bluuebunny/crossref_metadata_2025 huggingface dataset:
Asymptomatic deficiency in the peptide transporter associated to antigen processing (TAP)
Authors: DE LA SALLE H , SAULQUIN X , MANSOUR I , KLAYMÉ S , FRICKER D , ZIMMER J , CAZENAVE J-P , HANAU D , BONNEVILLE M , HOUSSAINT E , LEFRANC G , NAMAN R
Published: March 2003

Human HLA class I deficiency is a rare disease which, in most of the patients described to date, results from a defect in subunit 1 or 2 of the peptide transporter associated with antigen processing (TAP). The clinical features of TAP deficiency include a chronic inflammation of the respiratory tract and/or granulomatous skin lesions. In this report, we describe two adult siblings with an HLA class I deficiency. One individual had only spontaneously-healing skin granulomatous lesions, while the second did not display any of the symptoms associated with HLA class I deficiency and could be considered to be healthy. We show that the patients display a homozygous TAP2 mutation which blocks the maturation of HLA class I molecules. Cell surface expression of these molecules is strongly reduced, but three times higher than on cells from other previously described TAP-deficient individuals. This higher expression results, at least in part, from the presence of HLA-B7 molecules which are probably empty of peptide. The numbers of CD8+αβ T cells are almost normal in these patients. The anti-EBV T-cell response of one patient is mediated by HLA-B7 restricted CD8+αβ T lymphocytes recognizing the BMRF1 nuclear EBV antigen, demonstrating that CD8+αβ T cells can participate in anti-viral responses. This study shows that TAP deficiency can remain totally asymptomatic for several decades, and suggests that in some cases, TAP-independent immune responses provide efficient protection from most of the common intracellular pathogens.
Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis
Authors: HOLLAND M , TAKADA K , OKUMOTO T , TAKAHASHI N , KATO K , ADU D , BEN-SMITH A , HARPER L , SAVAGE C O S , JEFFERIS R
Published: March 2003

The triad of small vessel vasculitides (SVV) comprise Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg–Strauss syndrome (CS). All three are associated with presence of circulating IgG antineutrophil cytoplasm antibodies (ANCA) which target autoantigens contained, primarily, within neutrophil azurophilic granules. The widely accepted model of pathogenesis suggests that ANCA activate cytokine-primed neutrophils within the microvasculature, leading to by-stander damage to endothelial cells, and rapid escalation of inflammation with recruitment of mononuclear cells. Activation may be initiated, in vitro, by the coligation of the PR3 or MPO antigen, translocated to the cell surface, and FcγRIIa/FcγRIIIb receptors. This suggests that the IgG subclass profile of ANCA and, possibly, its glycosylation status could influence the inflammatory mechanisms activated. The glycosylation status of total IgG isolated from the sera of patients with WG (13), MPA (6) and CSS (1) was determined by analysis of the released oligosaccharides. A deficit in IgG galactosylation is demonstrated for all patient samples, compared to controls. The mean percentage values for the agalactosylated (G0) oligosaccharides were 57% (SD ± 9·71), 47% (SD ± 4·25) and 28% (SD ± 4·09) for WG, MPO and control samples, respectively. The G0 levels for polyclonal IgG isolated from the sera of both WG and MPA patients were significantly increased compared to controls (P < 0·0001). The major glycoform present therefore is agalactosylated (G0) IgG. In previous studies the G0 glycoform of IgG has been shown to bind and activate mannan binding lectin, and hence to activate the complement cascade, and to facilitate mannose receptor binding and the uptake of IgG complexes by macrophages and dendritic cells. Both of these activities could impact on the processing and presentation of self-antigens in autoimmune disease.
CpG ODN activates NO and iNOS production in mouse macrophage cell line (RAW 264·7
Authors: UTAISINCHAROEN P , ANUNTAGOOL N , CHAISURIYA P , PICHYANGKUL S , SIRISINHA S
Published: March 2003

Synthetic CpG containing oligodeoxynucleotide (CpG ODN) is recognized for its ability to activate cells to produce several cytokines, such as IL-12 and TNF-α. In the present study we have demonstrated that CpG ODN 1826, known for its immunostimulatory activity in the mouse system could, by itself, induce nitric oxide (NO) and inducible nitric oxide synthase (iNOS) production from mouse macrophage cell line (RAW 264·7). Neutralizing antibody against TNF-α was not able to inhibit NO or iNOS production from the CpG ODN 1826-activated macrophages, suggesting that although the TNF-α was also produced by CpG ODN-activated macrophages, the production of iNOS was not mediated through TNF-α. Although both CpG ODN 1826 and lipopolysaccharide (LPS) were able to stimulate NO and iNOS production, the exposure time required for maximum production of NO and iNOS for the CpG ODN 1826-activated macrophages was significantly longer than those activated with LPS. These results were due probably to a delay of NF-κB translocation, as indicated by the delay of IκBα degradation. Moreover, the fact that chloroquine abolished NO and iNOS production from the cells treated with CpG ODN 1826 but not from those treated with LPS suggested that the induction of NO and iNOS production from the cells stimulated with CpG ODN (1826) also required endosomal maturation/acidification.
Activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB in tumour necrosis factor-induced eotaxin release of human eosinophils
Authors: WONG C K , ZHANG J P , IP W K , LAM C W K
Published: March 2003

