncogene cause hereditary MTC, somatic activating RET mutations and loss of heterozygosity of markers in various chromosomal regions representing deletions of tumour suppressor genes, have been described in a variable number of sporadic MTC. A previous report suggested that the presence of a germline variant at RET codon 836 (S836S) was associated with the development of sporadic MTC and, furthermore, that the presence of S836S was highly correlated with somatic RET M918T mutation in the MTC. Thus, we sought to determine if the S836S variant would be associated with sporadic MTC from a completely different population base, that of Andalucia.

DESIGN This is a case–control study to determine whether the presence of RET germline S836S is correlated with sporadic MTC in Andalucia.

PATIENTS Thirty‐two patients with sporadic MTC from the Andalucia region of Spain, serviced by our University Hospital, were ascertained throughout the period 1995–99. Sporadic MTC was defined as a lack of personal or family history suggestive of multiple endocrine neoplasia type 2 (MEN 2) and lack of germline RET mutations which define any MEN 2 subtype. A region and race matched cohort of 250 controls was also obtained.

MEASUREMENTS The frequency of the S836S allele was determined in cases and controls and compared using the standard chi‐squared statistic and Fisher's exact test.

RESULTS The polymorphic allele frequency at codon 836 in the control population (18/500 chromosomes, 3·6%) differed significantly from the MTC case cohort, 9·3% of case chromosomes (six of 64 alleles, Fisher's exact test, two‐tailed, P = 0·043).

CONCLUSIONS Germline RET S836S variant is associated with a two‐ to three‐fold risk of sporadic MTC in the Spanish population, in accordance with a previous study based on German cases. Our observations suggest that this phenomenon might be universal and not limited to Germany.
Weight gain following treatment of hyperthyroidism
Authors: Dale J. , Daykin J. , Holder R. , Sheppard M. C. , Franklyn J. A.
Published: March 2003

OBJECTIVE Patients frequently express concern that treating hyperthyroidism will lead to excessive weight gain. This study aimed to determine the extent of, and risk factors for, weight gain in an unselected group of hyperthyroid patients.

DESIGN and SUBJECTS We investigated 162 consecutive hyperthyroid patients followed for at least 6 months. Height, weight, clinical features, biochemistry and management were recorded at each clinic visit.

RESULTS Documented weight gain was 5·42 ± 0·46 kg (mean ± SE) and increase in BMI was 8·49 ± 0·71%, over a mean 24·2 ± 1·6 months. Pre‐existing obesity, Graves' disease causing hyperthyroidism, weight loss before presentation and length of follow‐up each independently predicted weight gain. Patients treated with thionamides or radioiodine gained a similar amount of weight (thionamides, n = 87, 5·16 ± 0·63 kg vs. radioiodine, n = 62, 4·75 ± 0·57 kg, P = 0·645), but patients who underwent thyroidectomy (n = 13) gained more weight (10·27 ± 2·56 kg vs. others, P = 0·007). Development of hypothyroidism (even transiently) was associated with weight gain (never hypothyroid, n = 102, 4·57 ± 0·52 kg, transiently hypothyroid, n = 29, 5·37 ± 0·85 kg, on T4, n = 31, 8·06 ± 1·42 kg, P = 0·014). This difference remained after correcting for length of follow‐up. In the whole cohort, weight increased by 3·95 ± 0·40 kg at 1 year (n = 144) to 9·91 ± 1·62 kg after 4 years (n = 27) (P = 0·008), representing a mean weight gain of 3·66 ± 0·44 kg/year.

CONCLUSION We have demonstrated marked weight gain after treatment of hyperthyroidism. Pre‐existing obesity, a diagnosis of Graves' disease and prior weight loss independently predicted weight gain and weight continued to rise with time. Patients who became hypothyroid, despite T4 replacement, gained most weight.
GH administration and discontinuation in healthy elderly men: effects on body composition, GH‐related serum markers, resting heart rate and resting oxygen uptake
Authors: Lange Kai Henrik Wiborg , Isaksson Fredrik , Rasmussen Michael Højby , Juul Anders , Bülow Jens , Kjær Michael
Published: March 2003

BACKGROUND AND OBJECTIVES GH administration results in increased lean body mass (LBM), decreased fat mass (FM) and increased energy expenditure (EE). GH therapy may therefore have potential benefits, especially in the elderly, who are known to have decreased function of the GH/IGF‐I axis. Several studies have focused on effects of GH administration in the elderly in the last decade. However, very limited information is available regarding changes in body composition and EE upon GH discontinuation in the elderly. The present study therefore investigated the effects of 12 weeks of GH administration and subsequent discontinuation on body composition, resting oxygen uptake (VO2), resting heart rate (HR) and GH related serum markers in healthy elderly men.

