bluuebunny/crossref_metadata_2025 huggingface dataset:
Burden of disease attributable to selected environmental factors and injury among children and adolescents in Europe
Authors: Reading Richard
Published: December 2004

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Valent F,
Little D,
Bertollini R,
Nemer LE,
Barbone F &
Tamburlini G
. (
2004
)

,
363
,
2032
–
2039
.

Background  Environmental exposures contribute to the global burden of disease. We have estimated the burden of disease attributable to outdoor and indoor air pollution, inadequate water and sanitation, lead exposure, and injury among European children and adolescents.

Methods  Published studies and reports from international agencies were reviewed for calculation of risk‐factor exposure in Europe. Disability‐adjusted life years (DALYs) or deaths attributable to each factor, or both, were estimated by application of the potential impact fraction to the estimates of mortality and burden of disease from the WHO global database of burden of disease.

Findings  Among children aged 0–4 years, between 1.8% and 6.4% of deaths from all causes were attributable to outdoor air pollution; acute lower‐respiratory‐tract infections attributable to indoor air pollution accounted for 4.6% of all deaths and 3.1% of DALYs; and mild mental retardation resulting from lead exposure accounted for 4.4% of DALYs. In the age‐group 0–14 years, diarrhoea attributable to inadequate water and sanitation accounted for 5.3% of deaths and 3.5% of DALYs. In the age‐group 0–19 years, injuries were the cause of 22.6% of all deaths and 19.0% of DALYs. The burden of disease was much higher in European subregions B and C than subregion A. There was substantial uncertainty around some of the estimates, especially for outdoor air pollution.

Interpretation  Large proportions of deaths and DALYs in European children are attributable to outdoor and indoor air pollution, inadequate water and sanitation, lead exposure, and injuries. Interventions aimed at reducing children's exposure to environmental factors and injuries could result in substantial gains. The pronounced differences by subregion and age indicate the need for targeted action.
Expression of CC and CXC chemokines and chemokine receptors in human leprosy skin lesions
Authors: KIRKALDY A A , MUSONDA A C , KHANOLKHAR-YOUNG S , SUNEETHA S , LOCKWOOD D N J
Published: December 2004

We have investigated the expression of chemokines and their receptors in leprosy skin lesions using immunohistochemistry. Skin biopsies from 25 leprosy patients across the leprosy spectrum, 11 patients undergoing type I reversal reactions and four normal donors were immunostained by ABC peroxidase method using antibodies against CC and CXC chemokines and their receptors. Using an in situ hybridization technique we have also studied the expression of monocyte chemoattractant protein 1 (MCP-1), RANTES and interleukin (IL)-8 chemokines mRNA in leprosy skin lesions. Chemokines and receptor expression was detected in all leprosy skin biopsies. Expression of CC chemokines MCP-1 (P < 0·01) and RANTES (P < 0·01) were elevated significantly in borderline tuberculoid leprosy in reversal reaction compared to non-reactional borderline tuberculoid leprosy, but there was no difference in the expression of IL-8 chemokine. Surprisingly, there was no significant difference in the expression of CC (CCR2 and CCR5) and CXC (CXCR2) chemokine receptors across the leprosy spectrum. Similarly, there was no significant difference in the expression of mRNA for MCP-1, regulated upon activation normal T cell expressed and secreted (RANTES) and IL-8 chemokines. Here, the presence of a neutrophil chemoattractant IL-8 in leprosy lesions, which do not contain neutrophils, suggests strongly a role of IL-8 as a monocyte and lymphocyte recruiter in leprosy lesions. These results suggest that the chemokines and their receptors, which are known to chemoattract T lymphocytes and macrophages, are involved in assembling the cellular infiltrate found in lesions across the leprosy spectrum.
CD4 responses to conserved HIV-1 T helper epitopes show both negative and positive associations with virus load in chronically infected subjects
Authors: BOAZ M J , WATERS A , MURAD S , EASTERBROOK P J , D'SOUSA E , VAN WHEELEY C , VYAKARNAM A
Published: December 2004

Characterization of immune responses to immunodominant CD4 epitopes in HIV-1 that are associated with control of HIV infection could be used to strengthen the efficacy of polyepitope HIV vaccines. We measured both the proliferative and the CD4 interferon (IFN)-γ and interleukin (IL)-2 cytokine responses specific for 11 previously identified HIV-1 T helper epitopes in 10 HIV-infected non-progressors (LTNPs) (infected for a median of 15 years with a stable CD4 count of >500 cells × 106/l), and seven slow progressors (SPs) (infected for a median of 15 years with a CD4 count that had declined to <500 cells × 106/l). Both groups were antiretroviral treatment-naive at the time of evaluation. The median virus load of SP group was higher than that of the LTNP group (P = 0·0002). The CD4 response to a peptide pool representing all potential CD4 Gag epitopes and to Gag p24 protein was also studied. Compared to SPs, LTNPs had higher numbers of Gag-specific IFN-γ+IL-2+ CD4s (P = 0·0059). The Gag-specific cytokine and proliferative responses correlated inversely with virus load (P = 0·03 and 0·0002, respectively), highlighting the potential importance of this response in immunity to HIV. A direct correlation was noted between proliferation and the Gag-specific IL-2 (P = 0·0053) rather than IFN-γ response (P = 0·1336), demonstrating that the proliferation assay reflected the IL-2 rather than the IFN-γ secreting capacity of CD4 cells. Several subjects with diverse class II DRB1 alleles responded, confirming the 11 selected peptides to be both antigenic and conserved. CD4 cytokine responses to one Gag and two conserved Pol peptides correlated negatively with virus load. The cytokine response to two additional Pol peptides correlated positively with virus load. The data indicate that there is not an absolute correlation between the CD4 immune response to conserved and broadly antigenic helper T cell epitopes in HIV non-progression.
The role of antigen in the selection of the human V3-23 immunoglobulin heavy chain variable region gene
Authors: MACKWORTH-YOUNG C G , HARMER I J , MAGEED R A
Published: December 2004

