bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunological characterization of Echinococcus granulosus cyclophilin, an allergen reactive with IgE and IgG4 from patients with cystic echinococcosis
Authors: ORTONA E , VACCARI S , MARGUTTI P , DELUNARDO F , RIGANÒ R , PROFUMO E , BUTTARI B , RASOOL O , TEGGI A , SIRACUSANO A
Published: March 2003

By immunological screening of a cDNA library derived from protoscoleces of Echinococcus granulosus with IgE from patients with cystic echinococcosis (CE) and allergic manifestations, we isolated a protein identical to E. granulosus cyclophilin. The protein, named EA21, has close homology with Malassezia furfur cyclophilin allergen (Mal f 6) and with human cyclophilin. Using immunoblotting (IB) with a polyclonal antibody specific to EA21, we identified E. granulosus cyclophilin both in protoscoleces and in sheep hydatid fluid. Of the 58 sera from patients with CE, 29 (50%) were IgE positive to EA21, whereas, despite the high sequence homology, none were IgE positive to Mal f 6 or human cyclophilin. Only 26 of the 58 patients (45%) had IgG specific to EA21, whereas all patients (100%) had IgG specific to Mal f 6 and human cyclophilin. IB analysis showed that serum IgE-binding reactivity to EA21 differed significantly in patients with and without allergic reactions (20 of 25, 80%versus nine of 33, 27%; P < 10–4). Conversely, five of the 25 patients who had CE-related allergic manifestations (20%) and 21 of the 33 who did not (63%) had specific IgG4 (P = 10–3) and total IgG to EA21. EA21 induced a proliferative response in 15 of 19 (79%) patients’ PBMC regardless of the allergic manifestations, but it induced no IL-4 production. Overall, these findings suggest that E. granulosus cyclophilin is a conserved, constitutive, parasite protein that does not cross-react with cyclophilins from other organisms and is involved in the allergic symptoms related to CE.
Autoantibodies to photoreceptor membrane proteins and outer plexiform layer in patients with cancer-associated retinopathy
Authors: PEEK R , DIJKSTRA B G , MEEK B , KUIJPERS R W A M
Published: March 2003

Cancer-associated retinopathy (CAR) is a paraneoplastic syndrome that is characterized by degeneration of the retina as a remote effect of cancer outside the eye. The detection of autoantibodies associated with the retinopathy may precede the diagnosis of the underlying cancer. We have examined the sera of two patients with CAR by Western blot analysis. Autoantibodies to a 40kD antigen doublet and a 35 kD antigen were detected. Tissue specificity of the autoantigens was determined by testing several different tissues. The 40 kD antigen doublet was most abundant in retinal extract but was also present in lung and spleen extracts. The 35 kD antigen showed little tissue specificity and was present in all tissues tested. Fractionation of retinal proteins into water-soluble and -insoluble proteins revealed that the 40 kD antigen doublet was highly insoluble and probably represented membrane-associated proteins. Immunohistochemical analysis of the retina showed that the 40 kD antigens locate to the photoreceptors while the 35 kD antigen is located in the outer plexiform layer.
Activation-induced T cell death, and aberrant T cell activation via TNFR1 and CD95-CD95 ligand pathway in stable cardiac transplant recipients
Authors: ANKERSMIT H J , MOSER B , ZUCKERMANN A , ROTH G , TAGHAVI S , BRUNNER M , WOLNER E , BOLTZ-NITULESCU G
Published: March 2003

Specific blockade by antibodies (Abs) utilized in induction therapy may cause activation-induced cell death (AICD) in lymphocytes of transplant recipients, preactivated via CD95 and tumour necrosis factor-α receptor type 1 (TNFR1), and reduce allograft rejection frequency. Amongst 618 heart transplant (HTX) patients receiving antithymocytes globulin (ATG) therapy, 14 recipients with IVUS-verified freedom of transplant vasculopathy were studied. The control group contained 14 patients awaiting transplantation, classified by the New York Hearth Association heart failure as class IV. From 618 HTX patients 89% were free of rejection grade ISHLT ≥2–3 within 3-month post transplantation and 86% after one year. The death inducing receptors (DIR) such as CD95, CD95L and soluble TNFR1 were significantly increased in HTX recipients versus controls, as demonstrated by FACS, immunoblotting or ELISA (P < 0·001). The presence of increased DIR and in vivo apoptosis in HTX recipients, indicated by annexin-V binding, was further confirmed by the presence of high concentration of histones in the sera of patients. ATG, anti-IL-2R and OKT-3 Abs inhibited cell proliferation in a dose-dependent manner. The induction of apoptosis and/or necrosis was demonstrated in cells cultured with these Abs by annexin-V and 7-aminoactinomycin staining, respectively. Our findings demonstrate that T cells from HTX recipients express high level of CD95, CD95L and soluble TNFR1, and undergo apoptosis and AICD. These cells recognizing donor alloantigens may be selectively eliminated in vivo, and should be responsible for the observed immunological unresponsiveness, indicated by low rejection rates in our patient cohort treated by conventional triple therapy.
Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection
Authors: ZUCKERMAN E , SLOBODIN G , KESSEL A , SABO E , YESHURUN D , HALAS K , TOUBI E
Published: March 2003