SUBJECTS AND METHODS Sixteen healthy men [age 74 ± 1 years (mean ± SEM), height 174·2 ± 1·6 cm, body weight 80·7 ± 2·6 kg, body fat 27·5 ± 1·1%] completed the study protocol. Recombinant human GH (1·80 ± 0·24 IU/day) was administered for 12 weeks in a single‐blinded, placebo‐controlled design. Body composition (dual energy X‐ray absorptiometry), resting VO2 (indirect calorimetry), resting HR (telemetry) and serum IGF‐I, IGF‐II, IGFBP‐3 and acid labile subunit (ALS) were measured at baseline, after 12 weeks of GH administration and, additionally in the GH group, 1, 2, 3, 4, 5 and 9 days after GH discontinuation.

RESULTS Body weight was unchanged from baseline to 12 weeks in both groups. However, GH administration caused a decrease in FM (3·4 ± 1·0 kg, P < 0·012), paralleled by a similar increase in LBM (3·2 ± 0·4 kg, P < 0·0002). Resting VO2 and resting HR increased by 31 ± 3·6% and 7·3 ± 1·9 per minute, respectively, in the GH‐group, where significant increases in serum IGF‐I, IGFBP‐3 and ALS also were noted. None of the above parameters changed in the placebo group. Within 2–3 days after GH discontinuation, the GH related serum markers and resting HR returned to baseline levels, whereas resting VO2 remained elevated even 9 days after GH discontinuation. In addition, GH discontinuation caused a significant decrease in body weight (1·86 ± 0·35 kg), derived exclusively from a decrease in LBM (1·63 ± 0·43 kg), while the decreased FM was maintained (12 weeks: 17·93 ± 1·65 kg, +9 days: 17·74 ± 1·62 kg).

CONCLUSIONS The increases in serum IGF‐I, IGFBP‐3, ALS and resting heart rate induced by 12 weeks of GH administration in elderly men returned to baseline levels within 2–3 days after GH discontinuation. However, resting VO2 remained elevated for a longer period. GH administration reduced fat mass but maintained body weight by increasing lean body mass. In contrast, 9 days of GH discontinuation reduced body weight exclusively by reducing lean body mass.
Cytotoxic T lymphocyte antigen 4 gene polymorphism confers susceptibility to Type 1 diabetes in Japanese children: analysis of association with HLA genotypes and autoantibodies
Authors: Kikuoka Noriko , Sugihara Shigetaka , Yanagawa Tatsuo , Ikezaki Ayako , Kim Hye Sook , Matsuoka Hisafumi , Kobayashi Yasuyuki , Wataki Kunio , Konda Susumu , Sato Hirokazu , Miyamoto Shigeki , Sasaki Nozomu , Sakamaki Tateo , Niimi Hiroo , Murata Mitsunori
Published: March 2003

OBJECTIVE Although the polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA4) gene have been shown to be associated with Type 1 diabetes in Caucasians, some conflicting results have been reported among subjects of different ethnic backgrounds. We examined a CTLA4 polymorphism and its relationship to human leucocyte antigen (HLA) genotypes and autoantibodies for glutamic acid decarboxylase 65 (GAD65) and IA‐2 in Japanese children with Type 1 diabetes.

SUBJECTS AND MEASUREMENTS The study group consisted of 125 childhood‐onset Japanese subjects (50 males, 75 females) with Type 1 diabetes. The CTLA4 A/G polymorphism at position 49 was analysed using a PCR‐restriction fragment length polymorphism (PCR‐RFLP) method. The HLA‐DRB1 and DQB1 genotypes were defined by DNA analysis using PCR‐sequence‐specific oligonucleotide (PCR‐SSO) probes. The GAD65 autoantibody (GAD65Ab) and IA‐2 autoantibody (IA‐2Ab) titres were measured using radioimmunoassay.

RESULTS The distribution of genotype frequencies differs between subjects with Type 1 diabetes (GG: 46%, AG: 50%, AA: 5%) and controls (GG: 39%, AG: 44%, AA: 17%) (P < 0·01). The frequency of the G allele is higher in the diabetes group than in the controls (P < 0·05). When the subjects were subdivided according to HLA genotype, the two major HLA high‐risk groups, with DR9‐DQ9 and DR4‐DQ4, that are unique to Japanese populations showed no difference in their CTLA4 polymorphism frequencies. Although no association between the CTLA4 polymorphism and the prevalence of GAD65Ab was found, CTLA4 GG subjects that had been newly diagnosed (< 9 months) had significantly higher levels of autoantibodies than AG subjects (P < 0·01). The prevalence and titres of IA‐2Ab were not associated with the CTLA4 polymorphism.

CONCLUSIONS The CTLA4 gene might confer a susceptibility to childhood‐onset Type 1 diabetes in the Japanese population. The association between this CTLA4 polymorphism and the HLA genotype was similar for both major groups with HLA high‐risk alleles. CTLA4 might contribute to the humoral immune response to GAD in newly diagnosed subjects.
Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain
Authors: Regal Milagros , Páramo Concepción , Sierra José M. , García‐Mayor Ricardo V.
Published: March 2003

OBJECTIVE To determine the prevalence and incidence of hypopituitarism in the general population.

POPULATION The study population comprised an average population sample of 146 000 adult inhabitants in South Galicia (northwestern Spain). The Medical Register of the General Hospital of Vigo ensured virtually complete case ascertainment for diagnosed hypopituitarism in this sample population. Only patients residing in the study area were included. The diagnosis of hypopituitarism was based on baseline and hormonal dynamic tests.

