bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of interferon-αon gene expression of chemokines and members of the tumour necrosis factor superfamily in HIV-infected patients
Authors: STYLIANOU E , YNDESTAD A , SIKKELAND L I , BJERKELI V , DAMÅS J K , HAUG T , EIKEN H G , AUKRUST P , FRØLAND S S
Published: March 2003

We examined the effect of interferon (IFN)-α on the expression of 375 genes relevant to inflammatory and immunological reactions in peripheral blood mononuclear cells (PBMC) from HIV-infected patients by cDNA expression array and real-time quantitative RT-PCR. Our main findings were: (i) IFN-α induced up-regulation of several genes in the tumour necrosis factor (TNF) superfamily including the ligands APRIL, FasL, TNF-α and TRAIL, with particularly enhancing effects on the latter in HIV-infected patients. (ii) While IFN-α markedly up-regulated the expression of anti-angionetic ELR– CXC-chemokines (e.g. MIG and IP-10), it suppressed the expression of angiogenic ELR+ CXC-chemokines (e.g. GRO-α, IL-8 and ENA-78), with similar patterns in both patients and controls. (iii) IFN-α induced a marked increase in gene expression of the HIV co-receptor CCR5 in both patients and controls. We suggest that these effects may contribute to both the therapeutic and toxic effects of IFN-α. Moreover, our findings underscore that the biological effects of IFN-α in HIV infection are complex and that the clinical net effects of IFN-α treatment may be difficult to predict. However, the potent enhancing effect of IFN-α on several pro-apoptotic genes in the TNF superfamily and the enhancing effect on CCR5 expression suggest a possible pathogenic role of IFN-α in the progression of HIV-related immunodeficiency and suggests caution in the therapeutic use of IFN-α in HIV-infected ­individuals.
Transcriptional regulation of the IL-5 gene in peripheral T cells of asthmatic patients
Authors: OGAWA K , KAMINUMA O , OKUDAIRA H , KIKKAWA H , IKEZAWA K , SAKURAI N , MORI A
Published: March 2003

Mechanisms that underlie the regulation of IL-5 gene expression in human peripheral T cells remain incompletely defined because of the low efficiency of transfection of plasmid constructs into non-transformed T cells. To elucidate the cellular and molecular mechanisms of IL-5 production, concanavalin A (ConA)-stimulated blastocytes derived from peripheral blood lymphocytes of asthmatic patients were employed in this study. Transcriptional activity of the synthetic human IL-5 promoter in ConA-stimulated blastocytes correlated with the production of IL-5. Deletion analysis of the reporter gene showed that the cis-regulatory element located at − 119 to − 80 is critical for inducible IL-5 promoter activity. Electrophoretic mobility shift assay revealed that an oligonucleotide probe corresponding to the element (− 119 to − 90) gave two specific bands. The slower migrating band was absolutely dependent on stimulation and was composed of a co-operative complex of the transcription factors, nuclear factor of activated T cells (NFAT) and activating protein-1 (AP-1). The faster migrating band was also inducible and was identified as AP-1-less NFAT. Mutation of either the NFAT or AP-1 element abrogated the slower migrating band and at the same time abolished transcriptional activity of the human IL-5 promoter/enhancer gene. Cyclosporin A equivalently suppressed DNA-binding activity of the composite NFAT/AP-1 site, promoter activity and protein production of IL-5. In conclusion, these data suggests that the composite NFAT/AP-1 binding element (− 115 to − 100) plays a crucial role in IL-5 synthesis by peripheral T cells of asthmatic patients.
Simultaneous evaluation of lymphocyte subpopulations in the liver and in peripheral blood mononuclear cells of HCV-infected patients: relationship with histological lesions
Authors: PERNOLLET M , JOUVIN-MARCHE E , LEROY V , VIGAN I , ZARSKI J-P , MARCHE P N
Published: March 2003

Intrahepatic lymphocytes are believed to be involved in the immunopathogenesis of hepatitis C virus (HCV) infection and the evolution of HCV-induced hepatitis. In the present study, we examined the three main intrahepatic lymphocyte subsets, namely CD3+CD56− conventional T lymphocytes, CD3+CD56+ natural T (NT) lymphocytes and CD3−CD56+ natural killer (NK) lymphocytes in HCV-infected patients. The proportion of each lymphocyte subset was evaluated both in liver biopsies and in samples of peripheral blood lymphocytes (PBL) by flow cytometry in 21 patients with histologically proven chronic hepatitis C. Simultaneously, alanine aminotransferase (ALT) levels, viral load and histological lesions were assessed. Neither NT nor NK populations correlated with any biochemical, viral or histological parameters. Furthermore, Vα24+ NT lymphocytes showed no preferential enrichment in the liver of HCV-infected patients. Regarding conventional T lymphocytes, a highly significant linear correlation was found between intrahepatic CD3+CD56− T lymphocytes and the Knodell score, a numerical score for assessing histological activity and fibrosis (r = 0·715, P < 0·0001) and more specifically with the periportal necrosis parameter, which is the main lesion of chronic hepatitis C. In addition, analysis of the peripheral compartment revealed a high correlation between values of CD3+CD56− lymphocytes and both Knodell score (r = 0·624, P = 0·003) and serum ALT levels and again with periportal necrosis. The strong correlation between the proportion of peripheral CD3+CD56− conventional T lymphocytes and the severity of hepatic lesions leads us to propose that evaluation of this accessible peripheral population could be used as an indicator test for the severity of histological lesions in chronic hepatitis C.