Hepatitis C virus (HCV) infection is associated with immune-mediated abnormalities and B-cell lymphoproliferation evolving to an overt lymphoma. Recently, CD81 was identified as an HCV receptor on B-lymphocytes, providing a mechanism by which B cells are infected and activated by the virus. In addition, expansion of CD5+ B lymphocytes was described to be associated with various non-HCV related autoimmune disorders. Therefore, we studied the possible role of peripheral B cells CD81 and CD5 over-expression in the development of HCV-related autoimmunity and their association with disease severity in chronic HCV infection. Peripheral B cells CD5 expression and mean fluorescence intensity (MFI) of CD81 were determined in 30 HCV-infected patients, 30 healthy controls and 15 patients with hepatitis B virus infection using fluorescence-activated cell scan (FACS). We have also investigated the association between peripheral CD5 and CD81 B-cell over-expression and markers of autoimmunity and disease severity in patients chronically infected by HCV. CD5+ B-cells were increased in chronic HCV infection (23·2 ± 7·2%) compared with those of healthy controls (15 ± 5·5%) (P < 0·0001) and chronic HBV infection (19 ± 3·7%) (P = 0·08). CD81 MFI was significantly higher in HCV-infected compared to HBV-infected patients and healthy controls. Both increased CD81 MFI and CD5+ B-cell expansion were associated with the production of rheumatoid factor and mixed cryoglobulins and positively correlated with HCV viral load and histological activity index. The overexpression of CD81 and the expansion of CD5+ peripheral B-cells in HCV-infected patients may possibly play a role in the development of HCV-associated autoimmunity and lymphoproliferation.
Increased expression of interleukin-13 but not interleukin-4 in CD4+cells from patients with the hyper-IgE syndrome
Authors: GUDMUNDSSON K O , SIGURJONSSON O E , GUDMUNDSSON S , GOLDBLATT D , WEEMAES C M R , HARALDSSON A
Published: March 2003

Hyper IgE syndrome (HIES) is a rare immunodeficiency disorder characterized mainly by high levels of polyclonal IgE in serum and recurrent staphylococcal abscesses of the skin and lungs. The raised IgE levels have led researchers to study the synthesis of cytokines that regulate switching of immunoglobulin production towards IgE such as interleukin-4 (IL-4), IL-12 and interferon-γ (IFN)-γ. However, the role of IL-13 in the disease pathogenesis has not been investigated extensively. In this study, we investigated intracellular expression of IL-4 and IL-13 in mononuclear cells and CD4+ cells isolated from patients with HIES and healthy controls. Cells were stained intracellularly with antibodies directed against IL-4 and IL-13 and analysed by flow cytometry before and after activation with PMA and calcium ionophore. The mean proportion of resting or activated IL-4 and IL-13 expressing mononuclear cells were comparable in the two groups as well as the proportion of IL-4 expressing CD4+ cells. In contrast, the mean proportion of IL-13 expressing CD4+ cells was increased significantly in patients with HIES in both the resting and the activated state compared to healthy controls. We conclude that increased expression of IL-13 in CD4+ cells from patients with HIES could account, at least partly, for raised IgE levels in those individuals.
Mice lacking the multidrug resistance protein 1 have a transiently impaired immune response during tuberculosis
Authors: VERBON A , LEEMANS J C , WEIJER S , FLORQUIN S , VAN DER POLL T
Published: March 2003

A T helper (Th) 1 immune response is important for host defense against tuberculosis. The multidrug resistance protein (Mrp) 1 is constitutively present at low levels on Th2 lymphocytes, and is expressed on Th1 lymphocytes upon activation. To determine the role of Mrp1 in the pathogenesis of tuberculosis, Mrp1 deficient (–/–) and normal wild type mice were intranasally infected with Mycobacterium tuberculosis. At 2 weeks after infection, Mrp1(–/–) mice had reduced levels of the Th1 cytokine interferon-γ and an impaired granuloma formation in their lungs. At 5 weeks postinfection, M. tuberculosis outgrowth was enhanced in lungs and livers of Mrp1(–/–) mice. A more prolonged observation of these mice, up to 4 months, revealed no differences in survival or mycobacterial outgrowth. These data suggest that Mrp1 plays an early but dispensable role in the protective immune response to pulmonary tuberculosis.
C5a is important in the tubulointerstitial component of experimental immune complex glomerulonephritis
Authors: WELCH T R , FRENZKE M , WITTE D , DAVIS A E
Published: March 2003

Interstitial injury is the hallmark of glomerulonephritis which is progressing to end-stage renal disease (ESRD). In humans and experimental animals, we have shown that interstitial disease is accompanied by up-regulation of complement components in tubular epithelial cells. Glomerulonephritis was induced in mice by the intraperitoneal injection of horse spleen apoferritin (HSA) and lipopolysaccharide (LPS). In addition to wild-type C57/B6 mice, animals in which the C5a receptor had been deleted (C5aR KO) were used. Animals were killed after 3 or 6 weeks, and kidneys harvested. At three weeks, both groups had evidence of mild mesangial matrix expansion and increased cellularity; there were no crescents, sclerotic lesions, or interstitial disease. At six weeks, glomerular lesions were advanced, but identical in the two groups. Both groups had evidence of an identical pattern of C3 gene expression in the tubular epithelium by in situ hybridization. There was a marked difference, however, in the extent of interstitial injury. Wild-type animals had significantly greater numbers of infiltrating interstitial cells, greater expansion of the peritubular space, more tubular atrophy, and more apoptotic tubular cells than did C5aR KOs. The anaphylotoxic fragment of C5, C5a, is not likely to be important in the glomerular component of this model of progressive glomerulonephritis. On the other hand, the interstitial component is markedly attenuated in knockout animals. These data support a role for complement in the interstitial component of this glomerulonephritis model. They are consistent with our hypotheses of a role for complement in the progression of some forms of glomerulonephritis to ESRD.
Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre
Authors: GREGOREK H , CHRZANOWSKA K H , MICHAL´KIEWICZ J , SYCZEWSKA M , MADALIN´SKI K
Published: March 2003