The CC chemokine eotaxin is a potent eosinophil-specific chemoattractant that is crucial for allergic inflammation. Allergen-induced tumour necrosis factor (TNF) has been shown to induce eotaxin synthesis in eosinophils. Nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPK) have been found to play an essential role for the eotaxin-mediated eosinophilia. We investigated the modulation of NF-κB and MAPK activation in TNF-induced eotaxin release of human eosinophils. Human blood eosinophils were purified from fresh buffy coat using magnetic cell sorting. NF-κB pathway-related genes were evaluated by cDNA expression array system. Degradation of IκBα and phosphorylation of MAPK were detected by Western blot. Activation of NF-κB was determined by electrophoretic mobility shift assay. Eotaxin released into the eosinophil culture medium was measured by ELISA. TNF was found to up-regulate the gene expression of NF-κB and IκBα in eosinophils. TNF-induced IκBα degradation was inhibited by the proteasome inhibitor N-cbz-Leu-Leu-leucinal (MG-132) and a non-steroidal anti-inflammatory drug sodium salicylate (NaSal). Using EMSA, both MG-132 and NaSal were found to suppress the TNF-induced NF-κB activation in eosinophils. Furthermore, TNF was shown to induce phosphorylation of p38 MAPK time-dependently but not extracellular signal-regulated kinases (ERK). Inhibition of NF-κB activation and p38 MAPK activity decreased the TNF-induced release of eotaxin from eosinophils. These results indicate that NF-κB and p38 MAPK play an important role in TNF-activated signalling pathway regulating eotaxin release by eosinophils. They have also provided a biochemical basis for the potential of using specific inhibitors of NF-κB and p38 MAPK for treating allergic inflammation.
Anti-CD45 isoform antibodies enhance phagocytosis and gene expression of IL-8 and TNF-αin human neutrophils by differential suppression on protein tyrosine phosphorylation and p56lck tyrosine kinase
Authors: YU C-L , YU H-S , SUN K-H , HSIEH S-C , TSAI C-Y
Published: March 2003

To determine the biological functions of membrane expressed CD45 isoforms on polymorphonuclear neutrophils (PMN), the monoclonal IgG F(ab′)2 antibody against CD45, CD45RA or CD45RO was used as surrogate ligand for binding with these molecules on PMN. We found 99·5 ± 3·2%, 42·3 ± 5·8% and 96·7 ± 2·6% PMN expressed CD45, CD45RA and CD45RO molecules on the cell surface, respectively. The interaction of CD45, CD45RA or CD45RO with its specific antibody on PMN enhanced phagocytosis markedly (34–83% increase), mainly via increased expression of complement receptor type 3 (CR3, CD11b) on the cells. The production of IL-8 by PMN was also increased significantly after binding with antibodies (anti-CD45 > anti-CD45RO > anti-CD45RA). Anti-CD45RA and anti-CD45RO, but not anti-CD45, enhanced TNF-α mRNA expression and decreased protein tyrosine phosphorylation of PMN. However, only anti-CD45RO suppressed Src family protein tyrosine kinase p56lck expression in the cells. These results suggest that the cross-linking of CD45 isoforms by their specific antibodies stimulated different PMN activities by differential suppression on protein tyrosine phosphorylation and Src family tyrosine kinase p56lck.
IL-10 enhances B-cell IgE synthesis by promoting differentiation into plasma cells, a process that is inhibited by CD27/CD70 interaction
Authors: KOBAYASHI N , NAGUMO H , AGEMATSU K
Published: March 2003

Interleukin-10 (IL-10) is a major regulatory cytokine of inflammatory responses that is considered to play an important role in specific immunotherapy. However, whether IL-10 enhances or inhibits B-cell IgE production has remained a matter of contention. To clarify the effect of IL-10 on IgE synthesis in the presence of IL-4 and CD40 signalling, we examined B-cell proliferation, germline ɛ transcripts and plasma cell differentiation. In addition, the effect of CD27 signalling on IgE synthesis in the presence of IL-10, IL-4 and CD40 signalling was investigated. IL-10 facilitated the production of IgE in mononuclear cells and highly purified B-cells, enhanced B-cell proliferation and, most importantly, promoted the generation of plasma cells. However, IL-10 did not enhance expression of germline ɛ transcripts. The addition of CD27 signalling through the use of CD32–CD27 ligand (CD70) double transfectants significantly diminished the B-cell proliferation, IgE synthesis and plasma cell differentiation enhanced by IL-10. IL-10 enhances B-cell IgE production by promoting differentiation into plasma cells. CD27/CD70 interactions under IL-10 and sufficient CD40 cosignalling exert the opposite effect on IgE synthesis. The results of this study indicate that precautions are critical when planning immunotherapy using IL-10 in IgE-related allergic diseases.
Allo-immunization elicits CCR5 antibodies, SDF-1 chemokines, and CD8-suppressor factors that inhibit transmission of R5 and X4 HIV-1 in women
Authors: WANG Y , UNDERWOOD J , VAUGHAN R , HARMER A , DOYLE C , LEHNER T
Published: March 2003

Studies in humans suggest that allo-immunization induces CC-chemokines, CD8-suppressor factors (SF) and anti-HIV immunity. Here we report that allo-immunization with unmatched leucocytes from partners of women with recurrent spontaneous abortion elicits specific antibodies to the CCR5 receptor. Such antibodies inhibit replication of M-tropic HIV-1 (R5) and MIP-1β-mediated chemotaxis. These CCR5 antibodies were also found in the sera of multiparous women that were naturally immunized by semi-allogeneic fetal antigens. The specificity of these antibodies was demonstrated by adsorption with CCR5 transfected HEK-293 cells, a baculovirus CCR5 preparation and a peptide of the 2nd extra-cellular loop of CCR5. Allo-immunization also stimulated increased concentrations of the CXC chemokine, SDF-1α and CD8-SF that inhibit T-tropic HIV-1 (X4) replication. We suggest that allo- immunization may elicit (a) CC chemokines, CCR5 antibodies and CD8-SF that inhibit M-tropic HIV-1 infection and (b) the CXC chemokine SDF-1α and CD8-SF that inhibit T-tropic HIV-1 infection.
Elevated levels of thymus and activation-regulated chemokine (TARC) in pleural effusion samples from patients infested withParagonimus westermani
Authors: MATSUMOTO N , MUKAE H , NAKAMURA-UCHIYAMA F , ASHITANI J-I , ABE K , KATOH S , KOHNO S , NAWA Y , MATSUKURA S
Published: March 2003