Abbreviations:
Dipeptidyl peptidase IV on activated T cells as a target molecule for therapy of rheumatoid arthritis
Authors: WILLIAMS Y N , BABA H , HAYASHI S , IKAI H , SUGITA T , TANAKA S , MIYASAKA N , KUBOTA T
Published: March 2003

The extracellular domain of the T cell co-stimulatory molecule CD26 possesses dipeptidyl peptidase IV (DP IV) enzyme activity. Activated T cells are known to increase expression of cell surface DP IV and some specific inhibitors of this enzyme have been reported to suppress T cell function. Previously we have identified a DP IV inhibitor, designated TMC-2, found in culture supernatant of Aspergillus oryzae. Administration of TMC-2 to rats with adjuvant arthritis caused marked suppression of paw swelling. To elucidate the mechanism of TMC-2 antiarthritic activity, we have studied its effects on T cell function. Here we show that TMC-2 inhibited DP IV activity of CD26 immunoprecipitated from T cell lysates, and also inhibited proliferative responses of T cells to specific antigen or anti-CD3 antibody. Suppression of IL-2 production was demonstrated at both the mRNA and protein levels. TMC-2 did not alter the PTPase activity of pure CD45, but when this molecule was co-precipitated from T cell lysates together with associated CD26, its PTPase was virtually completely abolished by TMC-2. These results suggest that modulation of CD45 PTPase activity might be responsible for functional suppression of T cells by TMC-2. Because the effects of TMC-2 on T cells were reversible and it was not toxic at the concentrations used, TMC-2 may be a candidate novel therapeutic agent for rheumatoid arthritis.
Stimulated proliferative responses in vertically HIV-infected children on HAART correlate with clinical and immunological markers
Authors: RESINO S , ABAD M L , NAVARRO J , BELLÓN J M , SÁNCHEZ-RAMÓN S , ÁNGELES MUÑOZ-FERNÁNDEZ M
Published: March 2003

The objective of the study was to investigate the relationship between various CD4+ T cell subsets and the ability of peripheral blood mononuclear cells (PBMC) to proliferate to several stimuli in vertically human immunodeficiency virus type 1 (HIV-1)-infected children. We studied 29 HIV-1-infected children on highly active antiretroviral therapy (HAART) (median duration: 12·3 months). T cell subsets were determined by flow cytometry. Plasma viral load (VL) was quantified using a standardized molecular method. Proliferative responses were evaluated by [3H]-thymidine incorporation. Decreased proliferative responses of PBMC to pokeweed mitogen (PWM) were found for HIV-1-infected children in Centers for Disease Control (CDC) clinical categories B and C when compared to the control group (P < 0·05). Similarly, children with ≤ 15% CD4+ T cells showed a decrease in proliferative responses to PWM (P < 0·01), anti-CD3 + anti-CD28 (P < 0·01) and phytohaemagglutinin (PHA) (P < 0·05) with respect to the control group and to children with CD4+ T cells ≥ 25%. Proliferative responses to PWM, anti-CD3+, anti-CD28 and PHA had a statistically significant positive correlation with CD3+/mm3, CD4+/mm3, % CD4 T cells, CD4/CD8 ratio and the percentage of naive T cell subsets (CD4+CD45RO–HLA-DR–, CD4+ CD45RA+ CD62L+, CD4+ CD45RA+), CD4+ CD62L+ and CD4+ T cells co-expressing CD38+ (CD4+ HLA-DR−CD38+, CD4+ CD38+). Moreover, we found a negative correlation between PBMC proliferative responses and % CD8 T cells, memory, memory-activated and activated CD4+ T cell subsets. Lower proliferative responses to PWM (P < 0·01) and PHA (P < 0·01) were associated with higher VL. Our data show that higher proliferative responses to PWM, anti-CD3 + anti-CD28 and PHA are associated with both non-activated and naive CD4+ T cell subsets in HIV-1-infected children on HAART.
Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitis
Authors: FAHLGREN A , HAMMARSTRÖM S , DANIELSSON Å , HAMMARSTRÖM M-L
Published: March 2003

The impact of chronic inflammation on the expression of human α-defensins 5 and 6 (HD-5, HD-6), β-defensins 1 and 2 (hBD-1, hBD-2) and lysozyme in epithelial cells of small and large intestine was investigated. Intestinal specimens from 16 patients with ulcerative colitis (UC), 14 patients with Crohn's disease (CD) and 40 controls with no history of inflammatory bowel disease were studied. mRNA expression levels of the five defence molecules were determined in freshly isolated epithelial cells by real-time quantitative RT-PCR. Specific copy standards were used allowing comparison between the expression levels of the different defensins. HD-5 and lysozyme protein expression was also studied by immunohistochemistry. Colonic epithelial cells from patients with UC displayed a significant increase of hBD-2, HD-5, HD-6 and lysozyme mRNA as compared to epithelial cells in controls. Lysozyme mRNA was expressed at very high average copy numbers followed by HD-5, HD-6, hBD-1 and hBD-2 mRNA. HD-5 and lysozyme protein was demonstrated in metaplastic Paneth-like cells in UC colon. There was no correlation between hBD-2 mRNA levels and HD-5 or HD-6 mRNA levels in colon epithelial cells of UC patients. Colonic epithelial cells of Crohn's colitis patients showed increased mRNA levels of HD-5 and lysozyme mRNA whereas ileal epithelial cells of Crohn's patients with ileo-caecal inflammation did not. Chronic inflammation in colon results in induction of hBD-2 and α-defensins and increased lysozyme expression. hBD-1 expression levels in colon remain unchanged in colitis. The high antimicrobial activity of epithelial cells in chronic colitis may be a consequence of changes in the epithelial lining, permitting adherence of both pathogenic bacteria and commensals directly to the epithelial cell surface.
Prospects for immunotherapy of malignant disease
Authors: MORRIS E C , BENDLE G M , STAUSS H J
Published: March 2003