During an 8-year period of observation, defects of immune responses were characterized and monitored in 40 of 50 Polish children with Nijmegen breakage syndrome referred to the Children's Memorial Health Institute in Warsaw. The following parameters were determined at diagnosis: (1) concentrations of serum IgM, IgG, IgA; (2) concentrations of IgG subclasses; and (3) lymphocyte subpopulations. In addition, naturally acquired specific antibodies against Streptococcus pneumoniae were determined in 20 patients with a history of recurrent respiratory infections. During follow-up, total serum immunoglobulins and IgG subclasses were monitored systematically in 17 patients who did not receive immunomodulatory therapy. Moreover, anti-HBs antibody response was measured after vaccination of 20 children against HBV. We found that the immune deficiency in NBS is profound, highly variable, with a tendency to progress over time. Systematic monitoring of the humoral response, despite good clinical condition, is essential for early medical intervention.
A preliminary assessment of alpha-1 antitrypsin S and Z deficiency allele frequencies in common variable immunodeficiency patients with and without bronchiectasis
Authors: SANSOM M E , FERRY B L , SHERRELL Z P M C , CHAPEL H M
Published: March 2003

Common variable immunodeficiency (CVID) is the name given to a clinically heterogeneous group of hypogammaglobulinaemic immunodeficiency states. Bronchiectasis is a feature of this disease and is believed to be the result of recurrent bacterial infection affecting the respiratory tract. Bronchiectasis is also a feature associated with emphysematous changes of the lung in alpha-1 antitrypsin (AAT) deficiency, a serious and relatively common disease, affecting 1 : 2000 in the United Kingdom. This has been demonstrated to result from possession of deficiency alleles, the most clinically important alleles being PI*Z and PI*S. Isolated reports of families with antibody deficiency and AAT deficiency have been published but to date no study has been performed to specifically investigate if AAT deficiency is associated with the lung damage seen in CVID patients. We have developed a PCR genotyping assay that identifies S and Z deficiency alleles and we have used this assay in a preliminary study to investigate the occurrence of these deficiency alleles of AAT in 43 CVID patients. Results of this preliminary study suggest that CVID patients did not have an altered distribution of AAT genes when compared to 70 normal controls. Subgrouping of CVID patients into those with and without bronchiectasis demonstrated a Z allele frequency of 0·077 in those patients with bronchiectasis, which is higher than found in normal controls, namely 0·029 (P < 0·15). Due to the relatively small numbers studied, these results are inconclusive in determining whether AAT deficiency may exacerbate lung damage in some CVID patient, the data does however, indicate that a larger multi-centre study involving many more CVID patients may be useful.
Inhibition by fenoterol of human eosinophil functions includingβ2-adrenoceptor-independent actions
Authors: TACHIBANA A , KATO M , KIMURA H , FUJIU T , SUZUKI M , MORIKAWA A
Published: March 2003

Agonists at β2 adrenoceptors are used widely as bronchodilators in treating bronchial asthma. These agents also may have important anti-inflammatory effects on eosinophils in asthma. We examined whether widely prescribed β2-adrenoceptor agonists differ in ability to suppress stimulus-induced eosinophil effector functions such as superoxide anion (O2–) generation and degranulation. To examine involvement of cellular adhesion in such responses, we also investigated effects of β2 agonists on cellular adhesion and on CD11b expression by human eosinophils. O2– was measured using chemiluminescence. Eosinophil degranulation and adhesion were assessed by a radioimmunoassay for eosinophil protein X (EPX). CD11b expression was measured by flow cytometry. Fenoterol inhibited platelet-activating factor (PAF)-induced O2– generation by eosinophils significantly more than salbutamol or procaterol. Fenoterol partially inhibited PAF-induced degranulation by eosinophils similarly to salbutamol or procaterol. Fenoterol inhibited phorbol myristate acetate (PMA)-induced O2– generation and degranulation by eosinophils, while salbutamol or procaterol did not. Fenoterol inhibition of PMA-induced O2– generation was not reversed by ICI-118551, a selective β2-adrenoceptor antagonist. Fenoterol, but not salbutamol or procaterol, significantly inhibited PAF-induced eosinophil adhesion. Fenoterol inhibited O2– generation and degranulation more effectively than salbutamol or procaterol; these effects may include a component involving cellular adhesion. Inhibition also might include a component not mediated via β2 adrenoceptors.
Characteristics of immunity induced by viral antigen or conferred by antibody via different administration routes
Authors: MATSUOKA T , OKAMOTO Y , MATSUZAKI Z , ENDO S , ITO E , TSUTSUMI H , WILLIAMSON R A , SAKURAI H , BURTON D R , SAITO I
Published: March 2003

The characteristics of the immunity induced by viral antigens or conferred by antiviral antibody via different routes of administration were evaluated comparatively. C57BL/6 mice were immunized via intranasal, intradermal or enteric routes with a live recombinant vaccinia virus expressing the respiratory syncytial virus (RSV) F glycoprotein (F·rVV) or RSV, and then challenged intranasally with RSV. Inhibition of RSV replication was observed in the lungs of all the mice; however, only intranasal immunization hindered virus replication in the nose. Lung inflammation, characterized by infiltration of neutrophils and of mononuclear cells was strongest in the intradermally immunized mice, but was observed in all F·rVV immunized mice to various degrees. Intranasal administration of a potently neutralizing human anti-RSV antibody Fab fragment to infected mice inhibited RSV replication in the nose and, when combined with intraperitoneal administration, protected both the lung and the nose in the absence of deleterious lung pathology. These data suggest that intranasal immunization with F·rVV reduces RSV replication in the respiratory tract, but still induces pathological lung inflammation, even though this is milder than that observed following intradermal immunization. Local neutralizing antibody is indispensable for protection in the nose.
CD4+ T regulatory cells from the colonic lamina propria of normal mice inhibit proliferation of enterobacteria-reactive, disease-inducing Th1-cells from scid mice with colitis
Authors: GAD M , BRIMNES J , CLAESSON M H
Published: March 2003