The immune system mounts antibody responses using few of the available immunoglobulin variable region (IgV) genes with some, such as the V3-23 heavy chain gene, regularly over-represented in responses to many antigens. The reasons for the over-representation of some V genes have not been established; the process could be either stochastic or selective. We demonstrated previously that the V3-23 gene, which is over-represented in the primary B lymphocyte repertoire in humans, encodes antibodies with differing antigen-binding reactivities in transgenic mice that express the human V3-23 gene. The aim of the current study was to assess if V3-23 gene over-representation is stochastic or could be influenced by antigen exposure. Transgenic mice were immunized with human IgG-Fc (hIgG-Fc), bovine collagen type II (bCII) or tetanus toxoid (TT), and hybridomas secreting human µ chain-containing  antibodies  generated.  These  were  tested  for  binding  to  the  immunogens  and  a  panel  of self- and exogenous antigens. In hybridomas derived from hIgG-Fc-immunized mice, 53% secreted antibodies specific for hIgG-Fc. A similar proportion (54%) of hybridomas from bCII-immunized mice secreted antibody that bound to collagen. By contrast, only 21% of hybridomas from mice immunized with TT bound to tetanus toxoid. Intriguingly, chimaeric antibodies generated from mice immunized with bCII or TT were mainly polyreactive, similar to antibodies generated from naive transgenic mice. However, hybridomas generated from mice immunized with hIgG-Fc were mainly specific, reacting exclusively with hIgG-Fc. These results suggest that selection and eventual expansion of B lymphocytes expressing the V3-23 gene are likely to be determined by exposure to self- and/or environmental antigens.
Serum nitric oxide (NO) levels in systemic sclerosis patients: correlation between NO levels and clinical features
Authors: TAKAGI K , KAWAGUCHI Y , HARA M , SUGIURA T , HARIGAI M , KAMATANI N
Published: December 2004

Vascular damage in systemic sclerosis (SSc) may be a factor in the abnormal regulation of several vasoactive agents. It has been well confirmed that plasma endothelin-1, as a vasoconstrictive factor, is elevated in patients with SSc. However, it is still controversial whether the levels of serum nitric oxide (NO), a strong vasodilator, are increased or decreased in SSc patients compared to healthy donors. In this study, we measured the levels of serum NO metabolites in SSc patients and determined the contribution of the excessive production of NO synthase (NOS)-2 by skin fibroblasts to NO synthesis. Serum NO levels of 45 patients with SSc were significantly higher than those of 20 healthy volunteers. In addition, some clinical features of SSc (the extent of skin fibrosis, short disease duration, and the complication of active fibrosing alveolitis) were all correlated positively with the levels of NO metabolites in SSc patients. To evaluate the levels of NOS-2 produced by skin fibroblasts, skin fibroblast cultures were established from SSc patients and healthy volunteers. Reverse transcription-polymerase chain reaction indicated that NOS-2 mRNA was spontaneously expressed in cultured fibroblasts derived from SSc patients, but not in those derived from healthy normal controls. Immunohistochemical staining also showed that NOS-2 proteins were detected in SSc fibroblasts but not in normal fibroblasts. The production of NO by cultured fibroblasts was visualized directly by a reagent (DAF-2 DA) used for the fluorescent detection of NO. Cultured SSc fibroblasts were capable of NO synthesis in culture media containing l-arginine, whereas normal fibroblasts (with no expression of NOS-2) did not synthesize detectable NO. These observations indicate that NO production is increased markedly in early-stage diffuse cutaneous SSc patients with active fibrosing alveolitis, and that constitutive NOS-2 expression in SSc fibroblasts may contribute to increased NO production.
Osteopenia, excess adiposity and hyperleptinaemia during 2 years of treatment for childhood acute lymphoblastic leukaemia without cranial irradiation
Authors: Davies J. H. , Evans B. A. J. , Jones E. , Evans W. D. , Jenney M. E. M. , Gregory J. W.
Published: December 2004

objective  Osteopenia and excess adiposity occur following treatment of childhood acute lymphoblastic leukaemia (ALL) and the use of cranial irradiation is thought to be a significant contributory factor. Hyperleptinaemia has also been demonstrated following cessation of treatment for childhood ALL. Therefore a prospective study was undertaken to evaluate serial changes in percentage bone mineral content (BMC), adiposity and serum leptin concentrations during 2 years of treatment of children with ALL with chemotherapy but without cranial irradiation.

design and patient  Only patients treated using the MRC ALL 97/ALL 97 (modified 99) protocols for childhood ALL were eligible for entry into the study. A total of 14 patients (seven male, with a median age of 7·5 years (range 3·4–16·7 years) were recruited. Serial dual energy X‐ray absorptiometry (DEXA) scanning was undertaken at diagnosis and during two years of treatment. Serum leptin concentrations were determined at the same time as the scans.