The majority of T cell-recognized tumour antigens in humans are encoded by genes that are also present in normal tissues. Low levels of gene expression in normal cells can lead to the inactivation of high-avidity T cells by immunological tolerance mechanisms. As a consequence, low-avidity T cell responses in patients are often inadequate in providing tumour protection. Recently, several technologies have been developed to overcome tolerance, allowing the isolation of high-affinity, HLA-restricted receptors specific for tumour-associated peptide epitopes. Furthermore, transfer of HLA-restricted antigen receptors provides an opportunity to empower patient T cells with new tumour-reactive specificities that cannot be retrieved from the autologous T cell repertoire.
T cell Vβrepertoires in childhood vasculitides
Authors: BROGAN P A , SHAH V , BAGGA A , KLEIN N , DILLON M J
Published: March 2003

Superantigens (SAgs) are potent stimulators of T cells bearing specific Vβ T cell receptors (TCR) and may play a role in the aetiopathogenesis of systemic vasculitis, although this remains contentious. To investigate the possible aetiological role of SAgs, this study examined peripheral blood T cell Vβ repertoires in children with systemic vasculitis. FACS analysis of 17 different peripheral blood T cell Vβ families was performed in 20 healthy control children, 27 disease control children with nonvasculitic inflammatory disease, 25 children with primary systemic vasculitis, six patients with Kawasaki disease (KD) and six patients with Henoch–Schönlein purpura (HSP). There was a significantly increased variance of CD4 Vβ12 and Vβ17, and CD8 Vβ1 in the primary systemic vasculitis group compared to control and disease controls. Moreover, 80% of the primary systemic vasculitis children had one or more CD4 Vβ expansions or deletions, compared with 30% of controls (P < 0·002), and 37% of the disease controls (P < 0·002). In the KD group, the mean percentage of CD4 Vβ2 T cells was higher than in controls or disease controls. In the HSP group, there was no consistent skewing of the T cell Vβ repertoire. We have observed changes in the T cell Vβ repertoire in children with vasculitis over and above those observed in disease controls. While these data provide impetus for further research into this contentious field, they do not resolve unequivocally the question of the role of SAgs in childhood vasculitic syndromes.
Streptococci andActinomycesinduce antibodies which cross react with epithelial antigens in periodontitis
Authors: YE P , HARTY D W S , CHAPPLE C C , NADKARNI M A , CARLO A A D E , HUNTER N
Published: March 2003

Perturbation of epithelial structure is a prominent but poorly understood feature of the immunopathological response to bacterial antigens which characterizes the destructive lesion of periodontitis. Western analysis of sera from 22 patients with periodontitis detected multiple antigens in extracts of epithelial cells whereas sera from 12 periodontally healthy subjects displayed only trace reaction with epithelial antigens. To investigate a possible relationship between the bacterial flora adjacent to diseased sites and the presence of antibodies reactive with epithelium, subgingival plaque samples were taken from deep periodontal pockets and cultured anaerobically. Gram positive bacteria containing antigens cross-reactive with epithelial cells were reproducibly isolated by probing membrane colony-lifts with affinity-isolated (epithelium-specific) antibodies and identified by 16S rDNA sequence homology as streptococci (S. mitis, S. constellatus and two S. intermedius strains) and Actinomyces (A. georgiae, and A. sp. oral clone). Conversely, when serum from patients with periodontitis was absorbed with the captured bacterial species the number of epithelial antigens recognized was specifically reduced. It was concluded that development of cross-reactive antibodies related to these organisms may contribute to perturbation of the epithelial attachment to the tooth and the progression of periodontitis. These autoreactive antibodies could also be a contributing factor in other diseases affecting epithelia.
Development of hyperandrogenism during treatment with insulin‐like growth factor‐I (IGF‐I) in female patients with Laron syndrome
Authors: Klinger  , Anin  , Silbergeld  , Eshet  , Laron
Published: March 2003

OBJECTIVE

Patients with Laron syndrome (LS) can now be treated with recombinant IGF‐I. We describe the development of androgenization during IGF‐I treatment of female LS patients.

PATIENTS

Six female patients with LS—two clinically prepubertal (11.6 and 13.8 years of age) and four young adults (30 to 39 years old)—underwent long‐term replacement treatment with recombinant IGF‐I. The daily doses were 150 μg/kg/day by subcutaneous (s.c.) injection in the girls and 120 μg/kg/day in the adult women.

METHODS

Testosterone, Δ4‐androstenedione, LH, FSH, insulin and IGF‐I were determined by radioimmunoassay. Blood samples were obtained after an overnight fast before the IGF‐I injection. Serum IGF‐I was also determined 4 hours after the s.c. injections.

RESULTS

During IGF‐I treatment, four out of the six patients (two girls and two adults) developed progressive clinical symptoms and signs of hyperandrogenism (oligo/amenorrhoea and acne). Laboratory determinations showed a significant elevation in serum testosterone, Δ4‐androstenedione and LH/FSH ratio. The hyperandrogenism occurred concomitantly with an increase in IGF‐I serum and a decrease in serum insulin concentrations. Reduction in IGF‐I dose or interruption in IGF‐I treatment restored androgen levels to normal values. At the same time, the acne and oligomenorrhoea resolved.

CONCLUSIONS

Overdosage of IGF‐I can lead to androgenization, a previously undescribed undesirable effect of IGF‐I. Long‐term IGF‐I treatment necessitates progressive adjustment of the IGF‐I dose to avoid overtreatment.
The development of the foetal thyroid: in utero ultrasonographic measurements
Authors: Achiron Reuwen , Rotstein Zeev , Lipitz Shlomo , Karasik Avi , Seidman Daniel S.
Published: March 2003

OBJECTIVE

The early recognition of potentially treatable thyroid disease in the foetus frequently depends on the detection of abnormal growth of the foetal thyroid gland. We have therefore established nomograms for foetal thyroid transverse width and circumference from 14 weeks of gestation until term, using transvaginal and transabdominal high‐resolution ultrasound techniques.

DESIGN

A prospective, cross‐sectional study of 193 normal singleton pregnancies was performed.

MEASUREMENTS

Thyroid size was measured by transvaginal ultrasonography between 14 and 17 weeks, and by abdominal ultrasound from 18 to 37 weeks of gestation.