DESIGN The study comprised two cross‐sectional surveys, the first from January to December 1992 and the second from January to December 1999, together with a longitudinal survey performed between January 1993 and December 1999.

MAIN RESULTS In the first survey the prevalence of hypopituitarism was 29/100 000 (CI, 19·88–37·72), without sex differences. In the second survey, the prevalence observed was higher than in the first, 45·5/100 000 (CI, 34·92–56·08). In the second survey, which included almost all cases registered in the first study, the cause of hypopituitarism was a pituitary tumour in 61%, a non‐pituitary tumour in 9% and a non‐tumour cause in 30%. Around 50% of patients had 3–5 pituitary hormonal deficiencies, with LH/FSH being the most prevalent. Patients with tumour‐induced hypopituitarism showed a tendency to suffer GH deficiency more frequently than those due to non‐tumour causes. In the longitudinal study with a population of 1020 764 people‐years of observation, the average annual incidence rate of hypopituitarism was 4·21 cases/100 000 (CI, 2·95–5·47), with this incidence being similar for both sexes. The annual incidence of hypopituitarism remained stable during the study period.

CONCLUSION We present for the first time data on the prevalence and incidence of hypopituitarism in the general adult population. These patients showed a tendency to suffer LH/FSH deficiency as the most prevalent hormone deficit. Furthermore, patients with hypopituitarism due to a tumour or its treatment showed a greater tendency to suffer GH deficiency than those with a non‐tumour cause. These data may be useful for producing a rational programme for patients suffering from this condition and also for comparison with future data in our country and elsewhere in the world.
Obesity, rather than menstrual cycle pattern or follicle cohort size, determines hyperinsulinaemia, dyslipidaemia and hypertension in ageing women with polycystic ovary syndrome
Authors: Elting Mariet W. , Korsen Ted J. M. , Schoemaker Joop
Published: March 2003

OBJECTIVE The aim of this study was to investigate if ageing women with polycystic ovary syndrome (PCOS) who gained regular menstrual cycles differed from women who continued to menstruate irregularly with regard to risk factors for developing diabetes mellitus and atherosclerosis.

DESIGN AND PATIENTS In the original study of a population of 346 PCOS patients, defined in the past as having oligo‐ or amenorrhoea and elevated LH concentrations, we had sent out a questionnaire to investigate changes in the pattern of their menstrual cycles while ageing. From this cohort of patients, a significantly older group of 53 women (mean age: 41·3 years, range: 33·3–49·4) who were not using oral contraceptives or other hormones visited the outpatient clinic. These women did not differ from the non‐participating group in BMI, ethnic origin, the proportion with regular menstrual cycles by age group, parity or the use of clomiphene citrate or gonadotrophins in the past.

MEASUREMENTS A physical examination and a transvaginal ultrasound were performed. The size of the follicle cohort was determined by counting the number of small follicles in the ovaries. Thirty‐four women were also willing to give two fasting blood samples for measuring their glucose, insulin and lipid status.

RESULTS Forty‐one of the 53 (77·4%) women had a regular menstrual cycle (shorter than 6 weeks) and 12 (22·6%) had an irregular cycle (longer than 6 weeks). The body mass index (BMI), waist : hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and prevalence of diabetes (1·9%) and hypertension (11·3%) did not differ between the two menstrual cycle groups. Also, the fasting glucose, insulin, glucose/insulin ratio, total cholesterol, HDL‐c, and LDL‐c concentrations did not show any significant difference between the two groups. Instead, these parameters all were significantly higher in women with a BMI > 27 kg/m2 compared to women with a BMI ≤ 27 kg/m2. Regularly menstruating PCOS women were older (P < 0·01), showed less follicles in their ovaries (n = 48, P < 0·01) and had lower androgens (n = 34, P < 0·05) than the irregularly menstruating women. Logistic regression analysis showed a second significant influence, after age, of the BMI on the menstrual cycle pattern (age, P < 0·01; BMI, P < 0·05). If age was excluded from the analysis, only the follicle count significantly predicted the menstrual cycle pattern (P < 0·02).

CONCLUSIONS We conclude that hyperinsulinaemia, dyslipidaemia and hypertension in our population of ageing women with polycystic ovary syndrome are not related to the menstrual cycle pattern but rather to obesity. Age and the size of the follicle cohort are the main factors determining the menstrual cycle pattern in ageing women with polycystic ovary syndrome, although an association with the BMI was also found.
Postpartum thyroid dysfunction and postpartum depression: are they two linked disorders?
Authors: Lucas Anna , Pizarro Eduarda , Granada María Luisa , Salinas Isabel , Sanmartí Anna
Published: March 2003

OBJECTIVE Postpartum has been considered as a period of risk for developing postpartum depression (PD) by some but not all authors, and this PD has been linked with postpartum thyroid dysfunction (PPTD). The major aim of this study was to evaluate the relation between the presence of PPTD and PD.