To investigate the pathogenic mechanisms of eosinophilic pleural effusion in patients with paragonimiasis, we measured the levels of various chemokines including thymus and activation-regulated chemokine (TARC), eotaxin, RANTES and IL-8 in pleural effusion samples. Samples were obtained from 11 patients with Paragonimus westermani infection, six patients with pleural transudate, eight with tuberculous pleurisy and five with empyema. High percentages of eosinophils were detected in pleural fluid (range 9–100%, median 81%) of patients with paragonimiasis. TARC concentrations in pleural effusions of paragonimiasis were markedly higher than those of other groups. Eotaxin levels were also higher in pleural effusions of paragonimiasis patients, although significant difference was noted only against transudate samples. There was a significant correlation between TARC concentrations and percentages of eosinophils, and between TARC and eotaxin concentrations in pleural effusion. There were also significant correlations between TARC concentration and the titre of anti-P. westermani IgG and between eotaxin concentration and the titre of anti-P. westermani IgG. Our findings suggest that TARC contributes to the pathogenesis of eosinophilic pleural effusion in paragonimiasis.
Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study
Authors: MELLEMKJÆR L , HAMMARSTRÖM L , ANDERSEN V , YUEN J , HEILMANN C , BARINGTON T , BJÖRKANDER J , OLSEN J H
Published: March 2003

The extremely high risk reported for some types of cancer among patients with common variable immunodeficiency (CVID) is based on a limited number of investigations. Therefore, we examined the risks for cancer among 562 Danish and Swedish patients with CVID or IgA deficiency and 2071 relatives in 1958–96. The patients were identified through an Immunodeficiency Register and hospital records, while the relatives were traced through population registers. Cancer incidence was assessed by linkage to the Cancer Registries and compared with that in the general population. Among 386 patients with IgA deficiency, the incidence of cancer was not increased (standardized incidence ratio (SI) = 1·0); but two cases of stomach cancer were found, resulting in a non-significant increase in risk (SIR = 5·4; 95% CI = 0·7–19·5). Among 176 patients with common variable immunodeficiency (CVID), the incidence of cancer at all sites combined was increased (SIR = 1·8; 95% CI = 1·0–2·9), which was due mainly to significant excesses of malignant lymphoma (obs = 4; SIR = 12·1; 95% CI = 3·3–31·0) and of stomach cancer (obs = 3; SIR = 10·3; 95% CI = 2·1–30·2). Among the 626 relatives of patients with CVID, no increase in risk was found for these types of cancer or for cancer overall (obs = 53; SIR = 1·0; 95% CI = 0·8–1·3). Our data show that the risks for malignant lymphoma and stomach cancer among patients with CVID may be lower than reported previously. The absence of an increased risk among relatives suggests that the increased cancer morbidity in patients with CVID is related to the immunodeficiency per se rather than to specific genetic traits shared with their relatives.
Nicotinamide is a potent inhibitor of proinflammatory cytokines
Authors: UNGERSTEDT J S , BLOMBÄCK M , SÖDERSTRÖM T
Published: March 2003

The present study investigates the modulating effects of nicotinamide on the cytokine response to endotoxin. In an in vitro model of endotoxaemia, human whole blood was stimulated for two hours with endotoxin at 1 ng/ml, achieving high levels of the proinflammatory cytokines IL-1β, IL-6, IL-8 and TNFα. When coincubating whole blood, endotoxin and the vitamin B3 derivative nicotinamide, all four cytokines measured were inhibited in a dose dependent manner. Inhibition was observed already at a nicotinamide concentration of 2 mmol/l. At a concentration of 40 mmol/l, the IL-1β, IL-6 and TNFα responses were reduced by more than 95% and the IL-8 levels reduced by 85%. Endotoxin stimulation activates poly(ADP-ribose)polymerase (PARP), a nuclear DNA repair enzyme. It has been hypothesized that the anti-inflammatory properties of nicotinamide are due to PARP inhibition. In the present study, the endotoxin induced PARP activation was dose dependently decreased with 4–40 mmol/l nicotinamide or 4–100 µmol/l 6(5H) phenanthridinone, a specific PARP inhibitor. 6(5H)phenanthridinone however, failed to inhibit the proinflammatory cytokines. Thus, the mechanism behind the cytokine inhibition in our model seems not to be due to PARP inhibition. In conclusion, the present study could not only confirm previous reports of a down-regulatory effect on TNFα, but demonstrates that nicotinamide is a potent modulator of several proinflammatory cytokines. These findings demonstrate that nicotinamide has a potent immunomodulatory effect in vitro, and may have great potential for treatment of human inflammatory disease.
Changes in immune parameters and their correction in human cases of tick-borne encephalitis
Authors: ATRASHEUSKAYA A V , FREDEKING T M , IGNATYEV G M
Published: March 2003

Tick-Borne Encephalitis virus (TBEV) causes dangerous central nervous system diseases in humans. General infection leads to the development of meningitis or encephalitis, which is characterized by swelling of the brain due to inflammation. Tetracyclines may act locally to moderate inflammation in the CNS. In this study, we investigated the potential clinical benefits of administering tetracycline hydrochloride to patients hospitalized due to suspected TBEV infection presenting with fever and evidence of a recent tick bite. We also characterized an acute immune response to TBEV by profiling certain cytokines and soluble receptors in Tetracycline-treated and untreated patients. Increased serum levels of TNF-α, IL-1α and IL-6 were found in all patients at admission.