RESULTS

Data was accurately obtained for 193 foetuses. The mean ± SD thyroid width and circumference were 11.7 ± 4.1 mm (95% confidence interval 11.1–12.3) and 39.5 ± 14.1 mm (95% confidence interval 37.4–41.6), respectively. Thyroid size as a function of gestational age was expressed by the regression equations: thyroid width (mm) =−3.94 + 0.68 × gestational age (weeks), and thyroid circumference (mm) =−1.38 + 0.23 × gestational age (weeks). The correlation coefficients, r = 0.91 and r = 0.93, for thyroid width and circumference, respectively, were found to be highly statistically significant (P < 0.0001). The normal mean of thyroid width and circumference for each week of gestational age and the 95% prediction limits were defined.

CONCLUSIONS

The present data offer normative measurements of the foetal thyroid that may facilitate the prenatal diagnosis of foetal goitre and make early administration of in utero treatment possible.
Amelioration of polyuria in nephrogenic diabetes insipidus due to aquaporin‐2 deficiency
Authors: Hochberg Ze’ev , Even Lea , Danon Abraham
Published: March 2003

OBJECTIVE

We have recently reported a large cluster of patients with nephrogenic diabetes insipidus (NDI) due to an autosomal recessive aquaporin‐2 (AQP‐2) early‐stop codon. This paper describes the clinical manifestations and evaluation of therapeutic approaches to this new entity.

PATIENTS AND DESIGN

Nine patients with an AQP‐2 mutation were studied. Urine osmolality was measured in five patients before and at 3 × 30 min intervals after desmopressin given in increasing doses of 5–100 μg. Urinary prostaglandins PGE2 and 6‐keto PGF1α, were extracted from 24‐h urine samples and estimated by radioimmunoassays. Eight NDI patients were given a combination of a low‐sodium diet and hydrochlorothiazide. Four to 11 weeks later, ibuprofen was added, and the patients were retested within the following 4–9 weeks.

RESULTS

Urine osmolality remained unchanged after supra‐pharmacological doses of desmopressin, at 60–70 mOsm/kg. Urinary PGE2 in control subjects was 0.74 ± 0.1 μg/g creatinine (mean ± SD) compared to 5.0 ± 2.6 μg/g creatinine in AQP‐2 deficient patients (P < 0.05). Urinary 6‐keto PGF1α, was 0.20 ± 0.03 μg/g creatinine in controls and 0.75 ± 0.31 μg/g creatinine in AQP‐2 deficiency (P < 0.05). Urinary volumes decreased by a mean 31% on a low‐salt diet and hydrochlorothiazide, and by a mean of 38% on the combination therapy. Plasma osmolality decreased by a mean 15 mOsm/kg on the low‐salt diet and hydrochlorothiazide, and by 22 mOsm/kg on the combination therapy. Urinary osmolality increased from a mean 80 mOsm/kg to 96 mOsm/kg on the low‐salt diet and hydrochlorothiazide, and to 146 mOsm/kg on the combination therapy.

CONCLUSION

AQP‐2 deficiency in these patients with an early‐stop codon is associated with complete unresponsiveness of the collecting duct to vasopressin, implying an indispensable role for AQP‐2 in vasopressin antidiuresis. Urinary PGE2 and 6‐keto PGF1α are elevated, the former being extremely high, apparently due to the extreme vasopressin unresponsiveness. Combination therapy with a combination of a low‐salt diet, thiazide and non‐steroidal anti‐inflammatory drug is partially effective.
Cortisol in dried blood screening specimens from newborns with raised 17‐hydroxyprogesterone and congenital adrenal hyperplasia
Authors: Mitchell Marvin L. , Hermos Rosalie J.
Published: March 2003

BACKGROUND AND OBJECTIVE

Screening for congenital adrenal hyperplasia (CAH) in newborns has become a routine part of many programmes by measuring levels of 17 α‐hydroxyprogesterone (17‐OHP) in the newborn filter‐paper blood specimen. Unfortunately, raised levels of 17‐OHP, which are largely the consequence of cross‐reacting metabolites, are also found in low birth weight, premature and ill neonates. We speculated that differences in concen_trations of cortisol in the newborn screening specimen would aid in distinguishing between CAH positive and CAH negative infants among those with raised levels of 17‐OHP.

DESIGN

Comparison of cortisol concen_trations was made between newborns with CAH and those without but with raised 17‐OHP levels.

PATIENTS

Newborn filter‐paper blood specimens from 31 infants with transient 17‐OHP elevations and 16 infants with confirmed CAH were analysed for cortisol. In addition, assay performance was validated by comparing cortisol values obtained from dried whole blood on filter‐paper with the corresponding plasma from 31 adults and six neonates.

MEASUREMENTS

Cortisol in filter‐paper blood specimens was determined by adapting a commercial radioimmunoassay kit that had been designed for the determination of cortisol in serum.

RESULTS

The mean cortisol level in the CAH negative group was significantly higher than the mean value in the group with documented CAH (means 1190 ± 795 nmol/l vs 627 ± 210 nmol/l; P < 0.01). However, approximately half of the CAH negative infants had cortisol values that overlapped those from the CAH positive group. There was no relationship between the magnitude of the 17‐OHP elevation and cortisol concen_trations.

CONCLUSION

The measurements of cortisol in dried blood on filter‐paper using a commercial radioimmunoassay kit has been shown to be reliable and simple to carry out. The level of cortisol in newborn blood specimens can be used to exclude some infants with elevated 17α‐hydroxyprogesterone levels from further testing for CAH. However, overlapping cortisol values between CAH positive and negative infants precludes the assay of cortisol from being used routinely as a reliable means of decision making.
Growth hormone status in adults treated for acute lymphoblastic leukaemia in childhood
Authors: Brennan  , Rahim  , Mackie  , Eden  , Shalet
Published: March 2003

OBJECTIVE

Growth hormone status was assessed in a cohort of 32 (16 male) adults who had received cranial irradiation (XRT) in childhood as part of their treatment for acute lymphoblastic leukaemia (ALL) and compared with 35 age matched young adults (18 male).