DESIGN and PATIENTS Six hundred and forty‐one healthy Caucasian women recruited between their 36th week of pregnancy and fourth day postpartum underwent clinical and laboratory evaluation and were checked again at 1 (n = 605), 3 (n = 552), 6 (n = 574), 9 (n = 431), and 12 (n = 444) months postpartum.

MEASUREMENTS At baseline and at each clinical evaluation, Beck Depression Inventory (BDI) was administered to screen PD. The definitive diagnoses of PD was performed by a psychiatrist according to the DSM‐III‐R criteria. At each visit, we determined serum free T4 and TSH concentrations. Thyroperoxidase and thyroglobulin antibodies were determined only in patients with abnormal hormone concentrations. Postpartum thyroiditis (PPT) was considered to be present in women with overt or subclinical transient hyperthyroidism between 1 and 3 months postpartum and/or overt or subclinical hypothyroidism between 3 and 6 months postpartum.

RESULTS Fifty‐six women developed postpartum thyroid dysfunction (PPTD), corresponding to an incidence rate of 11%: 45 with PPT [incidence rate 7·8%; confidence interval (CI) 5·6–10%], eight with Graves' disease (incidence rate 1·5%; CI 0·5–2·5%) and three with nonpalpable toxic thyroid adenoma (incidence rate 0·5%; CI 0–1·5%). Five hundred and eighty of the evaluated women (incidence rate 90·5%; CI 95% 88·2–92·8) presented BDI scores below 21 and therefore the PD diagnoses was excluded. In 50 cases (incidence rate 7·8%; CI 95% 5·7–9·8), we detected a BDI score over 21 in some evaluations, but the PD diagnosis was not confirmed. Another 11 (incidence rate 1·7%; CI 95% 0·7–2·7) were diagnosed as having PD and required psychiatric treatment. None of the PPTD was diagnosed as having PD. The BDI scores frequency over 21 was similar between healthy women and those with PPTD. Patients with a previous history of depression developed PD more often (P < 0·0001). One hundred and ninety women breast fed their babies for more than 2 months, without observing a higher PD rate or BDI scores over 21 (P = 0·5).

CONCLUSIONS We found a general PD incidence rate of 1·7% in our group of patients. This figure is not higher in women with hormone abnormalities caused by PPTD. Women with a past history of depression present a higher risk of PD while those who breast fed did not have an increased risk.
Isolated pituitary granuloma by atypical Mycobacterium in a nonimmunosuppressed woman
Authors: Florakis Dimos , Kontogeorgos George , Anapliotou Margarita , Mazarakis Nikos , Richter Elvira , Brück Wolfgang , Piaditis George
Published: March 2003

A 32‐year‐old woman presented with a 10‐day history of fever (38·0°C), headaches, nausea, vomiting and a 6‐month history of diabetes insipidus and amenorrhoea. Two months previously she had undergone a surgical drilling of the right mastoid area because of mastoiditis. Endocrine investigation showed elevated serum prolactin levels, secondary adrenal and gonadal failure and a normal thyroid function. Cranial MRI scan revealed a contrast enhancing intrasellar mass (∼2 cm) of heterogeneous appearance with suprasellar extension and thickening of the pituitary stalk. Lumbar puncture was suggestive of aseptic meningitis. The Ziehl–Neelsen stain of cerebrospinal fluid (CSF) and the tuberculin skin test were both negative. The pituitary mass was removed with a transsphenoidal approach. Histological examination demonstrated destruction of the adenohypophysis by epithelioid granulomas with partial caseous necrosis and microabscess formation, suggestive of a mycobacterial infection. A polymerase chain reaction analysis performed on paraffin‐embedded tissue was positive for mycobacterial DNA. According to the individual 16S sequence, it was identified as Mycobacterium malmoense, an atypical nontuberculous mycobacterium (NTM). In conclusion, this is the first case of an isolated pituitary granuloma caused by an NTM infection in a nonimmunosuppressed patient.
A novel bioassay for human somatogenic activity in serum samples supports the clinical reliability of immunoassays
Authors: Rowland Jennifer E. , Marshall Nicholas J. , Leung Kin‐chuen , Ho Ken K. Y. , Cotterill Andrew M. , Rowlinson Scott W. , Waters Michael J.
Published: March 2003

objective Because there is discordance between different immunoassay values for serum hGH, and because clinical state may not correlate with immunoreactive hGH, we have developed an assay to accurately measure serum hGH somatogenic bioactivity. The results of this assay were compared with the Elegance two‐site ELISA assay across 135 patient samples in a variety of clinical states.

design The somatogenic assay was based on stable expression of hGH receptor in the murine BaF line, allowing these cells to proliferate in response to hGH. To eliminate interference by other growth factors in serum, we created a specific antagonist of the hGH receptor (similar to Trovert or Pegvisomant) which allowed us to obtain a true measure of hGH somatogenic activity by subtraction of the activity in the presence of the antagonist. The assay was carried out in microtiter plates over 24 h, with oxidation of a chromogenic tetrazolium salt (MTT) as the endpoint.