results  Reductions in %BMC were observed at the hip and lumbar spine by 12 months (P < 0·01) and remained low after 24 months of treatment. Subanalysis of %BMC measurements at the hip demonstrated a greater reduction in %BMC at the trochanteric region compared to the femoral neck. The percentage corrected fat mass increased from 6 months whereas the body mass index (BMI) standard deviation score (SDS) was increased after 24 months of treatment (P < 0·05). Serum leptin concentrations increased following 24 months of therapy (P < 0·05).

conclusions  Children treated for ALL with contemporary regimens have a predisposition to osteopenia, excess adiposity and hyperleptinaemia during treatment without cranial irradiation administration. We speculate that in addition to glucocorticoid administration, leptin resistance may account in part for these observations.
The relationship of ghrelin to biochemical and anthropometric markers of adult growth hormone deficiency
Authors: Malik Iqbal A. , English Patrick J. , Ghatei Mohammed A. , Bloom Stephen R. , MacFarlane Ian A. , Wilding John P. H.
Published: December 2004

introduction  Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS‐R) and potently stimulates GH release in humans. Ghrelin is found in the hypothalamus, but most circulating ghrelin is derived from the stomach. Ghrelin stimulates food intake but circulating levels are low in obesity. We hypothesized that GH deficiency (GHD) might be associated with increased circulating ghrelin concentrations as a result of low GH levels. We therefore measured circulating ghrelin concentrations, leptin and body composition in subjects with GHD and healthy controls.

methods  Subjects with GHD (n = 18) were compared to healthy control subjects (n = 18), matched for body mass index (BMI). They underwent assessment of body composition [waist circumference, BMI and percentage body fat (using bioimpedance)]. Plasma ghrelin, leptin, insulin, GH and IGF‐1 were measured in the fasting state. Plasma ghrelin was measured using a specific radioimmunassay, and the other hormones using commercially available assays.

results  The groups were well‐matched for BMI (GHD vs. control; 32·9 ± 10·8 vs. 31·3 ± 11·7, P = ns) and waist circumference (GHD vs. control; 102·9 ± 20·0 vs. 99·8 ± 25·2, P = ns), but percentage body fat (GHD vs. control; 37·0 ± 9·1 vs. 29·4 ± 13·0, P = 0·06) tended to be higher in the GHD group. As expected, IGF‐1 was lower in GHD (GHD vs. control; 12·5 ± 6·8 vs. 19·2 ± 5·8 nmol/l, P = 0·003). Ghrelin [GHD vs. controls; geometric mean (95% CI); 828·8 (95% CI 639·9–1074·2) vs. 487·9 (95% CI 297·2–800·2) pmol/l] and leptin [GHD vs. controls; 13·2 (95% CI 6·6–26·5) vs. 7·9 (95% CI 3·7–16·9) ng/ml] were similar in the two groups. Plasma ghrelin correlated inversely with waist circumference and waist hip ratio in GHD subjects (r = −0·6, P = 0·02) but not with IGF‐1 or GH concentrations. There was no significant correlation in the control subjects.

conclusion  Circulating ghrelin concentrations are influenced by body fat distribution, but not by levels of either GH or IGF‐1. However, given that obesity is associated with reduced ghrelin concentrations and that GHD is commonly associated with increased body fat, it is possible that these two opposing influences on circulating ghrelin levels result in normal concentrations in subjects with GHD.
A reappraisal of the Rb1 gene abnormalities in the diagnosis of parathyroid cancer
Authors: Cetani Filomena , Pardi Elena , Viacava Paolo , Pollina Giada Di , Fanelli Giovanni , Picone Antonella , Borsari Simona , Gazzerro Elisabetta , Miccoli Paolo , Berti Piero , Pinchera Aldo , Marcocci Claudio
Published: December 2004

objectives  Some histological features may suggest the malignant nature of a parathyroid tumour. However, the diagnosis of parathyroid cancer can only be definitively established in the presence of local invasion or metastases.

design  We further investigated the role of the retinoblastoma gene (Rb1) and the breast cancer susceptibility gene (BRCA2) in the differential diagnosis between benign and malignant parathyroid tumours by evaluating loss of heterozygosity (LOH) at these loci and Rb protein (pRb) immunohistochemistry.

patients and measurements  Fifty‐three parathyroid adenomas from patients with sporadic primary hyperparathyroidism (PHPT) and 10 parathyroid cancer specimens were studied. Microsatellite polymorphisms at the Rb1 and BRCA2 loci were polymerase chain reaction (PCR) amplified from each patient's paired tumour and leucocyte DNA samples, using oligonucleotide primers flanking the repeat sequence. Immunohistochemical staining of pRb was carried out using a monoclonal antibody.

results  All but one of the 53 tumour–leucocyte pairs was informative for at least one of the three polymorphic markers of the Rb1 gene. Fifteen adenomas (28·8%) showed LOH. Regarding the BRCA2 gene, 46 tumour–leucocyte pairs were informative and LOH was present in eight (17·4%). All six carcinomas had LOH for at least one marker at the Rb1 locus. LOH for the BRCA2 microsatellite was found in three of the five informative primary tumour samples. Immunohistochemical analysis revealed that all adenomas were positive and the number of pRb‐positive cells varied significantly among different samples. The mean percentage of stained cells was 15·7%. Eleven of the 30 (36·7%) adenomas showed sparse positive staining, 13 (43·3%) intermediate staining and six (20%) extensive staining. All parathyroid cancers were entirely negative for pRb immunostaining.