DESIGN

Height and weight were measured in all subjects and the heights of the patients at XRT were obtained from their case notes. Each patient and control underwent two provocative tests of growth hormone (GH) secretion using insulin (0.2 IU/kg body weight) and arginine (20 g/m2). Basal serum insulin like growth factor‐1 (IGF‐1) and IGFBP‐3 (binding protein‐3) concen_trations were also measured.

RESULTS

The patient group had a significantly lower peak GH response to both provocative tests (P < 0.01), and lower IGF‐1 and IGFBP‐3 levels compared with the normal controls (P < 0.01). Nine of the patient group were severely GH deficient (peak GH response <9 mU/l to both provocative agents) and a further 12 patients were GH insufficient (peak GH response <20 mU/l to both tests with at least one peak GH response >9 mU/l). Overall a significant median change in height from XRT to final height of −0.5 SDS was found which was even greater in the severely GH deficient group (median change in height of −2.1 SDS).

CONCLUSION

These data suggest that a significant proportion of adults treated with cranial XRT in childhood with irradiation doses between 18–25 Gy, as part of their treatment for ALL, are severely GH deficient now and should be considered for GH replacement. Changes in GH secretion evolve with time following irradiation‐induced damage to the hypothalamic‐pituitary axis; therefore long‐term surveillance will be required in those remaining patients, in whom GH status is considered currently to be insufficient or even normal.
Growth hormone treatment improves body fluid distribution in patients undergoing elective abdominal surgery
Authors: Møller  , Jensen  , Frandsen  , Møller  , Kissmeyer  , Laurberg
Published: March 2003

OBJECTIVE

To investigate the possible beneficial effects of growth hormone (GH) in catabolic patients we examined the impact of GH on body fluid distribution in patients with ulcerative colitis undergoing elective abdominal surgery.

DESIGN AND MEASUREMENTS

Twenty‐four patients (14 female, 10 male) aged 19–47 years were in a double‐blinded study randomly assigned to receive either placebo (n = 12) or GH (n = 12) 6IU s.c. twice daily from 2 days before until 7 days after ileo‐anal J pouch surgery. Extracellular and plasma volume (ECV, PV) were determined using 82Br and 125I albumin dilution at day −2 and at day 7, and body composition was estimated by dual X‐ray absorptiometry and bioimpedance. Changes in body weight and fluid balance were recorded and hence intracellular volume was assessed.

RESULTS

During placebo treatment body weight decreased 4.3± 0.6 kg; during GH treatment body weight was constant (P < 0.01). There was a positive fluid balance in the GH‐treated patients compared to the placebo group (GH: 3.6 ± 0.7 l; plc: −0.7 ± 1.2 l, P < 0.01). ECV increased 2.12 ± 0.70 l during GH and was unaffected during placebo (P = 0.02). PV was unchanged by GH and decreased 0.39 ± 0.08 l during placebo administration (P = 0.03). Intracellular volume (ICV) decreased less during GH than during placebo (GH: −1.42 ± 0.45; plc: −3.70 ± 0.76; P = 0.02). Bioimpedance remained constant during GH administration and increased 60 ± 9 ohm in the placebo‐treated group (P < 0.05). Plasma renin and aldosterone remained unchanged in both study groups.

CONCLUSION

Body weight, plasma volume and intracellular volume is preserved during GH treatment in catabolic patients and ECV is increased. From a therapeutic point of view these effects may be desirable under conditions of surgical stress.
Serum prolactin concentration in patients taking neuroleptic drugs
Authors: Pollock Anne , McLaren E. H.
Published: March 2003

OBJECTIVE

Non‐tumour causes of hyperprolactinaemia, including prolactin‐elevating drugs, must be excluded. There is a general view that such drugs are unlikely to raise serum PRL above 3000 mU/l, but the literature is confusing. We report 8 patients receiving treatment with neuroleptic drugs, whose serum PRL concentrations were grossly elevated.

METHODS

Prolactin was measured using a 2‐site immunofluorometric assay (Abbott Laboratories; reference range < 500 mU/l). Seven of the eight women (age range 24–49 years) were symptomatic (galactorrhoea, oligo‐ or amenorrhoea).

RESULTS

Prolactin concentrations ranged from 3600 mU/l to 7300 mU/l. All patients had a normal pituitary CT scan. Five patients were treated with bromocriptine without detriment to their mental state.

CONCLUSION

Prolactin can rise to concentrations associated with prolactinomas in patients on neuroleptic drugs. As it is rarely possible to stop the drugs to see if the PRL concentration will decline to normal, neuroradiology is required in these patients to exclude a vision‐threatening macroprolactinoma before deciding on medical treatment.
Dual facets of hyponatraemia and arginine vasopressin in patients with ACTH deficiency
Authors: Yamamoto Toshihide , Fukuyama Jiro , Kabayama Yasuhiro , Harada Hiromasa
Published: March 2003

OBJECTIVE

Hyponatraemia is often observed in patients with ACTH deficiency who are thought not to suffer from volume depletion. Their high plasma AVP levels relative to plasma osmolality are presumed to be maintained by non‐osmotic mechanisms. We attempted to assess volume status from changes in selected clinical measurements related to body fluid balance in the course of i.v. fluid supplementation and following glucocorticoid (GC) replacement in ACTH‐deficient patients, and to interpret plasma AVP levels in the context of the estimated volume status.