patients These encompassed a number of different clinical conditions related to short stature, including idiopathic short stature, neurosecretory dysfunction and renal failure, as well as obese patients on dietary restriction and normal volunteers.

measurements In addition to the colourimetric (MTT) response to hGH, we measured free hGH by stripping out GHBP‐bound hGH using beads coupled to a monoclonal antibody to the GHBP (GH binding protein). All samples were measured in both bioassay and ELISA assay.

results This bioassay was sensitive (5 mU/l or 2 µg/l) and precise, and not subject to interference by the GHBP. There was a good correlation (r = 0·95) between bioactivity and immunoactivity across clinical states. There was, however, an increased bioactivity during secretory peaks (over 25 mU/l), which has been reported previously for the Nb2 bioassay. Free hGH did not correlate with clinical state.

conclusions Because the results of the Elegance ELISA and the bioassay correlate well, even though there is greater bioactivity at higher hormone concentrations, it is evident that an appropriate immunoassay is able to act as a reliable indicator for clinical assessment. In those rare cases where bio‐inactive GH exists, our bioassay should provide an appropriate means to demonstrate this.
MRI findings of the pituitary gland in short children born small for gestational age (SGA) in comparison with growth hormone‐deficient (GHD) children and children with normal stature
Authors: Arends N. J. T. , V.d. Lip W. , Robben S. G. F. , Hokken‐Koelega A. C. S.
Published: March 2003

Background Disturbances in the GH/IGF‐I axis are reported in 25–60% of short children born small for gestational age (SGA). We hypothesized that these abnormalities might be related to abnormalities in the pituitary region. Therefore, the results of magnetic resonance imaging (MRI) of short SGA children were compared to MRI results of other groups of short children and to normal controls.

Patients and Methods MRI was performed in four groups of short children: SGA children without GH deficiency (SGA group; n = 17), SGA children with isolated GH deficiency (SGA + IGHD group; n = 10), non‐SGA children with isolated GH deficiency (IGHD group; n = 24) and non‐SGA children with multiple pituitary hormone deficiencies (MPHD group; n = 15). MRI was also performed in children with normal stature (control group; n = 13). Pituitary height (PH) and thickness of the pituitary stalk (PS) were measured and their relationship with the maximum GH peak during a GH stimulation test, serum IGF‐I and IGFBP‐3 levels was evaluated.

Results Short SGA children either with or without IGHD did not show major anatomical abnormalities in the hypothalamic‐pituitary region in contrast to 58% of the non‐SGA IGHD children and 87% of the MPHD children who had anatomical abnormalities. PH in SGA children without GHD was normal whereas it was significantly lower in SGA children with IGHD. The lowest PHs were measured in non‐SGA children with MPHD. A moderate decrease in PH was associated with significantly lower maximum serum GH peaks and lower serum IGF‐I and IGFBP‐3 levels.

Conclusion Measuring PHs in children with less severe GHD, who underwent MRI as part of the diagnostic process, might support the diagnosis of GHD even in the absence of anatomical abnormalities. Our study demonstrates that there is no indication to perform MRI of the pituitary region in short children born SGA without GHD.
Antiangiogenic effects of somatostatin analogues
Authors: De La Torre N. García , Wass J. A. H. , Turner H. E.
Published: March 2003

Inhibition of angiogenesis has become a target for antineoplastic therapy and for treatment of retinal neovascularization. The presence of somatostatin receptors on tumour cells and on the proliferating vascular endothelium has led to several in vitro and in vivo studies to investigate the antiproliferative and antiangiogenic effects of somatostatin analogues. Currently available data suggest that somatostatin analogues might inhibit angiogenesis directly through somatostatin receptors present on endothelial cells and also indirectly through the inhibition of growth factor secretion such as IGF‐I and vascular endothelial growth factor (VEGF) and reducing monocyte chemotaxis. However, beneficial effects on inhibition of neovascularization have been questioned by some studies. More work is therefore required to firmly establish the role of somatostatin analogues as potential antiangiogenic therapy. The currently available somatostatin analogues have high affinity for somatostatin receptor subtype 2 (sst2) and, to a lesser extent, sst5 and sst3. However, because vascular endothelial cells express several types of somatostatin receptors, it will be important to investigate somatostatin analogues with different receptor subtype affinities, which might increase the spectrum of available therapy for tumours.
Oxidative stress and normal pregnancy
Authors: Toescu V. , Nuttall S. L. , Martin U. , Kendall M. J. , Dunne F.
Published: March 2003

objective To determine whether, in normal pregnancies, there is evidence of oxidative stress that is related to the lipid changes observed in pregnancy.

design Longitudinal study of healthy women having a normal pregnancy. Samples were obtained towards the end of each trimester and after 8 weeks postpartum.

patients Seventeen healthy women during a normal singleton pregnancy were compared with 12 healthy, non‐pregnant women.

measurements Oxidative stress was determined by measuring total antioxidant capacity (TAC), uric acid and lipid hydroperoxides (LHP). Lipid status was evaluated by measuring total and high‐density lipoprotein cholesterol, triglycerides and low‐density lipoprotein (LDL) subfractions.