conclusions  Inactivation of the Rb1 gene is a common event in parathyroid tumorigenesis. Retention of heterozygosity seems to exclude parathyroid malignancy, which is suggested by the combined finding of LOH and lack of protein expression.
Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome
Authors: Gambineri Alessandra , Pelusi Carla , Genghini Silvia , Morselli‐Labate Antonio Maria , Cacciari Mauro , Pagotto Uberto , Pasquali Renato
Published: December 2004

background  Hyperandrogenism, hyperinsulinaemia and obesity play a key and coordinating roles in the pathogenesis of polycystic ovary syndrome (PCOS), contributing in different ways to the clinical expression of the syndrome. Weight loss is beneficial, but the additional administration of insulin‐lowering drugs, such as metformin, and antiandrogens may produce further benefits, due to their different spectrum of action. The effects of long‐term metformin and flutamide, an antiandrogen drug, added alone or in combination with a low‐calorie diet, on body weight and fat distribution, androgens, metabolic parameters and clinical status in obese women with PCOS were investigated.

methods  Forty obese women with PCOS were enrolled in the study. After a 1‐month diet, according to single‐blind design, the patients were allocated to treatment with placebo, metformin (850 mg/orally, twice daily), flutamide (250 mg/orally, twice daily) or metformin (850 mg/orally, twice daily) + flutamide (250 mg/orally, twice daily) for the following 6 months, while continuing hypocaloric dieting. At baseline and at the end of the study, sex hormone, SHBG, lipid, insulin and insulin sensitivity determinations were evaluated. At the same time, clinical parameters such as anthropometry, total (TAT), visceral (VAT) and subcutaneous (SAT) adipose tissue, hirsutism and menses were also measured.

results  We found that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment had some specific additional favourable effects with respect to the low‐calorie diet alone. In particular, flutamide treatment seemed to add a significant effect in decreasing visceral fat, androstenedione, DHEA‐S, total and low density lipoprotein (LDL) cholesterol and in improving hirsutism. Conversely, metformin had significant benefits on the menstrual status. The two drugs showed an additive effect in reducing testosterone concentrations and a synergistic effect in increasing high density lipoprotein (HDL) cholesterol and SHBG levels. Improvement of insulin sensitivity and hyperinsulinaemia appeared to depend on hypocaloric diet, without any further significant effect of the pharmacological treatments, either alone or in combination.

conclusions  We conclude that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment appears to have a more favourable outcome on body fat distribution, androgens, lipids, hirsutism and menses. However, our data emphasize the dominant role of hypocaloric dieting in improving insulin resistance and hyperinsulinaemia. Therefore, this study provides a rationale for specifically targeting different therapeutical options for PCOS according to the required outcomes.
Insulin resistance and endothelial dysfunction in the brothers of Indian subcontinent Asian women with polycystic ovaries
Authors: Kaushal R. , Parchure N. , Bano G. , Kaski J‐C. , Nussey S. S.
Published: December 2004

background  Ultrasonographic appearances of polycystic ovaries (PCO) are found in 50% of South London Indian subcontinent Asians, a population at high risk of coronary disease and type 2 diabetes (DM). PCO is a familial condition but the genetics remain to be clarified. At present, the only characteristic documented in male family members is premature male pattern balding before the age of 30 years. Our aim was to quantify insulin resistance and endothelial cell function in the brothers of Indian subcontinent Asian women with PCO and/or a family history of type 2 DM.

methods  Indian subcontinent Asian women (n = 40, age 16–40 years) with a brother available for study were recruited from the local population. They were stratified into four groups according to the ultrasound appearances of PCO and/or a family history of type 2 DM. Control subjects had no PCO and no family history of DM. Insulin sensitivity (KITT) was measured using a short insulin tolerance test and endothelial function using brachial artery ultrasound to measure flow‐mediated dilatation (FMD).

findings  Groups were well matched for age, body mass index (BMI) and waist–hip circumference ratios. Asian women with PCO demonstrated insulin resistance independent of BMI or family history of diabetes. Women with PCO and a family history of DM have reduced FMD, though PCO alone was not a marker. The brothers of women with PCO also have insulin resistance, comparable to that associated with a family history of type 2 DM. This was associated with elevations of blood pressure, abnormalities in serum lipid concentrations and impaired endothelial cell function. Endothelial cell function was particularly impaired in those subjects with both a sister with PCO and a family history of DM.

interpretation  In an ethnic minority population at higher risk of coronary heart disease, brothers of women with PCO have evidence of insulin resistance and endothelial cell dysfunction in early adult life. Further study is required to establish whether these findings are associated with an increased incidence of cardiovascular events in this population.
Prevalence and determinants of left ventricular hypertrophy in acromegaly: impact of different methods of indexing left ventricular mass
Authors: Vitale Giovanni , Galderisi Maurizio , Pivonello Rosario , Spinelli Letizia , Ciccarelli Antonio , De Divitiis Oreste , Lombardi Gaetano , Colao Annamaria
Published: December 2004

background  Left ventricular hypertrophy (LVH) is the most common cardiac abnormality in acromegaly. Left ventricular mass (LVM) is an important parameter measured to detect LVH, but the relationship with body size should be considered by correcting LVM to body surface area (BSA), height or height2·7. All trials concerning acromegaly have detected LVH on the basis of LVM indexed for BSA, but have been criticized for disregarding the effects of obesity.

patients and measurements  97 patients with active acromegaly and a control group of 97 nonacromegalic subjects, were compared for the prevalence of LVH, calculated with different corrections of LVM for BSA, height and height2·7. In addition, we evaluated determinants of LVH in acromegalic group.