PATIENTS AND DESIGN

This report consists of three parts. First, an ACTH‐deficient patient with hyponatraemia and volume depletion who was followed through volume replacement to recovery after GC replacement is described (case report). Secondly, medical records of five ACTH‐deficient patients with hypovolaemia and hyponatraemia were surveyed retrospectively to observe changes in serum levels of sodium, uric acid (UA) and haematocrit (Hct) following i.v. fluid supplementation of low sodium content (retrospective study). Thirdly, five ACTH‐deficient patients with or without overt dehydration were studied with regard to body weight, blood pressure, serum sodium, total proteins, Hct and blood urea nitrogen before and after GC replacement (prospective study). Plasma AVP levels were measured after i.v. fluid supplementation without GC replacement in the patients of the retrospective study, and before and after GC replacement in the patients of the prospective study.

RESULTS

The first patient became more hyponatraemic after i.v. fluid supplementation and recovered ultimately from hyponatraemia after GC replacement. In five patients studied retrospectively, the serum sodium levels fell progressively following i.v. fluid supplementation, concurrent with reduction in UA levels and Hct, which indicated the dilutional nature of the hyponatraemia. In the patients observed prospectively, the accumulation of fluid and sodium was indicated by a rise in body weight, blood pressure and serum sodium levels and a decline in Hct and total proteins after GC replacement. Plasma AVP levels rose similarly in patients with dilutional hyponatraemia and in patients with borderline hyponatraemia before GC replacement.

CONCLUSION

Patients with untreated ACTH deficiency may have either of two kinds of hyponatraemia—i.e. borderline hyponatraemia associated with subclinical hypovolaemia, or dilutional hyponatraemia. Similarity of plasma AVP levels in two hyponatraemic states suggests their AVP secretion is regulated by nonosmotic, non‐volume mechanisms, possibly released from GC suppression at low plasma osmolality.
Oestrogen has no short‐term effect on intestinal strontium absorption in healthy postmenopausal women
Authors: ten Bolscher Marieke , de Valk‐de Roo Gerdien W. , Barto Rob , van der Vijgh Wim J. F. , Netelenbos J. Coen
Published: March 2003

OBJECTIVE

Impaired intestinal calcium absorption in postmenopausal women is often indirectly linked to decreased serum 1,25(OH)2D or to intestinal resistance to its action rather than directly to low circulating oestrogen levels following the menopause. The purpose of this clinical study was to investigate the short‐term effect of oral 17β‐oestradiol on intestinal calcium absorption, with strontium as a marker.

DESIGN AND PATIENTS

Twenty‐five healthy postmenopausal women participated in this randomised double blind placebo controlled clinical trial. Twelve women received oestradiol therapy (2 mg/day) and thirteen placebo for 2 months. Fractional strontium absorption (Fc240) was assessed at baseline and after 2 months of oestradiol/placebo therapy.

RESULTS

Intestinal strontium absorption (Fc240) was unchanged after treatment with 17β‐oestradiol (10.1 ± 5.0 vs. 10.2 ± 3.8 (%)). Serum total calcitriol (1,25(OH)2 D) was unchanged after treatment with placebo (88 ± 22 vs. 79 ± 21 (pmol/l)) but increased after treatment with oestradiol (88 ± 30 vs. 116 ± 33 (pmol/l); P < 0.005). Serum vitamin D binding protein (DBP) increased after oestradiol but not after placebo treatment. The free serum 1,25(OH)2D index was calculated. This index did not change after oestrogen therapy (1.6 ± 0.5 vs. 1.8 ± 0.5).

CONCLUSION

In healthy postmenopausal women, short‐term suppletion with exogenous oral oestrogen did not influence intestinal calcium absorption as measured by the strontium absorption test.
Familial non‐medullary thyroid carcinoma: pathology review in 27 affected cases from 13 French families
Authors: Leprat  , Bonichon  , Guyot  , Trouette  , Trojani  , Vergnot  , Longy  , Belleannée  , De Mascarel  , Roger
Published: March 2003

BACKGROUND AND OBJECTIVES

When familial non‐medullary thyroid cancer (FNMTC) develops with no obvious associated pathogenetic factor, an inherited predisposition may underlie the process. The present study was conducted because detailed pathological findings are lacking in most series of FNMTC.

PATIENTS AND METHODS

Thirteen families comprising 27 cases of FNMTC were included (1.8% of differentiated thyroid carcinoma). The family relationship (20 F, 7 M; age 46 ± 16 years; mean ± SD) was ‘siblings’ in eight families, ‘parent and child’ in four and ‘aunt and niece’ in one. Careful pathological review of the thyroid tumours (papillary/follicular: 25/2, size: 16 ± 11 mm) was performed.

RESULTS

initial staging according to extension was as follows: grade I (n = 16), II (n = 2), III (n = 6), IV (n = 3). Fourteen tumours were papillary microcarcinomas (size: 8 ± 2 mm). No tumour phenotype that may be considered specific for FNMTC was found when considering either age, pathological findings or tumour aggressiveness. Although rare events were found in both relatives of some families suggesting a putative ‘familial’ phenotype of FNMTC, this may be fortuitous.

CONCLUSION

Micro familial non‐medullary thyroid cancers are more common than previously reported and further studies are required to be able to distinguish this subgroup from sporadic papillary microcarcinomas. The careful pathological review of the familial non‐medullary thyroid cancer in this study does not seem to point to a distinct subgroup of familial differentiated thyroid carcinoma although the data are intriguing. Genetic studies are now required to investigate this issue.
Relationship between serum and urinary insulin‐like growth factor‐I through childhood and adolescence: their use in the assessment of disordered growth
Authors: Hall  , Gill  , Foster  , Pennells  , Tillmann  , Jones  , Price  , Clayton
Published: March 2003

OBJECTIVE

Serum insulin‐like growth factor‐I (sIGF‐I) measurement as an index of growth hormone status has become a common test in the investigation of disordered growth. IGF‐I may also be measured in the urine. The aims of this study were to investigate the correlation between serum and urinary IGF‐I in normal children and compare their use in the evaluation of growth disorders.