results Pregnancy was associated with decreased TAC and uric acid in the first trimester, which gradually increased during pregnancy, reaching normal values during the postpartum period. LHP significantly increased towards the end of pregnancy. The changes observed in LHP were significantly correlated with increases in LDL subfraction profile.

conclusions Late pregnancy was associated with the formation of susceptible, oxidisable particles (high LDL score) and an increase in oxidative damage. These biochemical changes may be relevant for the long‐term cardiovascular health of women, especially those of high parity or those who are at high risk for cardiovascular disease (e.g. women with diabetes).
Peripheral amino acid and fatty acid infusion for the treatment of necrolytic migratory erythema in the glucagonoma syndrome
Authors: Alexander Erik K. , Robinson Malcolm , Staniec Maryjane , Dluhy Robert G.
Published: March 2003

Necrolytic migratory erythema (NME), the characteristic rash associated with the glucagonoma syndrome, is a cause of substantial morbidity among patients with this rare malignancy. Treatment options are suboptimal, and often useful for only short or moderate durations. We report the effective, long‐term (> 1 year) use of intermittent infusions of amino acids (AA) and fatty acids (FA) administered via peripheral intravenous access for the treatment of NME in the glucagonoma syndrome. Despite resolution of the NME, serum amino acid (initially subnormal) and fatty acid (initially normal) levels remained unchanged. Tumour growth and other symptoms related to the glucagonoma syndrome appear unaffected by such infusions.
The Arg16Gly polymorphism of human β2‐adrenoreceptor is associated with type 2 diabetes in Taiwanese people
Authors: Chang Tien‐Jyun , Tsai Ming‐Han , Jiang Yi‐Der , Lee Borheng , Lee Kuan‐Ching , Lin Jin‐Yu , Chiu Ken C. , Tai Tong‐Yuan , Chuang Lee‐Ming
Published: March 2003

objective  The significance of the association of amino terminal polymorphisms in β2‐adrenoreceptor (ADRB2) with obesity and type 2 diabetes is controversial and differs among ethnic groups. In this study, the association of ADRB2 with risk and age of onset of type 2 diabetes has been examined in a Taiwanese population.

design The study design is a case–control study to investigate the impact of the two amino acid polymorphisms in ADRB2.

patients and measurements  This study includes 130 patients with type 2 diabetes [female : male = 1 : 1, age: 52·4 ± 10·0 years; body mass index (BMI): 24·2 ± 2·9 kg/m2; mean ± SD] and 130 controlled subjects matched for gender, age and BMI with normal glucose tolerance (female : male = 1 : 1, age: 51·7 ± 10·6 years; BMI: 23·9 ± 2·7 kg/m2). The Arg16Gly and Gln27Glu polymorphisms of ADRB2 were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR–RFLP) assays. The genotypic and allelic frequencies between two groups were compared and the relationship between the genotypes and clinical phenotypes was examined.

results A difference in genotypic frequency in the Arg16Gly polymorphism was noted between groups in this gender‐, age‐ and BMI‐matched case–control study (P = 0·039). Multivariate regression analysis revealed that the Arg16Gly polymorphism was the only independent factor for development of type 2 diabetes (P = 0·021). In addition, we utilized the log‐rank test to compare the differences in age of onset between wild‐type and nonwild‐type polymorphisms. The Arg16Gly polymorphism was independently associated with age of onset in type 2 diabetes (P = 0·017). There was no difference in the Gln27Glu polymorphism between diabetic and control groups in this study.

conclusions In a Taiwanese population, homozygosity of Arg16 in the ADRB2 gene was associated with a higher frequency (odds ratio 1·87, 95% confidence interval 1·34–2·40) for development of type 2 diabetes. Moreover, this polymorphism was also associated with an earlier onset of type 2 diabetes. However, the Glu27Gln polymorphism had no impact on either BMI or type 2 diabetes in a Taiwanese population.
Reversal of acromegalic cardiomyopathy in young but not in middle‐aged patients after 12 months of treatment with the depot long‐acting somatostatin analogue octreotide
Authors: Colao Annamaria , Marzullo Paolo , Cuocolo Alberto , Spinelli Letizia , Pivonello Rosario , Bonaduce Domenico , Salvatore Marco , Lombardi Gaetano
Published: March 2003

background Cardiovascular disease is the most frequent cause of death of patients with acromegaly.

aim To investigate whether young patients with a presumed short disease duration are more likely to reverse the acromegalic cardiomyopathy than older patients with longer disease duration.

design An open prospective design.

patients Ten young (aged < 40 years), and 12 middle‐aged (41–59 years) patients with active acromegaly well controlled after 12 months of treatment with the depot formulation of octreotide (OCT‐LAR); 22 sex‐ and age‐matched healthy subjects as controls.

methods Left ventricular (LV) mass (LVM) by echocardiography and performance by equilibrium radionuclide angiography were measured before and after 12 months of OCT‐LAR treatment.