results  In controls, the prevalence of LVH, determined by correcting LVM for BSA (10·3%) was significantly lower than correcting by LVM/height (21·6%, P = 0·05) and LVM/height2·7 (33%, P < 0·0001). Similarly, in the acromegalic population the prevalence of LVH was significantly higher when measured by LVM/height (86·6%) or LVM/height2·7 (89·7%), than by LVM/BSA (67%) (P = 0·002 and P < 0·0001, respectively). A lower prevalence of LVH detected by LVM/BSA than LVM/height and LVM/height2·7 has been observed in an acromegalic overweight group, while in patients with normal weight there was no significant differences using different corrections. In acromegalic patients with disease duration of ≤ 10 years the prevalence of LVH by correcting LVM for height2·7 was higher than when correcting for BSA. No difference in the prevalence of LVH determined by different corrections was observed in patients with disease duration > 10 years. By separate multiple regression analyses systolic blood pressure was the only independent determinant of LVM/BSA or LVM/height, while systolic blood pressure and GH levels were both predictors of LVM/height2·7.

conclusions  LVM indexed for height2·7 appears to be the most appropriate method to identify LVH in acromegaly, particularly in overweight patients and those with shorter disease duration.
Efficacy of Sandostatin® LAR® (long‐acting somatostatin analogue) is similar in patients with untreated acromegaly and in those previously treated with surgery and/or radiotherapy
Authors: Ayuk John , Stewart Susan E. , Stewart Paul M. , Sheppard Michael C. ,   the European Sandostatin LAR Group
Published: December 2004

background and objectives  Somatostatin analogues have been used as an adjunct to surgery and radiotherapy in the treatment of acromegaly for over 15 years, but debate surrounds their use as primary therapy. Newman suggested that octreotide was equally effective as primary or adjuvant therapy, but the effects of previous surgery/radiotherapy may have led to a preselection bias. In an attempt to eliminate this bias, the efficacy of the depot somatostatin analogue Sandostatin® LAR® as primary and adjuvant therapy has been assessed using GH and IGF‐I levels at diagnosis as baseline values.

design  We retrospectively analysed the GH and IGF‐I data from a large multicentre study in which patients’ biochemical response to treatment with the depot somatostatin analogue Sandostatin LAR as primary and adjuvant therapy was assessed. We used GH and IGF‐I levels at diagnosis as baseline values to eliminate any preselection bias.

patients and results  In 91 patients (42 male) studied, mean serum GH fell from 36·2 ± 3·3 µg/l (SEM) at diagnosis to 2·2 ± 0·2 µg/l after 48 weeks of treatment (P < 0·0001). In the primary (n = 34) and adjuvant (n = 57) therapy groups, mean GH fell from 30·7 ± 5·7 to 2·6 ± 0·4 µg/l (P < 0·0001) and from 39·5 ± 4·1 to 2·0 ± 0·2 µg/l (P < 0·0001), respectively. Sixty‐two percent of patients in the primary therapy group and 70% in the adjuvant therapy group achieved GH < 2 µg/l. Serum IGF‐I levels were available in 67 patients (34 male). In the primary therapy group (n = 25) mean IGF‐I fell from 764 ± 68 to 414 ± 31 µg/l (P < 0·0001) at 48 weeks. In the adjuvant therapy group (n = 42) mean IGF‐I was 666 ± 50 µg/l, falling to 384 ± 30 µg/l (P < 0·0001) at 48 weeks. 72% of patients achieved normal age‐related IGF‐I‐values. There were no statistically significant differences in GH or IGF‐I levels between the primary and adjuvant therapy groups at diagnosis, pre Sandostatin LAR or after 48 weeks of treatment.

conclusion  This retrospective study demonstrates that in a group of patients with similar diagnostic GH and IGF‐I levels, Sandostatin LAR was equally effective as primary therapy in acromegalic patients as in patients previously treated with surgery and/or radiotherapy.
Ghrelin secretion is modulated in a nutrient‐ and gender‐specific manner
Authors: Greenman Yona , Golani Nehama , Gilad Susan , Yaron Mariana , Limor Rona , Stern Naftali
Published: December 2004

background  Ghrelin is a potent GH secretagogue that also plays an important role in appetite and weight regulation. Ghrelin increases hunger and food intake, and its levels decrease after a standard meal or glucose.

objective  To examine the effects of standard oral glucose, lipid and protein loads on ghrelin levels, investigating the possibility that these responses may be modulated by several anthropometric and metabolic factors.

subjects and methods  There were 24 adult nondiabetic subjects (13 men/11 women; mean age 55·3 ± 2·9 years, range 26–74 years). Each participant underwent one or more of the following nutrient loads: (i) a standard oral glucose (75 g) load (n = 18); (ii) an oral lipid load (40 g, with 24 g saturated fat; n = 13); (iii) an oral protein load (40 g; n = 11).

results  Fasting ghrelin levels were negatively related to body mass index (BMI; r =−0·47; P = 0·02), waist circumference (r = −0·58; P = 0·0028), waist/hip ratio (r = −0·56; P = 0·0046), fasting insulin (r = −0·44, P = 0·03), and homeostasis model assessment insulin resistance index (HOMA‐R; r = −0·43, P = 0·034). Glucose load induced a decrease in ghrelin levels (P < 0·0001), and this response was modulated by sex (P < 0·0001), in that levels were significantly higher in females. The presence of obesity affected ghrelin response to glucose (< 0·0217), in that log‐transformed ghrelin levels started to increase back to baseline after its initial decline earlier in obese than in lean subjects. Ghrelin levels after a glucose load were lower over time in subjects with more pronounced insulin resistance (P < 0·0001). Similarly, ghrelin levels decreased significantly following the lipid meal (P = 0·035), and were modulated by HOMA‐R (P = 0·027) and gender (P = 0·029). Protein did not affect ghrelin levels.