DESIGN

Normal ranges for serum and urinary IGF‐I were devised from a cross‐sectional study of normal schoolchildren. These were then used to assess the sensitivity and specificity of serum and urinary IGF‐I in the diagnosis of childhood GH deficiency.

PATIENTS

A cohort of 333 (M = 156, F = 177) healthy schoolchildren aged 5–19 years were recruited and data previously collected from 22 growth hormone deficient (GHD) and 47 short normal (SN) children were compared with those of the normal children.

MEASUREMENTS

Height, weight and pubertal status were assessed in all children. Serum IGF‐I (sIGF‐I) (n = 305) and total amount of urinary IGF‐I excreted overnight (TuIGF‐I) (n = 205) were measured by RIA using excess IGF‐II to block the interference of IGFBPs.

RESULTS

Serum IGF‐I was loge transformed and overall levels (geometric mean  ± 1 tolerance factor) were higher in females than males (F: 569 (329, 985)μg/l; M: 398 (227, 696)μg/l). LogeIGF‐I correlated with age (F: r = + 0.76, P < 0.001, M: r = + 0.71, P < 0.001) and was significantly affected by both sex and Tanner stage of puberty (TS) (both P < 0.001). The distribution of TuIGF‐I was normalized by performing a square root transformation (√TuIGF‐I). √TuIGF‐I was correlated with age (F: r = + 0.36, P < 0.001; M: r = + 0.5, P < 0.001) and was significantly affected by TS (P < 0.001). In both sexes there was a highly significant correlation between logeIGF‐I and √TuIGF‐I (F: r = + 0.39, P < 0.001; M: r = + 0.41, P < 0.001). Using the third centile of our normal ranges as a cut off to identify GHD, sIGF‐I had a sensitivity of 82% and specificity of 62%, whereas TuIGF‐I had a sensitivity of 18% and specificity of 79%.

CONCLUSIONS

This study demonstrates that although urinary IGF‐I has no place in the diagnosis of growth disorders, in normal children there is a highly significant relationship between serum and urinary IGF‐I with levels of each changing in a similar manner through childhood and adolescence. Thus, TuIGF‐I could be used as a valid surrogate for sIGF‐I in the physiological assessment of the relationship between IGF‐I status and the normal growth process.
Amniotic fluid levels of dimeric inhibins, pro‐αC inhibin, activin A and follistatin in Down's syndrome
Authors: Wallace Euan M. , D'Antona Donato , Shearing Catherine , Evans Lee W. , Thirunavukarasu Prema , Ashby Peter J. , Shade Mary , Groome Nigel P.
Published: March 2003

OBJECTIVE

In the second trimester of pregnancy, inhibin A is significantly increased in maternal serum and decreased in amniotic fluid in Down's syndrome pregnancies compared to normal. We wished to further evaluate the levels of inhibin A, inhibin B, pro‐αC inhibin, activin A and the binding protein follistatin in amniotic fluid in Down's syndrome and control pregnancies.

DESIGN

Case‐matched control study.

PATIENTS

29 Down's syndrome and 290 chromosomally normal control pregnancies were identified from records and amniotic fluid, collected at second tri‐mester amniocentesis, retrieved from routine storage for analysis.

MEASUREMENTS

Inhibin A, inhibin B, pro‐αC inhibin, total activin A and follistatin were measured using sensitive and specific enzyme linked immunosorbent assays.

RESULTS

The median (10th–90th percentiles) amniotic fluid inhibin A level in the control pregnancies increased from 334 (122–553) ng/l at 14 weeks' to 695 (316–1475) ng/l at 19 weeks' gestation. The corresponding figures for inhibin B and the α‐subunit precursor inhibin pro‐αC were 632 (185–1354) and 2062 (1237–3381) ng/l, respectively at 14 weeks' and 2439 (748–5307) and 3115 (2021–6567) ng/l, respectively at 19 weeks' gestation. Total activin A increased from 3795 (1554–5296) at 14 weeks' to 5086 (3059–8224) at 18 weeks' gestation. Expressed as multiples of the median (MoM) the median (95% CI) amniotic fluid levels of inhibin A, inhibin B, pro‐αC inhibin and acitivin A in the Down's syndrome samples were 0.77 (0.59–0.85), 0.94 (0.63–1.23), 0.77 (0.49–0.84) and 0.77 (0.53–0.87), respectively. Compared to controls the levels of inhibin A, pro‐αC inhibin and activin A were significantly lower in Down's syndrome pregnancies (P < 0.01, Mann‐Whitney U test). Follistatin levels in the controls declined slightly from 2106 (1421–3538) ng/l at 14 weeks' to 1600 (1281–2543) ng/l at 18 weeks' gestation. Levels in the Downs' syndrome pregnancies were similar to controls.

CONCLUSIONS

The data suggest that the production, secretion or metabolism of the inhibin α‐ and βA‐subunits is altered in Down's syndrome pregnancies in the second trimester.
Postmenopausal osteoporosis is more related to hormonal aberrations than to lifestyle factors
Authors: Landin‐Wilhelmsen Kerstin , Wilhelmsen Lars , Bengtsson Bengt‐Åke
Published: March 2003

OBJECTIVE

Serum insulin‐like growth factor‐1 (IGF‐1) decreases with increasing age and this process is more pronounced in women after the menopause in parallel with the increasing prevalence of osteoporosis. This study was designed to compare IGF‐1 concentrations, vitamin D, intact parathyroid hormone (PTH) and lifestyle factors in postmenopausal, osteoporotic women with and without oestrogen replacement therapy (HRT), with an age‐matched random population sample of women.

DESIGN

Case control study.

PATIENTS

Postmenopausal, osteoporotic women, n = 128, mean age 59 ± 6 years, were compared with a female random population sample matched for age, n = 227, mean age 59 ± 5 years, from the WHO MONICA Project, Göteborg, Sweden. Osteoporotic fractures had occurred in 56% of the patients compared with 4% of the controls (P < 0.001).