results At study entry, none of the controls and 14 patients (63·4%) of whom six were young (χ2 = 17·7; P < 0·0001) had LV hypertrophy (LVH); none of the controls and four patients of whom one was young had insufficient LV ejection fraction (LVEF) at rest (< 50%); one control and 13 patients (59·1%) of whom five were young (χ2 = 12·7; P < 0·0001) had inadequate LVEF at peak exercise (ΔLVEF; < 5% increase of baseline). After 12 months, no change in haemodynamic and diastolic parameters was observed in both groups, except for a significant decrease in heart rate at peak exercise in young patients (P < 0·0001). The LVM index decreased significantly in both young (124·4 ± 5·8 vs. 103·4 ± 3·9 g/m2; P = 0·01) and middle‐aged patients (140·9 ± 7·9 vs. 117·8 ± 6·6 g/m2; P = 0·03). LVH disappeared in 10 of 14 patients (71·4%): all six young and four of eight middle‐aged patients (50%). LVEF at rest and at peak exercise increased significantly in both groups but ΔLVEF increased significantly only in young patients (1·5 ± 2·9 vs. 13·7 ± 5·2%, P = 0·04); it normalized in nine of 13 patients (69·2%), four of five young (80%) and four of eight middle‐aged patients (50%). Exercise capacity (82·5 ± 5·3 vs. 110·0 ± 5·5 W, P = 0·005) and duration (7·3 ± 0·3 vs. 9·9 ± 0·4 min, P = 0·0003) also increased only in young patients.

conclusions The acromegalic cardiomyopathy is reversed in most young patients with short disease duration and achieving disease control after OCT‐LAR treatment for 12 months, indicating that early diagnosis and effective treatment are essential.
Electrocardiographic changes during prolonged coronary artery occlusion in man: comparison of standard and high‐frequency recordings
Authors: Pettersson  , Lander  , Pahlm  , Sörnmo  , Warren  , Wagner
Published: March 2003

Detection of acute myocardial ischaemia using electrocardiographic methods is generally based on assessment of the ST segments in the standard 12‐lead electrocardiogram (ECG). Several studies have also shown changes in high‐frequency QRS components during acute ischaemia. The purpose of the present study was to determine the changes in high‐frequency QRS components during prolonged percutaneous transluminal coronary angioplasty (PTCA) and to compare these changes with ST‐segment deviations in the standard 12‐lead ECG. The study population consisted of 19 patients receiving prolonged PTCA. Standard and high‐resolution signal‐averaged ECGs were recorded before and during balloon inflation. The high‐resolution recordings were performed using bipolar X, Y and Z leads. The QRS complexes in the high‐resolution signal‐averaged ECGs were analysed within a bandwidth of 150–250 Hz. During inflation, significant reductions in high‐frequency QRS components were observed (12–72%). Changes in the high‐frequency QRS components were seen in four of the patients without ST‐segment deviation in the standard ECG. The correlation between the ST‐segment deviation and the reduction in high‐frequency QRS components was weak (r = 0·27). Acute coronary artery occlusion produces changes in high‐frequency QRS components, even in the absence of ST‐segment deviation in the standard ECG. Further studies need to be carried out to evaluate whether analysis of high‐frequency QRS components could provide a method for detecting myocardial ischaemia and give additional information to that available in the ST segment in the standard ECG.
Myocardial SPET: artificial neural networks describe extent and severity of perfusion defects
Authors: Lindahl  , Palmer  , Edenbrandt
Published: March 2003

Artificial neural networks are computer programs that learn from examples. They have been successfully used to detect coronary artery disease from myocardial perfusion images. The purpose of the present study was to develop neural networks that could classify myocardial scintigrams regarding reversibility, localization, severity and extent of perfusion defects. Rest/exercise technetium‐99m sestamibi scintigrams from 338 patients were studied. The classifications of two experts were employed as the gold standard. Artificial neural networks were trained to classify both reversible (ischaemia) and non‐reversible (infarct) defects in three vascular territories, corresponding to the main coronary arteries. The extent (small or large) and severity (mild or severe) of the defects were described by the networks. After the training process, separate test sets were used to compare the neural networks with one of the experts who reclassified the scintigrams two months later. The neural networks made correct classifications in 71% of the test cases and the human expert in 70% (P=0·10). It was concluded that artificial neural networks can be trained to make clinical interpretations of myocardial perfusion scintigrams. The results indicate that networks can assist physicians in achieving correct interpretations and thereby improve the diagnostic accuracy of medical imaging.
Pulmonary capillary blood flow by partial CO2 rebreathing: importance of the regularity of the respiratory pattern
Authors: De Abreu M. Gama , Melo M. F. V. , Giannella‐Neto A.
Published: March 2003