Soluble receptors presented in the serum of patients in a magnitude higher levels than the corresponding cytokines and were increasing during first weak of hospitalization. Levels of IL-10 were also rising during that period. In our study tetracycline hydrochloride acted as an immunomodulator, which was able to reduce manifestations of inflammation response during TBE course; this action led to quicker improvement of symptoms and, consequently, to a faster clinical recovery. The positive result of tetracycline hydrochloride treatment was accompanied by certain particularities in the dynamics of studyied cytokines and receptors: the concentrations of IL-6, IL-1β, TNF-α dropped quicker and reached lower levels, and the concentrations of sIL-6R, IL-1RA, sTNFR1 increased faster and reached higher maximum levels in the tetracycline-treated groups. Children had the highest levels of IL-6, which were not neurotoxic.
Endogenous glucocorticoids attenuate Shiga toxin-2-induced toxicity in a mouse model of haemolytic uraemic syndrome
Authors: GÓMEZ S A , FERNÁNDEZ G C , VANZULLI S , DRAN G , RUBEL C , BERKI T , ISTURIZ M A , PALERMO M S
Published: March 2003

The concept that during an immune challenge the release of glucocorticoids (GC) provides feedback inhibition on evolving immune responses has been drawn primarily from studies of autoimmune and/or inflammatory processes in animal models. The epidemic form of haemolytic uraemic syndrome (HUS) occurs secondary to infection with Gram-negative bacteria that produce Shiga toxin (Stx). Although Stx binding to the specific receptors present on renal tissue is the primary pathogenic mechanism, inflammatory or immune interactions are necessary for the development of the complete form of HUS. The aim of this study was to investigate the influence of endogenous GC on Stx-toxicity in a mouse model. Stx2 was injected into GC-deprived mice and survival rate, renal damage and serum urea levels were evaluated. Plasma corticosterone and cytosolic GC receptor (GR) concentration were also determined at multiple intervals post-Stx2 treatment. Higher sensitivity to Stx2 was observed in mice lacking endogenous GC, evidenced by an increase in mortality rates, circulating urea levels and renal histological damage. Moreover, Stx2 injection was associated with a transient but significant rise in corticosterone secretion. Interestingly, 24 h after Stx inoculation significant increases in total GR were detected in circulating neutrophils. These results indicate that interactions between the neuroendocrine and immune systems can modulate the level of damage significantly during a bacterial infection.
Local immune responses and systemic cytokine responses in zoster: relationship to the development of postherpetic neuralgia
Authors: ZAK-PRELICH M , MCKENZIE R C , SYSA-JEDRZEJOWSKA A , NORVAL M
Published: March 2003

Varicella zoster virus (VZV) causes varicella (chickenpox) as the primary infection and zoster (shingles) on reactivation from latency, often many years later. One of the most common and most severe sequela of zoster is postherpetic neuralgia (PHN). Apart from age, factors which predispose towards PHN are unknown. In the present study, the concentration of a variety of Th1 and Th2 cytokines in the serum of 30 zoster patients at the time of the acute disease were correlated with the subsequent development of PHN in nine of these patients, but no association was found. In addition, although some cytokines such as IFN-γ, IL-6 and IL-8 were slightly raised in the zoster group compared with a group of normal healthy subjects of a similar age distribution, these differences only verged on significance. Antibody titres to VZV were raised in the zoster group compared with the controls but these did not differ between the patients who developed PHN and those who did not. Biopsies of zoster lesions were collected from nine patients. There were significantly fewer infiltrating lymphocytes in the lesions of the three patients who subsequently developed PHN compared with the six who did not, although the expression of the neuropeptide, substance P, did not differ between the two groups. It is possible that the poor inflammatory response at the time of the acute zoster may result in less effective containment of the VZV and more damage in the dermatome, thus contributing to the persistence of the neuralgia.
Bright light exposure and pituitary hormone secretion
Authors: Kostoglou‐Athanassiou Ifigenia , Treacher David F. , Wheeler Michael J. , Forsling Mary L.
Published: March 2003

OBJECTIVE

Exposure to bright light inhibits melatonin secretion in man. As the relationship between melatonin and pituitary function remains controversial, we investigated the effect of altering the melatonin rhythm by bright light during the early hours of darkness on pituitary hormone secretion in man.

DESIGN

The investigation took the form of a randomized controlled clinical trial.

SUBJECTS

Ten adult healthy male volunteers, who were non‐smokers and aged 21–33 years, were studied on two occasions: once during exposure to bright light from 2000 h to 0200 h and once during exposure to normal room lighting over the same period. On each day of the study, the subjects were allowed to sleep after lights were switched off at 0200 h. Observations were also performed when subjects were exposed to normal room lighting from 2000 h to 2400 h, thereafter being allowed to sleep. On each study day the subjects undertook their normal duties but refrained from taking heavy exercise and drinking alcohol.

MEASUREMENTS

Serum cortisol, GH and PRL, plasma vasopressin, oxytocin, melatonin, sodium, potassium and osmolality and packed cell volume were measured over 24 hours.