Adoptive transfer of CD4+ T cells into scid mice leads to a chronic colitis in the recipients. The transferred CD4+ T cells accumulate in the intestinal lamina propria (LP), express an activated Th1 phenotype and proliferate vigously when exposed ex vivo to enteric bacterial antigens. As LP CD4+ T cells from normal BALB/c mice do not respond to enteric bacterial antigens, we have investigated whether colonic LP-derived CD4+ T cells from normal mice suppress the antibacterial response of CD4+ T cells from scid mice with colitis. LP-derived CD4+ T cells cocultured with bone marrow-derived dendritic cells effectively suppress the antibacterial proliferative response of CD4+ T cells from scid mice with colitis. The majority of these LP T-reg cells display a nonactivated phenotype and suppression is independent of antigen exposure, is partly mediated by soluble factor(s) different from IL-10 and TGF-β, and is not prevented by the addition of high doses of IL-2 to the assay culture. Functionally and phenotypically the T-reg cells of the present study differ from previously described subsets of T-reg cells. The presence of T cells with a regulatory potential in the normal colonic mucosa suggests a role for these cells in the maintenance of local immune homeostasis of the gut.
Benzylpenicillin differentially conjugates to IFN-γ, TNF-α, IL-1β, IL-4 and IL-13 but selectively reduces IFN-γactivity
Authors: BROOKS B M , THOMAS A L , COLEMAN J W
Published: March 2003

It is known that β-lactam antibiotics can conjugate to lysine and histidine residues on proteins via the carbonyl group of the opened β-lactam ring. However, it is not known which proteins these drugs target and there is little work addressing whether conjugation is preferential for some proteins over others or if conjugation has functional consequences for the protein. We have previously shown that the β-lactam antibiotic benzylpenicillin (BP) conjugates to IFN-γ and reduces its activity. This interaction demonstrates selectivity, as BP does not bind to IL-4. Here, we extend our study to include other Th1 and Th2 cell-associated cytokines and two cytokines associated with inflammatory responses. We demonstrate by Western blotting that BP also conjugates to IL-1β, IL-2, IL-5, IL-13 and TNF-α but not to IL-10. Densitometric analysis of leading cytokine bands on blots revealed that IFN-γ always gave more intense BP-positive bands than any other cytokine analysed. Cytokines pre-incubated with BP at 37°C in a protein-containing, serum-free medium were assayed for their biological activity. By in vitro bioassay, BP inhibited the ability of IFN-γ but not IL-1β or TNF-α to induce CD54 expression on epithelial cells. In addition, BP did not affect IL-4 or IL-13 inhibition of mast cell proliferation. When the pre-incubation temperature was reduced to 4°C, BP did not conjugate to IFN-γ or modulate its activity. BP retained its inhibitory effect on IFN-γ activity when 20% FCS was added to the pre-incubation medium. In conclusion, BP conjugates to some cytokines but not others and this does not appear to be related to primary protein structure. Furthermore, of the cytokines studied, conjugation only to IFN-γ is accompanied by inhibition of activity. This phenomenon is temperature dependent and occurs in the presence of serum. These findings provide further evidence for differential, direct drug–cytokine interactions. Such interactions may have therapeutic implications in terms of targeting cytokines to regulate their activity.
Anti-SSB/La is one of the antineutrophil autoantibodies responsible for neutropenia and functional impairment of polymorphonuclear neutrophils in patients with systemic lupus erythematosus
Authors: HSIEH S-C , YU H-S , LIN W-W , SUN K-H , TSAI C-Y , HUANG D-F , TSAI Y-Y , YU C-L
Published: March 2003

Decreased number and impaired functions of polymorphonuclear neutrophils (PMN) due to the presence of anti-PMN autoantibodies in the serum render patients with systemic lupus erythematosus (SLE) susceptible to bacterial infections. However, the cognate antigens and pathological mechanisms of anti-PMN autoantibodies in SLE are rarely reported in the literature. In this study, we found approximately 20% of SLE sera contained anti-PMN autoantibodies detected by human PMN-coated cellular ELISA. A membrane protein with molecular weight of 50 kDa was identified as the cognate antigen of anti-PMN in Western blot after membrane-biotinylation and streptavidin column elution. The 50 kDa molecule was proved to be SSB/La after immunoscreening, molecular cloning and nucleotide sequencing of the gene from the human leucocyte cDNA library. Human anti-SSB/La autoantibodies purified from active SLE sera passing through the recombinant SSB/La conjugated Sepharose 4B affinity column could bind and penetrate into normal human PMN. Functional analysis revealed that the anti-SSB/La autoantibodies exerted a number of potent effects on human PMN, including suppressed phagocytosis, accelerated apoptosis and enhanced IL-8 production. These in vitro results suggest that anti-SSB/La is one of the anti-PMN autoantibodies capable of penetrating into PMN and responsible for neutropenia and functional impairment of PMN in patients with SLE.
The prevalence of hyperprolactinaemia and association with markers of autoimmune thyroid disease in survivors of the Whickham Survey cohort
Authors: Vanderpump  , French  , Appleton  , Tunbridge  , Kendall‐Taylor
Published: March 2003

OBJECTIVE

Few data exist on the prevalence of hyperprolactinaemia in the community. This study was intended to determine the prevalence of hyperprolactinaemia in a sample closely matched to the current British population aged 38 years and over.