The partial CO2 rebreathing technique has been shown to be a reliable non‐invasive method for measurement of pulmonary capillary blood flow (Q˙c), but experience with this technique has been limited to controlled mechanical ventilation. In this study, we evaluated this technique during spontaneous and oriented ventilation in nine subjects without known cardiopulmonary disease. Subjects underwent 10 consecutive (Q˙c) measurements with both spontaneous and oriented ventilation. Breath‐by‐breath gas exchange was measured and (Q˙c) was calculated from changes in CO2 elimination and PETCO2, which were achieved by sudden increase of the apparatus deadspace (rebreathing period). An exponential curve was fitted to the PETCO2 values in the rebreathing period in order to estimate PETCO2 at equilibrium. We found that mean (Q˙c) values were not influenced by the ventilation pattern (P=0·51), but that the intra‐individual variability with oriented ventilation (median=16·0%) was significantly lower than with spontaneous ventilation (median=31·8%, P=0·039). Accordingly, the curve fitting for rebreathing PETCO2 rise failed in 4·4% of measurements with oriented ventilation vs. 18·9% of measurements with spontaneous ventilation (P=0·039). Our results suggest that the performance of the partial CO2 rebreathing technique is adversely affected by spontaneous ventilation and, consequently, that this method should be reserved for patients with regular respiratory patterns.
Plantar flexor muscle function in open and closed chain
Authors: Carlsson U. , Lind K. , Möller M. , Karlsson J. , Svantesson U.
Published: March 2003

In the present study, the torque or work produced during isometric, pure concentric and eccentric–concentric plantar flexions, performed in sitting, standing and prone were measured. The electromyographic (EMG) activity was measured from the soleus, gastrocnemius medialis, tibialis anterior and rectus femoris muscles. The isometric tests showed the highest torques in the standing test. The rectus femoris and gastrocnemius activities were lower in the prone than in the standing test. The sitting test showed lower activities in all muscles of the lower leg compared with the standing test. No differences in work between the prone and sitting tests were found during the concentric phases. Higher rectus femoris activity in the eccentric–concentric test and lower activity in the triceps surae during the concentric phases were seen in the sitting compared with the prone test. We conclude that tests of overall functional ability should be performed in the standing position while specific tests of the plantar flexors should be performed in the prone position.
Changes in cardiac autonomic regulation after prolonged maximal exercise
Authors: Hautala Arto , Tulppo Mikko P. , Mäkikallio Timo H. , Laukkanen Raija , Nissilä Seppo , Huikuri Heikki V.
Published: March 2003

Harmful cardiac events occurs frequently after exercise. However, the cardiac autonomic regulation after vigorous exercise is not well known. This study was designed to assess heart rate (HR) variability before and after a 75 km cross‐country skiing race. HR variability was assessed by using standard statistical measures along with spectral and quantitative Poincarè plot analysis of HR variability in 10 healthy male subjects (age 36 ± 11 years). The average HR was at the same level 1 day after the race as before the race, but on the second day, HR was significantly lower (P<0·001) compared with the prerace and 1 day after values. The normalized high‐frequency (HF) spectral component of HR variability (nuHF) was lower (P<0·01) on the first day after the maximal exercise compared with the pre‐exercise values but returned to or even exceeded the prerace level on the second day (P<0·01). The changes in short‐term R‐R interval variability analysed from the Poincaré plot were similar to those observed in the HF spectral component. The normalized low‐frequency (LF) spectral component of HR variability (nuLF) was higher (P<0·01) on the first day after the exercise compared with the prerace levels and it also returned to the pre‐exercise level or even dropped below it on the second day after the race. The mean time it took the HF spectral component to return to the pre‐exercise level was 4·2 ± 4·2 h (ranging from 0 to 12 h). This recovery time correlated inversely with the maximal oxygen consumption (VO2max) measured during the bicycle exercise test before the skiing race (r=−0·712, P<0·016). The cardiac vagal outflow is blunted for several hours after prolonged vigorous exercise. The recovery time of reduced vagal outflow depends on individual cardiorespiratory fitness and there is an accentuated rebound of altered autonomic regulation on the second day after prolonged exercise.
Sympathetic skin vasoconstriction – further evaluation using laser Doppler techniques
Authors: Holmlund F. , Freccero C. , Bornmyr S. , Castenfors J. , Johansson A.‐M. , Nordquist J. , Sundkvist G. , Svensson H. , Wollmer P.
Published: March 2003

The aim of this study was to quantify the reflex sympathetic vasoconstriction in skin at different depths. Twenty healthy subjects were studied. Finger skin blood flow was measured using laser Doppler perfusion imaging (LDPI) and laser Doppler perfusion monitoring (LDPM). In LDPM, a probe with fibres separated 0·25 mm (deep) and 0·14 mm (superficial) from the illuminating fibre was used. Local heating (40°C) was achieved with a Peltier element, and reflex vasoconstriction induced by immersion of the contra‐lateral hand and forearm for 3 min in water at 15°C. The change in skin blood flow was measured and a vasoconstriction index (VAC: cooling/before cooling) calculated. VAC indices of LDPI, LDPM‐0·25 and LDPM‐0·14 were 0·60, 0·59 and 0·60, respectively. The two components of the LDPM perfusion value, blood cell velocity and concentration, were studied separately. Their contributions in LDPM‐0·25 were roughly the same, whereas the velocity component dominated in LDPM‐0·14, although their relative responses in the two channels were similar. We conclude that sympathetic skin vasoconstriction does not significantly differ in two compartments, as probed with fibres separated by 0·25 and 0·14 mm. Blood cell velocity is influenced in a proportional way, as is concentration.