conclusions  This study demonstrates that ghrelin levels respond in a different manner to glucose, lipid and protein loads, and are subject to modulation according to gender, obesity and insulin sensitivity.
Reduced p18INK4c, p21CIP1/WAF1 and p27KIP1 mRNA levels in tumours of primary and secondary hyperparathyroidism
Authors: Buchwald Pamela Correa , Åkerström Göran , Westin Gunnar
Published: December 2004

objective  Hyperparathyroidism (HPT) refers to states of excessive production of parathyroid hormone (PTH). The eukaryotic cell cycle is driven forward by cyclins and their cyclin‐dependent kinase (CDK) partners. Cyclin‐dependent kinase inhibitors (CKIs), which generally inhibit cell cycle progression, modulate the activity of cyclin–CDK complexes.

design  In order to quantify the expression of the CKI genes p18, p21, and p27 semiquantitative RT–PCR with mRNA specific‐primers was performed on four normal parathyroid biopsies, 31 parathyroid adenomas of primary HPT and 13 hyperplastic glands from uraemic patients with secondary HPT.

patients  Parathyroid adenomas and secondary hyperplastic glands were obtained from 31 and 13 randomly selected patients undergoing parathyroidectomy in the clinical routine, respectively. Four normal parathyroid gland biopsies were obtained at surgery for pHPT or from normocalcemic patients undergoing thyroidectomy for goitre.

results  The relative p27 expression (p27/GAPDH) was significantly reduced in parathyroid adenomas compared to normal parathyroid gland biopsies. Furthermore, 42% and 53% of the parathyroid adenomas displayed undetectable p18 and p21 expression levels, respectively. All 13 adenomas that lacked p18 expression showed undetectable p21 expression. The p18 expression was significantly lower in tumours of uraemic sHPT as compared to normal parathyroids and an undetectable expression level was observed for p21 and p27 in 61% and 53%, respectively.

conclusion  Parathyroid adenomas and secondary hyperplastic glands exhibit aberrant reduced expression of the CKIs p18, p21, and p27. This suggests that deranged collaboration of different CKIs may contribute to the development of both primary and secondary HPT.
Unchanged fasting and postprandial adiponectin levels following a 4‐day caloric restriction in young healthy men
Authors: Imbeault Pascal , Pomerleau Marjorie , Harper Mary Ellen , Doucet Éric
Published: December 2004

objective  Adiponectin is an adipocyte‐secreted protein that has been shown to promote fat oxidation and insulin sensitivity in animals. Whether acute energy restriction is associated with modulation of adiponectin in humans remains largely unknown. The purpose of this study was to examine the effects of a short‐term caloric restriction on fasting and postprandial adiponectin levels in young healthy men.

research design and methods  Fifteen young healthy men were subjected to a 4‐day energy restricted diet (−800 kcal/day). Before and after the intervention, anthropometric measurements, fasting and postprandial glucose, insulin and adiponectin were measured at 0, 30 and 60 min after a fixed breakfast.

results While fat mass remained stable, minor but significant changes in weight were observed after the 4‐day energy‐restricted diet. Glucose and insulin levels increased postprandially, and patterns did not differ before and after the intervention. Fasting levels of adiponectin remained unchanged after the energy restriction, and postprandial levels were not significantly different from fasting levels either before, or after, the intervention.

conclusions Fasting and postprandial adiponectin levels are not acutely modulated by a short‐term energy restriction in young healthy men.
The effects of GH replacement in adult GH‐deficient patients: changes in body composition without concomitant changes in the adipokines and insulin resistance
Authors: Hana Vaclav , Silha Josef V. , Justova Vlasta , Lacinova Zdena , Stepan Jan J. , Murphy Liam J.
Published: December 2004

background  Growth hormone deficiency (GHD) in adult life has been associated with increased central adiposity, decreased insulin sensitivity, dyslipidaemia and increased risk of cardiovascular disease. The effects of GH replacement on adiponectin and resistin, adipokines which have a role in modulating insulin sensitivity have not been previously reported.

aim  To examine the effects of GH replacement on adipokine levels and insulin resistance in GHD patients.

design  Seventeen adult GHD patients were examined at baseline and after 1 year of treatment with recombinant human GH (mean dose 0·31 mg/day, range 0·13–0·67 mg/day).

results  GH replacement significantly increased IGF‐I levels. The mean IGF‐I SD score increased from − 1·98 at baseline to 0·76 at study end. GH replacement was associated with a significant reduction in percentage body fat (34·11 ± 1·33 vs. 30·65 ± 1·27%, P < 0·0005) and a significant increase in lean body mass (63·57 ± 1·24 vs. 66·96 ± 1·18%, P < 0·0004), before and after treatment, respectively. Surprisingly, there was no effect of GH replacement on the plasma levels of leptin, resistin or adiponectin or on plasma lipid profile. Insulin sensitivity did not deteriorate during GH replacement despite the known ‘anti‐insulin’ effect of GH. Fasting glucose, insulin and insulin resistance as calculated using the homeostasis model assessment insulin resistance index (HOMA‐R) were unchanged by GH treatment.