DESIGN AND PATIENTS

The 1877 survivors at the 20‐year follow‐up of the Whickham Survey were a cross‐sectional sample of the community aged 38 years and over. Serum was frozen and stored at −30°C from 90% of the survivors (751 men, 924 women, median age 58 years (range 38 to 93 years)) who participated in the follow‐up survey.

MEASUREMENTS

Two years after the follow‐up survey, serum prolactin concentrations were measured by ELISA/1 step sandwich assay (reference range ≤ 600 mU/l in men and women). A repeat prolactin measurement was made in those subjects who had prolactin levels within the top 2.5% of men and women in this sample.

RESULTS

At screening, 0.7% of the men and 2.5% of the women had serum prolactin levels greater than 600 mU/l. For men, 2.5% were above 400 mU/l. The prevalence of hyperprolactinaemia, if defined as greater than 400 mU/l in men and greater than 600 mU/l in women on repeat testing, was 1.4% in the men and 1.2% in the women. The aetiology in men was prolactin‐raising drugs (n = 3), renal failure (n = 1), microprolactinoma (n = 1), and unknown (n = 2), and in women it was prolactin‐raising drugs (n = 7), microprolactinoma (n = 1), and unknown (n = 1). Logarithmic transformation of serum prolactin concentrations produced Gaussian distributions with 95% reference ranges of 60–430 mU/l in men and 40–560 mU/l in women. No significant relationship was found in either sex between hyperprolactinaemia and age or evidence of autoimmune thyroid disease at either survey. In women, there was no association with age, distance beyond the menopause or duration of reproductive years but prolactin levels were slightly higher in those on oestrogen therapy (geometric mean prolactin 226 mU/l compared to 178 mU/l; t‐test on log prolactin t = 3.79; P < 0.0001).

CONCLUSIONS

This study has demonstrated that a gender‐related reference range for serum prolactin is necessary. Pituitary pathology is not common and screening with measurement of serum prolactin is not warranted in middle‐aged and elderly subjects. In asymptomatic subjects with modestly elevated serum prolactin levels (< 3 SD above the mean), extensive pituitary imaging and investigation is unwarranted. Autoimmune thyroid disease was not a significant cause of hyperprolactinaemia in this sample.
Adrenal steroid hormones in short children born small for gestational age
Authors: Dahlgren Jovanna , Boguszewski Margaret , Rosberg Sten , Albertsson‐Wikland Kerstin
Published: March 2003

OBJECTIVE

Programming of the endocrine axis has been postulated to occur during critical phases of fetal development and is affected by intrauterine growth retardation. The aim of this study was to investigate this hypothesis with regard to adrenal steroid hormones. Thus, serum cortisol and dehydroepiandrosterone sulphate (DHEAS) levels were compared in children born small for gestational age (SGA) who remained short and in children born at an appropriate size for gestational age (AGA), of both short and normal stature.

DESIGN AND PATIENTS

Seven serum samples for cortisol measurements were taken during a 24‐h period from a total of 184 prepubertal individuals. The study group comprised 53 children born SGA who remained short (41 boys, 12 girls; mean chronological age, 8.8 ± 2.5 years). The reference groups of children born AGA were as follows: 75 healthy short children (56 boys, 19 girls; mean chronological age, 10.8 ± 2.6 years) and 56 healthy children of normal height (37 boys, 19 girls; mean chronological age, 11.3 ± 1.8 years). A single serum sample for measurement of DHEAS was taken between 1000 and 1400 h in 110 of the 184 children (33 short SGA, 42 short AGA and 35 AGA of normal height).

MEASUREMENTS

Serum cortisol and DHEAS were measured by radioimmunoassay.

RESULTS

No differences were found between children born SGA and children born AGA in either cortisol levels, calculated as area under the curve (AUC), or the circadian cortisol rhythm, estimated from the calculated nadir, the peak and the amplitude. No difference between the groups was found for serum DHEAS concentrations. Serum cortisol levels, expressed as AUC, and serum DHEAS levels did not correlate with size at birth. However, when adjusted for age at investigation, serum DHEAS, but not serum cortisol, correlated with weight at birth.

CONCLUSIONS

Serum cortisol levels and rhythms do not correlate with size at birth and are similar in children born small for gestational age who remain short and children born appropriate size for gestational age of both short and normal stature. However, DHEAS levels in young children before adrenarche correlated inversely with weight at birth, indicating a relationship with fetal growth.
The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post‐menopausal women
Authors: Orr‐Walker Brandon J. , Evans Margaret C. , Ames Ruth W. , Clearwater Judith M. , Cundy Tim , Reid Ian R.
Published: March 2003

OBJECTIVE

Depot medroxyprogesterone acetate (DMPA), an injectable progestogen, is a widely used contraceptive acting primarily by inhibiting secretion of pituitary gonadotrophins, thus producing oestrogen deficiency. Cross‐sectional and prospective studies in pre‐menopausal women have shown DMPA use to be associated with reduced bone density, but bone density increases following discontinuation of the drug. Because fracture rates are low in pre‐menopausal women, the principal concern arising from the effects of DMPA on bone is that there may be residual osteopenia in former users such that their post‐menopausal fracture risk is increased. The present study addresses this question.

DESIGN

Cross‐sectional study of bone density in post‐menopausal former users of DPMA and controls.

SUBJECTS

Three hundred and forty‐six normal post‐menopausal women, of whom 34 had previously used DMPA. The median age at which DMPA use began was 41 years and the median duration of use was 3.0 years.

MEASUREMENTS

Bone density was measured in the spine, proximal femur and total body by dual‐energy, X‐ray absorptiometry.