RESULTS

Bright light delayed the nocturnal melatonin peak by 2 hours and resulted in a decrease in cortisol concentrations. Growth hormone levels decreased but subsequently there was a significantly greater nocturnal increase. The PRL peak was delayed and nocturnal vasopressin concentrations were lower in both the studies where subjects were exposed to a modified sleep schedule.

CONCLUSION

Exposure to bright light during the early hours of darkness delays the nocturnal melatonin peak and alters cortisol, GH, PRL and nocturnal vasopressin secretion, while modification of the sleep pattern decreases vasopressin concentrations and alters its nocturnal peak.
Radiotherapy for non‐functioning pituitary tumours
Authors: Gittoes  , Bates  , Tse  , Bullivant  , Sheppard  , Clayton  , Stewart
Published: March 2003

OBJECTIVE

Pituitary radiotherapy (RT) is often used as adjuvant treatment in the post‐operative period for patients with clinically non‐functioning pituitary tumours (NFTs). There is a distinct lack of objective data, however, describing the efficacy of RT in preventing the regrowth of these tumours. We have therefore determined whether the recurrence rate for NFTs is significantly lower in patients treated with post‐operative RT compared with that observed in patients not treated with RT.

PATIENTS AND METHODS

A retrospective case notes review was performed on 126 patients with NFTs treated at two institutions in the UK. One hospital routinely administered RT within 12 months of initial pituitary surgery whereas the other used post‐operative RT only rarely. The main outcome measure was regrowth of pituitary tumours following surgery in patients who did or did not receive post‐operative RT.

RESULTS

There was no significant difference between patients who received RT versus those who did not in terms of age, sex, initial tumour size or mode of operation. The actuarial progression‐free survival was 93% at both 10 years and at 15 years for the RT treated group, and was 68% and 33%, respectively, for the non‐RT‐treated group. Using Cox's model for proportional hazard analysis, we found the only prognostic factor for NFT regrowth was the administration of pituitary RT (P < 0.00005).

CONCLUSIONS

Radiotherapy administered within 12 months of initial pituitary surgery for non‐functioning pituitary tumours significantly reduces the risk of tumour regrowth. It remains to be determined whether sequential MRI scanning can help delineate those patients who should receive radiotherapy following pituitary surgery for non‐functioning pituitary tumours.
Increased body weight associated with prolactin secreting pituitary adenomas: weight loss with normalization of prolactin levels
Authors: Greenman Yona , Tordjman Karen , Stern Naftali
Published: March 2003

OBJECTIVE

Hyperprolactinaemia in humans may be associated with a high prevalence of obesity but the nature of this link is poorly defined. The aim of this study was to establish the relationship between hyperprolactinaemia and body weight in patients with prolactin‐secreting pituitary tumours.

DESIGN

We conducted a retrospective study of prolactinoma patients treated at the Endocrine Institute of the Tel Aviv Medical Center, Israel, during the period 1989–1996. Patients with clinically nonfunctioning pituitary macroadenomas (NFA) served as the control group. Data on demographic parameters, body weight before and during treatment, clinical presentation including history of weight fluctuations, tumour size as measured by computed tomography or magnetic resonance imaging, modalities and response to treatment, and pituitary function before and during treatment were recorded from medical files.

PATIENTS

Forty‐two patients with prolactinomas (PR) and 36 patients with clinically non‐functioning macroadenomas (NFA) comprised the study population.

RESULTS

Mean weight was 93 ± 3.4 kg and 78 ± 2.7 kg in male patients with PR and NFA respectively (P = 0.0007). Recent weight gain (8 to 22 kg) was a presenting symptom in 13 PR patients, whereas only one NFA patient had this clinical presentation (P = 0.001). Seventeen PR patients lost weight (mean change −8.3 ± 1.5 kg, range −2–28 kg), during prolactin lowering therapy, 11 of whom had entirely normalized prolactin levels. Fourteen of the 18 patients who did not lose weight still had elevated prolactin levels (P = 0.01). Weight loss in patients with PR could not be attributed to altered pituitary function nor to compression of the third ventricle. In contrast to PR, no significant weight loss was observed in NFA patients.

CONCLUSION

Weight gain and elevated body weight are frequently associated with prolactinomas regardless of a mass effect on the hypothalamus or pituitary function. In this series, weight loss was recorded in 70% of prolactinomas patients and in 90% of male patients who normalized their prolactin levels. We propose the inclusion of hyperprolactinaemia in the differential diagnosis of endocrine obesity and weight gain.
Diurnal variation of the serum leptin concen_tration in patients with anorexia nervosa
Authors: Støving  , Vinten  , Handberg  , Ebbesen  , Hangaard  , Hansen‐Nord  , Kristiansen  , Hagen
Published: March 2003

OBJECTIVE

In rodents, leptin is involved in regulating eating behaviour, fat storage, and reproductive function. In humans, the serum leptin concen_tration in obese and normal weight subjects correlates with body mass index, reflecting the body fat store. The serum leptin exhibit diurnal variation, however, this has been reported to be absent in normal weighted amenorrheic athletes. Anorexia nervosa is associated with multiple endocrine abnormalities. Hypothalamic amenorrhoea often precedes the weight loss and may persist after weight recovery. We hypothesized that leptin could be involved in the regulation of eating behaviour and gonadal function in anorexia nervosa.

DESIGN

We measured the concen_tration of leptin in serum samples taken after an overnight fast in 18 female anorexia nervosa patients and 11 controls. To study diurnal variation, eight patients and 11 controls were hospitalized for 24 h and had a standardized diet at regular times. Seven blood samples were obtained at 4 h intervals from each subject.