MEASUREMENTS

Anthropometry, occupation, smoking habits, physical activity, blood pressure, IGF‐1, vitamin D, intact PTH, blood lipids.

RESULTS

There were no differences in occupational class, current or previous smoking habits, degree of physical activity during occupational or leisure time between the patients and controls. Osteoporotic women had lower body weight and body mass index than the controls (P < 0.001). Height, waist/hip ratio and osteocalcin were similar. 25(OH) vitamin D and 1,25(OH)2 vitamin D were lower (P < 0.05 and P < 0.01, respectively), PTH was higher (P < 0.001) and IGF‐1 lower (P < 0.01) in osteoporotic women compared with the controls. IGF‐1 was lower (P < 0.05), in spite of similar bone mineral density, in osteoporotic women without HRT than in those with HRT, who had IGF‐1 concentrations similar to those of the population sample, of whom fewer than 10% had HRT. Among patients, IGF‐1 did not correlate with serum oestradiol or bone mineral density. PTH correlated negatively to bone mineral density at the femoral site (r = − 0.29; P = 0.003).

CONCLUSION

Osteoporosis in postmenopausal women is more related to hormonal aberrations than to lifestyle factors.
Weight gain reverses bone turnover and restores circadian variation of bone resorption in anorexic patients
Authors: Caillot‐Augusseau Anne , Lafage‐Proust Marie‐Hélène , Margaillan Philippe , Vergely Nathalie , Faure Sylvie , Paillet Stephane , Lang François , Alexandre Christian , Estour Bruno
Published: March 2003

OBJECTIVE

The present study was conducted in order to describe the variations and circadian rhythm of biochemical markers of bone remodelling at baseline and after weight gain in patients with aneroxia nervosa (AN).

SUBJECTS

We studied 9 women (mean age 21 years, range: 16–30) with established AN who remained amenorrhoeic during the study and with a low body mass index (BMI) after refeeding and 6 female controls (mean age 20 years, range, 18–24 and BMI: 20.6 ± 1.1 kg/m2). Refeeding was not associated with any other intervention or treatment, especially oestrogen replacement or hormonal contraception. Serum levels of oestradiol remained below 70 pmol/l before and after refeeding.

MEASUREMENTS

During the study, PTH and 25‐hydroxyvitamin D measurements were performed. Markers of bone formation: serum intact osteocalcin (iBGP) and serum intact BGP + fragments (iBGP+F) and markers of bone resorption: urine C‐teloptide of type I collagen (uCTX) and serum C‐telopeptide ofvtype 1 collagen (s‐CTX) were measured.

RESULTS

At baseline, PTH and 25 OH‐vitamin D concentrations were within the normal range in AN patients and no significant variation was observed after refeeding. Bone formation markers were found to be significantly different at baseline between AN patients and controls. After refeeding, iBGP and iBGP+F levels increased by 172% and 154%, respectively, to values no different from controls. Intact BGP and iBGP+F exhibited a significant circadian variation in controls (P < 0.05 and P < 0.002, respectively), whereas we did not find any such circadian rhythm in AN patients. After refeeding no significant circadian variation was observed; however, iGBP+F tended to peak in early morning and exhibited a nadir in the afternoon. At baseline, sCTX was 2‐fold higher in AN patients than in controls. After weight gain sCTX decreased significantly and reached control values. Refeeding induced a non‐significant 40% decrease in uCTX. We found positive correlations between uCTX and the 24‐h mean value of sCTX levels (r2 = 0.93, P < 0.0001) and between uCTX and the mean value of sCTX peak levels at 0800 h (r2 = 0.65, P < 0.0003). Serum CTX exhibited a significant circadian variation in controls (P < 0.001) with a peak at 0800 h and a nadir at 1600 h with a 60% decrease between peak and nadir values. We found that anorexia nervosa suppressed the sCTX circadian variation which was restored by refeeding. We found a significant non‐linear relationship between BMI and sCTX/iBGP ratio in AN (r2 = 0.6, P < 0.0001), thus illustrating the influence of nutritional status on bone remodelling.

CONCLUSIONS

In this study we found that weight gain, related to refeeding only, reversed the anorexia nervosa‐induced uncoupling of bone remodelling and restored circadian variation of a bone resorption marker.
The prevalence of polycystic ovaries in women with type 2 diabetes mellitus
Authors: Conn Jennifer J. , Jacobs Howard S. , Conway Gerard S.
Published: March 2003

OBJECTIVE

Polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus are both common conditions associated with insulin resistance and compensatory hyperinsulinaemia. Previous reports have noted that impaired glucose tolerance and diabetes are common in women with PCOS. In this report we present the results of the converse study: the prevalence of polycystic ovaries in premenopausal women presenting with type 2 diabetes mellitus.

SUBJECTS

Subjects were recruited from a hospital Diabetes Clinic. A search of computerized records identified 49 premenopausal women with type 2 diabetes mellitus being treated with diet alone or oral hypoglycaemic agents of whom 38 (76%) patients agreed to be studied.

DESIGN

A cross‐sectional study recording clinical, demographic and anthropometric data. Measurements of fasting metabolic parameters, reproductive endocrine profiles and ovarian dimensions were taken.

RESULTS

Eighty‐two percent of women with type 2 diabetes mellitus had polycystic ovaries on ultrasound. Of these women, 52% had clinical evidence of cutaneous hyperandrogenism and/or menstrual disturbance. Correlations between metabolic and reproductive parameters were consistent with a stimulatory action of insulin on the ovary. There was no significant difference between the PCO and non‐PCO groups with respect to metabolic profiles.

CONCLUSIONS

Women with type 2 diabetes mellitus have a higher prevalence of polycystic ovaries than that reported in the general population. Not all women with hyperinsulinaemia due to type 2 diabetes mellitus, however, develop PCO suggesting that hyperinsulinaemia alone is not sufficient for the expression of this ovarian morphology.