RESULTS

There were no significant differences in bone density at any site between the women who had previously used DMPA and the others in the cohort. However, in those who had used DMPA for > 2 years there was a trend towards bone densities being lower in the former users, the differences from non‐users being 1.6% in the lumbar spine (P = 0.6), 3.1% in the femoral neck (P = 0.4) and 0.5% in the total body (P = 0.8). There was no correlation between bone densities and the duration of DMPA use, the age at discontinuation of DMPA, or the time between DMPA discontinuation and the menopause.

CONCLUSIONS

Any residual effects of depot medroxyprogesterone acetate use on post‐menopausal bone density are small and therefore unlikely to have a substantial impact on fracture risk in the post‐menopausal years.
Sleep deprivation effects on the activity of the hypothalamic–pituitary–adrenal and growth axes: potential clinical implications
Authors: Vgontzas Alexandros N. , Mastorakos George , Bixler Edward O. , Kales Anthony , Gold Philip W. , Chrousos George P.
Published: March 2003

OBJECTIVES

Although several studies have shown that sleep deprivation is associated with increased slow wave sleep during the recovery night, the effects of sleep deprivation on cortisol and growth hormone (GH) secretion the next day and recovery night have not been assessed systematically. We hypothesized that increased slow wave sleep postsleep deprivation is associated with decreased cortisol levels and that the enhanced GH secretion is driven by the decreased activity of the HPA axis.

DESIGN AND SUBJECTS

After four consecutive nights in the Sleep Laboratory, 10 healthy young men were totally deprived of sleep during the fifth night, and then allowed to sleep again on nights six and seven. Twenty‐four hour blood sampling was performed serially every 30 minutes on the fourth day, immediately following the previous night of sleep and on the sixth day, immediately after sleep deprivation.

MEASUREMENT

Eight‐hour sleep laboratory recording, including electroencephologram, electro‐oculogram and electromyogram. Plasma cortisol and GH levels using specific immunoassay techniques.

RESULTS

Mean plasma and time‐integrated (AUC) cortisol levels were lower during the postdeprivation nighttime period than on the fourth night (P < 0.05). Pulsatile analysis showed significant reduction of both the 24 h and daytime peak area (P < 0.05) and of the pulse amplitude (P < 0.01), but not of the pulse frequency. Also, the amount of time‐integrated GH was significantly higher for the first 4 h of the postdeprivation night compared to the predeprivation night (P < 0.05). Cross‐correlation analyses between the absolute values of the time‐series of each hormone value and percentage of each sleep stage per half hour revealed that slow wave sleep was negatively correlated with cortisol and positively correlated with GH with slow wave sleep preceding the secretion of these hormones. In contrast, indices of sleep disturbance, i.e. wake and stage 1 sleep, were positively correlated with cortisol and negatively correlated with GH.

CONCLUSION

We conclude that sleep deprivation results in a significant reduction of cortisol secretion the next day and this reduction appears to be, to a large extent, driven by the increase of slow wave sleep during the recovery night. We propose that reduction of CRH and cortisol secretion may be the mechanism through which sleep deprivation relieves depression temporarily. Furthermore, deep sleep has an inhibitory effect on the HPA axis while it enhances the activity of the GH axis. In contrast, sleep disturbance has a stimulatory effect on the HPA axis and a suppressive effect on the GH axis. These results are consistent with the observed hypocortisolism in idiopathic hypersomnia and HPA axis relative activation in chronic insomnia. Finally, our findings support previous hypotheses about the restitution and immunoenhancement role of slow wave (deep) sleep.
The quality of life of adults with growth hormone deficiency: comparison with diabetic patients and control subjects
Authors: Wallymahmed  , Foy  , MacFarlane
Published: March 2003

OBJECTIVE

Adults with GH deficiency (GHD) frequently report a poor quality of life (QOL). Whether this poor QOL is specifically due to hormone deficiency or a non specific effect of a chronic condition is not known. We therefore assessed QOL in adults with hypopituitarism and GHD and compared scores with a group of patients with diabetes mellitus, another life‐long condition with potentially serious complications and a group of healthy controls.

PATIENTS

We studied 57 patients with hypopituitarism and GHD (peak stimulated GH response < 9 mU/l) (23 male, mean age 36.4 years, mean stimulated GH response 2.3 mU/l), secondary to a variety of hypothalamic‐pituitary disorders. Fifty had been treated surgically (39 cranial surgery, 11 transsphenoidal) and 37 had received external cranial irradiation involving the hypothalamic region. Fifty‐seven age and sex matched patients with diabetes mellitus (31 insulin treated, 18 on oral hypoglycaemic agents, 8 on diet alone) and 57 matched healthy controls were also studied.

DESIGN AND MEASUREMENTS

We assessed and compared health related QOL in the 3 groups using 4 self rating questionnaires: Hospital Anxiety and Depression Scale, Self Esteem Scale, Mental Fatigue Questionnaire and Life Fulfilment Scale. In addition the GHD and diabetic groups also completed the Disease Impact Scale.

RESULTS

The GHD group reported significantly more depression (P < 0.05) and mental fatigue (P < 0.05) and significantly less self esteem (P < 0.05) and life fulfilment (P < 0.05) than either the group with diabetes or the controls. Patients with GHD reported significantly higher anxiety scores (P < 0.05) than the controls. Within the GHD group there were no differences in QOL scores between patients with pituitary tumours (n = 24), craniopharyngiomas/hypothalamic tumours (n = 18) or other brain tumours. In addition there were no significant differences according to surgical treatment modality or radiotherapy. However subgroup analysis revealed that the patients who had undergone transsphenoidal surgery (n = 11) differed significantly from the control group in life fulfilment and depression (P < 0.01) only and did not differ from the DM group in any of the questionnaires used. There were no significant differences between the group with diabetes and the control group in any of the measures except depression (P < 0.05).