conclusion  These data demonstrate GH replacement in adult subjects with GHD is effective in changing body composition and restoring IGF‐I levels over a 12‐month period; however, in our study, these changes were not accompanied by changes in adipokine levels or beneficial effects on plasma lipids or insulin resistance.
Sex hormones in hereditary angioneurotic oedema
Authors: Visy B. , Füst G. , Varga L. , Szendei G. , Takács E. , Karádi I. , Fekete B. , Harmat G. , Farkas H.
Published: December 2004

objective  The fluctuations in sex hormone levels at the beginning of adolescence, in the perimenopausal period, during pregnancy or during the use of oral contraceptives can precipitate oedematous attacks in hereditary angioneurotic oedema (HANO). Attacks usually disappear after the onset of menopause. This study was undertaken to establish any relationship between the serum levels of sex hormones and the incidence of HANO attacks.

patients and measurements  Serum levels of LH, FSH, progesterone, oestradiol, testosterone, PRL and SHBG were measured in 78 patients [mean age 30·3 years (range 4–70 years)] with HANO. A questionnaire was used to explore the medical history of adult patients to characterize the evolution and the characteristics of attacks.

results  The number of attacks was significantly higher [odds ratio (OR) 6·36 (1·31–30·81); P = 0·022] in females with high progesterone levels (≥ 4 nmol/l), irrespective of age, menstrual cycle and danazol dose. The OR was even higher [13·4 (2·2–81·4); P = 0·005] when only subcutaneous attacks were considered. Multiple logistic regression analysis demonstrated a significantly lower attack frequency during 1‐year follow‐up in patients with a higher (40 nmol/l) SHBG level (OR 0·25 (0·07–0·90); P = 0·034). This difference existed independently of age and danazol dose.

conclusion  In view of these results, the monitoring of progesterone and SHBG levels can prove useful in the prediction of attacks in hereditary angioneurotic oedema.
The endocrine response to acute ghrelin administration is blunted in patients with anorexia nervosa, a ghrelin hypersecretory state
Authors: Broglio F. , Gianotti L. , Destefanis S. , Fassino S. , Abbate Daga G. , Mondelli V. , Lanfranco F. , Gottero C. , Gauna C. , Hofland L. , Van der Lely A. J. , Ghigo E.
Published: December 2004

objective  Ghrelin, a gastric‐derived natural ligand of the GH secretagogue (GHS)‐receptor (GHS‐R), strongly stimulates GH secretion but also possesses other neuroendocrine actions, stimulates food intake and modulates the endocrine pancreas and energy homeostasis. Ghrelin secretion is negatively modulated by food intake. Similarly, glucose and also insulin probably exert an inhibitory effect on ghrelin secretion. Fasting ghrelin levels are reduced in obesity, elevated in anorexia nervosa and restored by weight recovery. The chronic elevation of circulating ghrelin levels in anorexia suggested the hypothesis of an alteration of the sensitivity to the orexigenic action of ghrelin in this condition. The aim of this study was to define the endocrine actions of ghrelin in patients with anorexia nervosa.

design  We enrolled nine women with anorexia nervosa of restricter type [AN; age (mean ± SEM) 24·2 ± 1·8 years; body mass index (BMI) 14·7 ± 0·4 kg/m2] and seven normal young women in their early follicular phase as control group (NW; age 30·6 ± 3·1 years; BMI 20·3 ± 0·5 kg/m2).

measurements  In all the subjects we studied the GH, PRL, ACTH, cortisol, insulin and glucose responses to acute ghrelin administration (1·0 µg/kg as i.v. bolus). The GH response to GHRH (1·0 µg/kg as i.v. bolus) and basal ghrelin and IGF‐I levels were also evaluated in all the subjects.

results  Basal morning ghrelin and GH levels in AN (643·6 ± 21·3 ng/l and 10·4 ± 0·5 µg/l, respectively) were higher (P < 0·05) than in NW (233·5 ± 14·2 ng/l and 0·7 ± 0·7 µg/l, respectively). However, IGF‐I levels in AN (145·3 ± 10·9 µg/l) were lower (P <  0·05) than in NW (325·4 ± 12·6 µg/l). The GH response to GHRH in AN was higher (P < 0·05) than that in NW, but in AN the GH response to ghrelin was lower (P < 0·05) than that in NW. In AN and NW ghrelin also induced similar increases (P < 0·05) in PRL, ACTH and cortisol levels. Ghrelin administration was followed by significant increase in glucose levels in NW (P < 0·05) but not in AN.

conclusions  This study demonstrates that anorexia nervosa, a clinical condition of ghrelin hypersecretion, shows a specific reduction in the GH response to ghrelin, despite the hyper‐responsiveness to GHRH administration. The impaired GH response to ghrelin in anorexia nervosa agrees with previous evidence of blunted GH response to synthetic GH secretagogues and could reflect desensitization of the GHS receptor induced by the chronic elevation of ghrelin levels in this pathological state.
Circulating ghrelin levels in the newborn are positively associated with gestational age
Authors: Bellone S. , Rapa A. , Vivenza D. , Vercellotti A. , Petri A. , Radetti G. , Bellone J. , Broglio F. , Ghigo E. , Bona G.
Published: December 2004

objective  Ghrelin exerts potent GH‐releasing activity and stimulates food intake. Circulating ghrelin levels are increased in anorexia and cachexia, reduced in obesity and restored by weight recovery. Newborns are characterized by GH hypersecretion associated with low IGF‐I levels reflecting peripheral GH resistance.