PATIENTS

The patients fulfilled the DSM‐IV criteria for anorexia nervosa. The mean body mass index for the patients was 14.2 ± 2.3 kg/m2 and for controls 20.3 ± 1.7 kg/m2.

RESULTS

The mean fasting leptin concen_tration as well as the 24 h mean concen_tration were significantly lower in the anorectic group than in the control group (2.5 ± 0.9 vs 10.1 ± 6.1 μg/l, P < 0.01 and 2.7 ± 1.5 vs 10.6 ± 7.1 μg/l, P < 0.01 respectively). In the whole group of subjects (n = 28) a significant positive correlation between the leptin level and body mass index was found (r = 0.63, P < 0.001). In the anorectic group it was found that the leptin level correlated better with body fat percen_tage than with body mass index. In normalized data the time course of the mean leptin levels showed a monophasic variation with nadir and zenith at about 0900 and 0100 h respectively. However, the individual coefficients of variance were significantly lower in the anorectic group compared to the group of healthy women.

CONCLUSION

In patients with anorexia nervosa the leptin level is low, reflecting the low body fat mass, and the relative diurnal variation is strikingly reduced. The similarity to that of normal weighted women with hypothalamic amenorrhoea suggest that altered leptin oscillations may be of particular significance in the hypothalamic regulation of reproductive function.
Leptin is involved in gender‐related differences in insulin sensitivity
Authors: Fernández‐Real Jośe‐Manuel , Casamitjana Roser , Ricart‐Engel Wifredo
Published: March 2003

BACKGROUND

Although the effects of insulin on leptin levels are relatively well characterized, the possible actions of leptin on insulin sensitivity are not so well studied. This study was undertaken to examine whether gender‐related differences in insulin sensitivity could be explained partially by leptin levels.

SUBJECTS

The study involved 22 women (13 obese) and 20 (11 obese) fat mass‐ and age‐matched men. All participants were healthy.

MEASUREMENTS

Several anthropometric measures of body fatness were quantified and the percentage of body fat was determined through bioelectric impedance. Oral glucose tolerance test and a frequently sampled intravenous glucose tolerance test was performed in all subjects. Serum leptin was measured by radioimmunoassay.

RESULTS

Nine lean women (BMI 20.4±2 kg m2 mean±SD) showed increased leptin levels (7.8±2.7 vs. 4.3±1.3 μg/l, P=0.003), increased insulin sensitivity (5.2±1.3 vs. 2.9±0.9 min−1/mU/l, P=0.001) and similar fat mass (11.1±3.7 vs. 13.2±7.8 kg, P=NS) in comparison with 9 age‐matched lean men (33.6±6 vs. 34.5±6.3 years, P=NS). Thirteen obese women (BMI 32.5±2.7) kg m2 also showed increased leptin levels (29.6±8.4 vs. 11.7±4.8 μg/l, P < 0.0001), increased insulin sensitivity (1.7±0.7 vs. 0.95±0.9 min−1 mU/l, P = 0.04) and similar fat mass (34.4±8.0 vs. 30.9±9.6 kg, P = NS) in comparison with 11 age‐matched obese men (34.5±7.8 vs. 38.7±8.2 years, P = NS). A strong linear association between leptin levels and insulin sensitivity (SI) was found (r = −0.67, P = 0.001, in men; r = −0.82, P<0.0001, in women). After controlling for percentage of body fat, this association remained significant only in men (r = −0.56, P = 0.01, in men; r = −0.30, P = NS in women). In stepwise regression analysis models, both gender (P = 0.00001) and leptin (P = 0.00001) contributed to 67% of the variance in SI independently of body fat.

CONCLUSIONS

Leptin levels and gender contribute to the variance of insulin sensitivity, independently of body fat. These results suggest that leptin could affect insulin sensitivity.
Growth hormone replacement inhibits renal and hepatic 11β–hydroxysteroid dehydrogenases in ACTH‐deficient patients
Authors: Walker Brian R , Andrew Ruth , MacLeod Kenneth M , Padfield Paul L
Published: March 2003

OBJECTIVES

The commonest side‐effects of GH replacement therapy relate to sodium retention but its mechanism is unclear. In rats, GH inhibits renal and hepatic 11β–hydroxysteroid dehydrogenase (11β–HSD) activities. In man, this action might impair inactivation of cortisol to cortisone in the distal nephron thereby allowing cortisol to activate mineralocorticoid receptors. In this study, we examined the effects of GH replacement on cortisol metabolism.

DESIGN

A randomized double‐blind study comparing 6 months GH replacement with placebo in adults with GH deficiency due to pituitary or hypothalamic disease.

PATIENTS

6 men and 8 women received placebo and 8 men and 9 women received GH.

MEASUREMENTS

Cortisol and its metabolites were measured in overnight urine samples and in a fasting morning plasma sample at baseline and at 6 months.

RESULTS

Five patients withdrew from the study, 4 because of adverse effects of GH. Amongst those who completed the study, the effects of GH on cortisol metabolism differed between patients with and without ACTH deficiency. Amongst those receiving hydrocortisone replacement (n = 18), GH had no effect on plasma cortisol/cortisone ratio, or urine tetrahydrocortisols/tetrahydrocortisone ratio, but produced a substantial reduction in total urinary cortisol metabolites (from 1326±191 to 777±229 μg/mmol creatinine; P < 0.01) and an increase in urinary free cortisol/cortisone ratio (from 0.88±0.10 to 2.57±0.74; P < 0.02). By contrast, GH had none of these effects in patients with normal ACTH secretion. There were no changes in blood pressure or plasma electrolytes, aldosterone, or renin activity with GH, and no changes in any variables with placebo.