CONCLUSIONS

This study revealed a significant impairment of QOL in adults with GHD, particularly those who had undergone cranial surgery, when compared to matched patients with diabetes and healthy controls.
The insulin resistance syndrome and the binding capacity of cortisol binding globulin (CBG) in men and women
Authors: Fernández‐Real  , Grasa  , Casamitjana  , Ricart
Published: March 2003

BACKGROUND

Both insulin resistance and cortisol binding globulin (CBG) capacity have been found to correlate with plasma free fatty acid (FFA) concentration.

OBJECTIVE

To examine the changes in CBG binding with varying degrees of insulin resistance and plasma FFA levels.

SUBJECTS AND METHODS

Anthropometric parameters, serum cortisol levels, plasma CBG, CBG binding and insulin sensitivity (using the frequently sampled intravenous glucose tolerance test with minimal model analysis) were measured in a group of 38 healthy subjects (19 men, mean age 36.2 ± 1.9; body mass index (BMI) 28.8 ± 1.2, range 22.2–35.7), and 19 women, age 34.9 ± 1.4; BMI 28.1 ± 0.8, range 19–37.9)].

RESULTS

Plasma CBG levels did not differ between men and women. In men, CBG binding was associated with several parameters of the insulin resistance syndrome, including area under the curve for glucose during an oral glucose tolerance test (MBG, r = 0.45, P = 0.04), fasting insulin (r = 0.66, P = 0.002), plasma triglycerides (r = 0.75, P < 0.0001), VLDL‐triglycerides (r = 0.59, P = 0.007), fasting FFA (r = 0.72, P = 0.002), uric acid (r = 0.57 (P = 0.01) and insulin sensitivity (SI, r = − 0.58, P = 0.008). Free cortisol (estimated as the ratio of cortisol to CBG) was not associated with waist‐to‐hip ratio (WHR) or parameters of insulin sensitivity. In contrast to men, CBG binding was not associated with MBG, fasting insulin, plasma triglycerides, VLDL‐triglycerides, FFA, uric acid or SI (all P = NS) in women. Serum free cortisol, however, correlated positively with WHR (r = 0.62, P = 0.02) and negatively with SI (r = − 0.68, P = 0.01) in obese women. A multiple linear regression to predict CBG binding was constructed, with plasma CBG concentration and insulin sensitivity as independent variables. In this model, only SI entered the equation at a statistically significant level (P = 0.0012) contributing to 52% of the variance in CBG binding in men. When plasma FFA levels were added to the model, both SI (P = 0.04) and FFA levels (P = 0.039) contributed to 66% of the variance of CBG binding in men. In women, both plasma CBG concentration (P = 0.0005) and insulin sensitivity (P = 0.047) entered the equation at a statistically significant level, contributing to 60% of the variance in CBG binding. When plasma FFA levels were added to the model, only plasma CBG concentration (P = 0.043) was found to significantly contribute to 38% of the variance in CBG binding. The latter finding suggests that FFA levels constituted a confounding variable in the association between SI and CBG binding in women.

CONCLUSIONS

Both plasma free fatty acid and insulin sensitivity influence cortisol binding globulin binding capacity in men. Whether cortisol binding globulin binding is a factor implicated in the pathophysiology of insulin resistance or represents an adaptative tool in this situation awaits further studies.
α2‐adrenoceptor regulation of the hypothalamic‐pituitary‐adrenocortical axis in obesity
Authors: Pasquali Renato , Vicennati Vaientina , Calzoni Fabio , Gnudi Umberto , Gambineri Alessandra , Ceroni Luana , Cortelli Pietro , Menozzi Renata , Sinisi Rosa , Del Rio Grariano
Published: March 2003

BACKGROUND Abdominal obesity is associated with hyper‐responsiveness of the hypothalamic‐pituitary‐adrenocortical (HPA) axis to stimulatory neuropeptides and to stress. Catecholamines are involved in the regulation of the HPA axis, particularly during stress, via α‐adrenoceptor modulation.

DESIGN In this study, we investigated the effects of pre‐treatment with an α2‐adrenoceptor agonist, clonidine (2μg/kg over 10 minutes) and antagonist, yohimbine (0.125 mg/kg bolus, followed by 0.001 mg/ kg/minutes per 90 minutes infusion) on the HPA axis, measured by ACTH and cortisol response to combined CRH (human, 100μg) plus AVP (0.3 IU) administration, and on noradrenalin (NA) and adrenalin (A) blood levels, in a group of obese women with abdominal (A‐BFD) or peripheral (P‐BFD) body fat distribution and in nonobese controls.

RESULTS During the control CRH+AVP test the ACTH but not the cortisol response was higher (P<0.05) in obese A‐BFD women than In controls, with minor and transient variations of NA levels. Neither the control test nor clonidine or yohimbine influenced basal or post CRH + AVP A concentrations. Clonidine pretreatment similarly and significantly decreased NA levels in all women and, compared to the control test, marginally influenced the ACTH response to CRH + AVP. Conversely, during yohimbine infusion NA levels steadlly and similarly increased to values more or less double baseline values in all groups. Compared to the control test, however, the ACTH response to the CRH + AVP test performed during yohimbine infusion significantly decreased in the control subjects whereas a tendency to a further increase occurred in the obese groups and, specifically, in the A‐BFD group significantly (P<0.05) more than in the P‐BFD group.