study design  The aim of our study was to measure cord ghrelin levels in 117 newborns appropriate for gestational age, born either at term or preterm.

results  Ghrelin levels in cord blood (median; 25th−75th centile: 327·6; 206·0–413·0 pg/ml) were higher (P < 0·0001) than those in maternal blood at delivery (133·0; 89·0–173·7 pg/ml), without gender differences. A positive correlation between ghrelin levels in mothers and newborns (r = 0·26, P < 0·01) was observed. Ghrelin levels in newborns born at term (399·0; 229·0–438·0 pg/ml) were remarkably higher (P < 0·0001) than those in born preterm (208·0; 144·5–278·9 pg/ml). A clear positive association was present between ghrelin levels and gestational age. No association between ghrelin and GH, IGF‐I, insulin, glucose and leptin levels were found.

conclusions  Cord ghrelin levels show clear gestational age‐related dependency. The lack of any direct relationship between ghrelin and anthropometric or biochemical parameters in adequate for gestational age newborns does not support the hypothesis that ghrelin has major role in foetal GH secretion and growth.
Neuroendocrine dysfunction in the acute phase of traumatic brain injury
Authors: Agha Amar , Rogers Bairbre , Mylotte Darren , Taleb Faisal , Tormey William , Phillips Jack , Thompson Christopher J.
Published: December 2004

background  Pituitary hormone abnormalities have been reported in up to 50% of survivors of traumatic brain injury (TBI) who were investigated several months or longer following the event. The frequency of pituitary dysfunction in the early post‐TBI period is unknown.

aim  To evaluate the prevalence of anterior and posterior pituitary dysfunction in the early phase following TBI.

subjects  Fifty consecutive patients admitted to the neurosurgical unit with severe or moderate TBI [initial Glasgow Coma Scale (GCS) score 3–13], and 31 matched healthy control volunteers were studied.

methods  The glucagon stimulation test (GST) was performed at a median of 12 days (range 7–20) following TBI. Baseline thyroid function, PRL, IGF‐1, gonadotrophins, testosterone or oestradiol, plasma sodium, plasma and urine osmolalities or the standard observed water deprivation test were performed. The control subjects underwent the GST for GH and cortisol responses; other parameters were compared to locally derived reference ranges.

results  Control data indicated that peak serum GH of > 5 ng/ml and cortisol > 450 nmol/l following glucagon stimulation should be taken as normal. Nine TBI patients (18%) had GH response < 5 ng/ml (12 mU/l). Eight patients (16%) had peak cortisol responses < 450 nmol/l. Compared to controls, basal cortisol values were significantly lower in patients with subnormal cortisol responses to glucagon and significantly higher in patients with normal cortisol responses (P < 0·05). GH and cortisol deficiencies were unrelated to patient age, BMI, initial GCS or IGF‐1 values (P > 0·05). Forty patients (80%) had gonadotrophin deficiency, with low sex steroid concentrations, which was unrelated to the presence of hyperprolactinaemia. In males there was a positive correlation between serum testosterone concentration and GCS (r = 0·32, P = 0·04). One patient had TSH deficiency. Hyperprolactinaemia was present in 26 patients (52%) and serum PRL levels correlated negatively with the GCS score (r =−0·36, P = 0·011). Thirteen patients (26%) had cranial diabetes insipidus (DI) and seven (14%) had syndrome of inappropriate ADH secretion.

conclusion  Our data show that post‐traumatic neuroendocrine abnormalities occur early and with high frequency, which may have significant implications for recovery and rehabilitation of TBI patients.
Interest of Chromogranin A for diagnosis and follow‐up of endocrine tumours
Authors: Nehar D. , Lombard‐Bohas C. , Olivieri S. , Claustrat B. , Chayvialle J‐A. , Penes M‐C. , Sassolas G. , Borson‐Chazot F.
Published: December 2004

objective  To determine the interest of Chromogranin A (CgA) determination for diagnosis and follow‐up in patients with gastroenteropancreatic endocrine tumours (GEP‐ET) and multiple endocrine neoplasia type 1 (MEN‐1).

patients and methods  CgA levels were measured with an immunoradiometric assay in 124 sporadic GEP‐ET, 34 MEN‐1 and 127 controls. Serial determinations were performed in 56 patients (212 visits). Changes in CgA levels over 25% were considered as significant.

results  Using a cut‐off value of 130 µg/l, established from a receiver‐operating characteristic curve, the specificity of CgA was 98·4%, with a sensitivity of 62·9%, higher in secreting than in nonsecreting tumours (73%vs. 45%; P < 0·003) and related to the extent of metastatic spreading (P < 0·001). In nonsecreting tumours, the positive predictive value (PPV) of CgA for the presence of metastases was 100% but the negative predictive value (NPV) was only 50%. In MEN‐1, high CgA levels indicated a pancreatic tumour with a 100% specificity but the sensitivity was 59%. During the follow‐up, the concordance between CgA and tumour evolution was 80%, whatever the secretory status. In patients with carcinoid tumours, the concordance was higher for CgA than for serotonin (81%vs. 54%; P < 0·001).

conclusion  Due to its high specificity, CgA determination may help to discriminate the endocrine character of a GEP tumour and to indicate a pancreatic tumour in MEN‐1. However, its low NPV in nonsecreting tumours limits its interest for diagnosis and staging. By contrast, serial evaluation of CgA seems of particular interest for the follow‐up of GEP‐ET tumours.