CONCLUSIONS

The increase in cortisol/cortisone ratio in urine but not in plasma, and the lack of effect on hepatic cortisol metabolites, suggests that GH inhibits both the conversion of cortisol to cortisone by renal 11β–HSD2 and the conversion of cortisone to cortisol by hepatic 11β–HSD1. It is unclear why this action of GH only affects patients with ACTH deficiency. The reduction in total cortisol metabolite excretion suggests that GH also affects bioavailability of hydrocortisone tablets. These observations suggest that glucocorticoid replacement therapy may need to be adjusted in hypopituitary patients who are commenced on GH replacement.
The effect of chronic hexarelin administration on the pituitary–adrenal axis and prolactin
Authors: Rahim A. , O'Neill P. A. , Shalet S. M.
Published: March 2003

OBJECTIVE

With the development of growth hormone (GH) releasing agents and their use in human subjects, it is clear that these agents are not specific for GH release. More recent studies in humans have demonstrated acute increases in adrenocorticotrophic hormone (ACTH), cortisol and prolactin (PRL) after boluses of intravenous or subcutaneous GHRPs. The potential adverse effects of repeated episodes of transient hyperprolactinaemia and hypercortisolaemia during long‐term therapy with growth hormone releasing peptides (GHRPs) and similar agents have raised concern. We have therefore assessed the impact of chronic hexarelin administration on the pituitary‐adrenal axis and serum prolactin levels.

DESIGN

Each subject received twice‐daily subcutaneous hexarelin therapy (1.5 μg/kg body weight) for 16 weeks. The ACTH, cortisol and PRL responses to the morning subcutaneous injection of hexarelin were assessed. Hexarelin was administered at time 0 and blood samples were taken at −10, 0, 10, 20, 30, 40, 50, 60, 90, 120, 170 and 180 min. The ACTH and PRL responses were assessed at baseline and after 16 weeks of therapy. The cortisol response was assessed at baseline, 16 weeks and also 4 weeks after completion of hexarelin therapy. Basal levels of cortisol binding globulin (CBG), 24‐h urinary free cortisol (UFC) estimations, thyroid stimulating hormone (TSH) and total thyroxine (TT4) were performed at baseline, weeks 16 and 20.

RESULTS

The mean (±SEM) area under the cortisol curve (AUCCORT) at baseline, week 16 and week 20 were 1506 (±77) nmol/l/h, 1222 (±92) nmol/l/h and 1586 (±58) nmol/l/h, respectively. There was a significant change in AUCCORT over the study period (P = 0.008). Compared with baseline, AUCCOPRT had decreased significantly (P < 0.05) after 16 weeks of hexarelin therapy. Four weeks after completion of hexarelin therapy, the AUCCORT increased significantly compared with AUCCORT at week 16 (P < 0.01) and was no longer significantly different from baseline values. There were no significant changes in UFC (P = 0.3), basal cortisol measurements (P = 0.19), area under the ACTH curve (AUCACTH) (P = 0.24) or CBG (P = 0.6) over the study period. The mean (±SEM) area under the PRL curve (AUCPRL) at the baseline and week 16 were 624 (±82) mU/l/h and 641 (±83) mU/l/h, respectively. There was no significant change in AUCPRL over the study period (P = 0.35).

CONCLUSION

The present study demonstrates clearly that in this hexarelin dosage regimen, overstimulation of the pituitary adrenal axis and prolactin secretion do not occur. In fact the impact of chronic hexarelin therapy on the pituitary–adrenal axis, i.e. decreased AUCCORT, contradict the findings reported after acute hexarelin administration and cannot be explained by changes in CBG. The lack of change in UFC, however, suggests that these changes are unlikely to be of clinical significance although the underlying mechanism requires further study.
Salivary cortisol for screening of Cushing's syndrome in children
Authors: Martinelli Carlos E. , Sader Soraya L. , Oliveira Eduardo B. , Daneluzzi Júlio C. , Moreira Ayrton C.
Published: March 2003

OBJECTIVE

Cushing's syndrome (CS) is characterized by changes in diurnal cortisol variation and total or partial resistance to cortisol suppression by dexamethasone (DEX). Diagnosing CS is a challenge especially in childhood and requires differentiation from primary obesity. The aim was verify the efficacy of salivary cortisol in differentiating primary obesity from CS in children.

SUBJECTS AND METHODS

We studied 11 patients with CS confirmed by standard laboratory investigation and surgical findings aged 1–16 years, and 21 age‐matched primary obese controls. Salivary samples were collected at 0900 h, 2300 h, and after an overnight DEX suppression test (20 μg/kg up to 1 mg). Salivary cortisol was measured by RIA.

RESULTS

Diurnal variation of salivary cortisol levels was observed in all controls, as opposed to only 5 of 11 patients with CS. Suppression of salivary cortisol was detected in all controls but in no CS patient after the overnight DEX test. Mean salivary cortisol levels were higher in the CS than in the control group both at 2300 hours and at 0900 hours after DEX but no difference was observed at 0900 hours of the first day. The sensitivity and specificity of salivary cortisol at 0900 h, 2300 hours and after‐DEX in diagnosing CS were 27% and 95.2%, 100% and 95.2%, and 100% and 95.2%, respectively. Sensitivity and specificity of 100% were obtained by combining the data for 2300 hours and after‐DEX.