CONCLUSIONS This study shows that α2‐adrenoceptor regulation of the HPA axis is different in obese and nonobese women, particularly in stressed conditions. We suggest that the abnormal ACTH response to CRH+AVP challenge with increased noradrenergic tone may represent a specific pathophysiological aspect of the abnormal response to stress or to other specific stimulatory factors in obese women, particularly those with abdominal body fat distribution.
CSF rhinorrhoea following treatment with dopamine agonists for massive invasive prolactinomas
Authors: Leong King S. , Foy Patrick M. , Swift Andrew C. , Atkin Steve L. , Hadden David R. , MacFarlane Ian A.
Published: March 2003

OBJECTIVE

The management of CSF rhinorrhoea following dopamine agonist (DA) treatment for invasive prolactinomas is difficult and there is no clear consensus for its treatment. Our objective was therefore to investigate the different treatments for this condition.

DESIGN AND PATIENTS

We examined the case notes of five patients with invasive prolactinomas and CSF rhinorrhoea following DA treatment. The different ways in which this complication had been managed is detailed along with a review of the literature.

RESULTS

Five patients aged 24–67 years (3 male) with massive invasive prolactinomas (serum prolactin 95000–500000 mU/l) eroding the skull base were treated with dopamine agonists (3 bromocriptine, 1 cabergoline and 1 both). CSF rhinorrhoea developed in all patients between 1 week and 4 months after commencing dopamine agonist treatment. In two patients (cases 1 and 4), CSF rhinorrhoea ceased within a few days of stopping bromocriptine but restarted when treatment was resumed. One of these (case 4), a 67‐year‐old woman had no further treatment and CSF leakage stopped completely. She died of unrelated medical problems 3 years later. In one patient staphylococcus aureus meningitis and pneumocephalus developed as a complication of CSF rhinorrhoea. Three patients had endoscopic nasal surgery to repair the fistula using muscle grafts, and to decompress the pituitary tumour, with success in two. One patient had intracranial surgery and dural repair, which was successful in sealing the leak.

CONCLUSIONS

We suggest that surgery as soon as is feasible is the treatment of choice for the repair of a CSF leak following dopamine agonist treatment. An additional strategy is the withdrawal of dopamine agonist to allow tumour re‐growth to stop the leak.
Clinical features and pathogenesis of thyrotoxicosis in adult Melanesians in Papua New Guinea
Authors: Michelangeli  , Pawape  , Sinha  , Ongugu  , Linge  , Sengupta B  , Tait  , Colman
Published: March 2003

OBJECTIVE

To investigate the cause of an apparent increase in the incidence of thyrotoxicosis in the Melanesian population of the coastal areas around Port Moresby, Papua New Guinea.

DESIGN

Consecutive patients attending the thyroid clinic at Port Moresby General Hospital were included in the study which collected clinical and immunogenetic data.

PATIENTS

One hundred and ninety‐four patients with thyrotoxicosis were studied. The mean age was 31 years. The clinical features were typical for thyrotoxicosis apart from increased pigmentation, which occurred in the majority of patients and which reversed with treatment with antithyroid drugs and resolution of the thyrotoxicosis.

MEASUREMENTS

Antibodies to thyroid peroxidase, thyroglobulin and the thyrotropin receptor were present in 99%, 52% and 69% of patients, respectively, confirming that all cases were caused by autoimmune thyroid disease. Fine needle aspirations in 42 of 43 patients were consistent with Graves' disease.

CONCLUSIONS

The cause of this apparent sudden increase in Graves' disease in the coastal region around Port Moresby, an apparently iodine‐replete area, remains unexplained.
Insulin sensitivity and secretion influence the relationship between growth hormone‐binding‐protein and leptin
Authors: Fernandez‐Real José‐Manuel , Granada Maria Luisa , Ruzafa Ana , Casamitjana Roser , Ricart Wifredo
Published: March 2003

BACKGROUND

A direct relationship between body mass index (BMI), visceral adipose tissue, insulin levels and growth hormone‐binding protein (GHBP) activity has consistently been reported. It was recently described that GHBP directly depends on serum leptin levels. Since leptin co‐varies with insulin secretion and/or sensitivity, we aimed to study the influence of these variables on plasma GHBP activity.

SUBJECTS

In order to isolate the effects of obesity per se from those of insulin secretion, three groups of subjects were prospectively studied: 14 lean, 10 obese and nine obese subjects with glucose intolerance.

MEASUREMENTS

The percentage of body fat was measured through bioelectric impedance. Insulin sensitivity and secretion were determined through a frequently sampled intravenous glucose tolerance test with minimal model analysis. Serum leptin was measured by radioimmunoassay. GHBP activity was determined by the high performance liquid chromatography‐gel filtration method.

RESULTS

Plasma GHBP activity was found to correlate with BMI (r = 0.65, P < 0.0001), fat mass (r = 0.51, P = 0.003), waist circumference (r = 0.64, P < 0.0001), waist‐to‐hip ratio (r = 0.42, P = 0.01), insulin sensitivity (SI, r = − 0.61, P = 0.0001), insulin secretion (expressed as the acute insulin response to intravenous glucose, AIRg) (r = 0.48, P = 0.006) and leptin concentration (r = 0.49, P = 0.004). The associations with SI (r = − 0.42, P = 0.02) and AIRg (r = 0.38, P = 0.03) persisted even after controlling for fat mass. Since insulin secretion and insulin sensitivity usually covary in glucose tolerant subjects (an increased insulin secretion is necessary to compensate a decreased insulin sensitivity), we constructed a multiple linear regression to predict GHBP activity. In this model, SI (P = 0.005), AIRg (P = 0.02) and SD score‐leptin (P = 0.03) independently contributed to 34, 10 and 8% of the variability in serum GHBP activity.

CONCLUSIONS

Our results suggest that plasma GHBP activity is simultaneouslly influenced by insulin secretion and sensitivity and leptin. Perhaps leptin, through increased insulin secretion, might induce GHBP/GH secretion, explaining the normal to high insulin‐like growth factor (IGF)‐I levels found in overnutrition.