CONCLUSION

The combination of salivary cortisol determination at 2300 hours and after‐Dexamethasone is an easily performed and noninvasive method with high specificity and sensitivity for diagnosing Cushing's syndrome in children.
Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L‐T4 replacement therapy
Authors: Monzani Fabio , Caraccio Nadia , Del Guerra Paolo , Casolaro Arturo , Ferrannini Eleuterio
Published: March 2003

DESIGN, PATIENTS AND MEASUREMENTS

The presence of neuromuscular symptoms was ascertained by questionnaire in 33 consecutive patients with subclinical hypothyroidism (sHT) as compared to 44 age‐ and sex‐matched controls. Blood was sampled for PTH, magnesium, phosphate, and total and ionized calcium determination. Patients reporting three or more symptoms were also studied by surface electromyography (sEMG). The study was repeated following a six‐month L‐T4 course.

RESULTS

Neuromuscular symptoms were significantly more frequent in patients than in controls (P = 0.0001), and correlated with TSH values (r = 0.52; P = 0.0001). Among patients showing three or more symptoms (n = 11), sEMG documented the presence of repetitive discharges in 8 patients. L‐T4 therapy led to a significant improvement of symptoms (P = 0.0001); persistent repetitive discharges were no longer observed. Total and ionized calcium values, always within the normal limits, were significantly lower in patients than controls (P < 0.0001). An inverse relationship was observed between ionized calcium and: TSH values (r = −0.69, P = 0.0001); the number of neuromuscular symptoms (r = −0.53, P = 0.0001). L‐T4 replacement induced a significant increase in both total and ionized calcium levels (P < 0.01 and P < 0.0001, respectively).

CONCLUSIONS

Neuromuscular symptoms and dysfunction are rather common in subclinical hypothyroidism, and may be associated with abnormalities in serum calcium balance and surface electromyography. The ability of L‐T4 treatment to reverse all these changes suggests that subclinical hypothyroidism patients may require early therapy not only to prevent progression to frank hypothyroidism, but also to improve their neuromuscular dysfunction.
The insulin‐like growth factor‐I (IGF‐I) gene in individuals born small for gestational age (SGA)
Authors: Johnston Linda B. , Leger Juliane , Savage Martin O. , Clark Adrian J. L. , Czernichow Paul
Published: March 2003

OBJECTIVE

To investigate the association of genetic variation of the insulin‐like growth factor‐I (IGF‐I) gene with birth size small for gestational age (SGA).

SUBJECTS

We have studied a cohort of 120 SGA patients and 147 appropriate for gestational age (AGA) controls from Haguenau, France.

METHODS

PCR‐SSCP analysis was performed to detect sequence variation in the coding region of the IGF‐I gene. Microsatellite markers near the IGF‐I gene (intronic and D12S78) were selected and amplified to perform further analysis by association studies.

RESULTS

A novel polymorphism in intron 2 was discovered, but allele‐specific PCR analysis in the 120 SGA patients and 147 AGA controls found no association between this polymorphism and birth size SGA. Chi squared (χ2) analysis found no statistically significant association between the allele distribution of the microsatellite markers in the SGA subjects and the AGA controls. Power calculations estimate that the D12S78 marker has an 80% chance of detecting a 10–15% difference.

CONCLUSIONS

These studies suggest that genetic variation of IGF‐I alone does not result in birth size small for gestational age in this population. Thus, if this gene influences fetal size, it plays only a minor role in a multifactorial disorder which involves other genetic and environmental factors.
The prevalence of thyroid dysfunction in a population with borderline iodine deficiency
Authors: Knudsen Nils , Jørgensen Torben , Rasmussen Susanne , Christiansen Erik , Perrild Hans
Published: March 2003

OBJECTIVE

We lack information on the influence of borderline iodine deficiency on the occurrence of thyroid dysfunction. Iodine deficiency has been reported to facilitate the development of toxic nodular goitre, whereas a high iodine intake may increase the prevalence of autoimmune hypothyroidism.

SUBJECTS AND METHODS

In a cross‐sectional study of a random sample of the general population in our region with borderline iodine defficiency 2656 (65%) of 4073 men and women aged 41 to 71 years participated. Records were made of previous thyroidal illness. Blood samples were drawn for thyroid parameters and TPO Ab values. Iodine and creatinine was assessed in casual urine samples.

RESULTS

Previous or present hyperthyroidism was reported by 1.4% of the participants whereas 0.6% had unknown biochemical hyperthyroidism. All cases of undiagnosed hyperthyroidism were among women. Previously diagnosed and treated hypothyroidism was reported by 1.0% and undiagnosed hypothyroidism was found in 0.4%. Subclinical hyperthyroidism was found in 1.3% and subclinical hypothyroidism in 0.7%. TPO Ab titres >200 kU/l were found in 16.9% of the women and 6.6% of the men, and 83% of participants with TSH >5 mU/l had TPO Ab titres >200 kU/l. Participants with TPO Ab titres between 100 and 200 kU/l had no increased frequency of thyroid dysfunction. The median iodine excretion rate was estimated as 103 μg/day. Serum TSH values were higher in women than in men and showed higher dispersion in women as well as in old age. Serum free T3 was found to be higher in women than in men and increased with age. Serum free T4 showed no sex difference but values increased with increasing age.

CONCLUSION

In our region with borderline iodine deficiency more than 5% of the general population has clinical or subclinical thyroid dysfunction. We found a relatively high prevalence of hyperthyroidism, especially previously undiagnosed disease, but a low prevalence of hypothyroidism as would be expected in an area of iodine deficiency. Hypothyroidism was related to TPO Ab titres of >200 kU/l. Thyroid hormone levels varied with age and sex.