bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Gonadotropin-Releasing Hormone Agonist Treatment in Boys with Central Precocious Puberty: Final Height Results
Authors: Mul D. , Bertelloni S. , Carel J.-C. , Saggese G. , Chaussain J.L. , Oostdijk W.
Published: April 2003

Objective: The small number of boys present in most studies on final height (FH) after gonadotropin-releasing hormone agonist (GnRHa) treatment for central precocious puberty (CPP) offers difficulties in the evaluation of the effects of treatment on FH in males. Method: We therefore combined FH data from The Netherlands, Italy and France to study the effect of GnRHa treatment in a large group of 26 boys with CPP. Results: The mean chronological age at the start of treatment was 7.6 ± 2.0 (SD) years, bone age (BA) was 11.0 ± 2.1 years. All boys were treated with depot formulations of the GnRHa triptorelin with established gonadal suppression for a mean treatment period of 4.7 ± 2.1 years. FH was 172.9 ± 6.6 cm. FH standard deviation score (SDS) was –0.66 ± 1.22, not significantly different from the target height SDS of –0.23 ± 0.75. FH-SDS was significantly lower in the subgroup of 12 patients with organic CPP compared to patients with idiopathic CPP (–1.34 ± 1.06 vs. –0.08 ± 1.06, respectively; p = 0.01), but no difference in height gain was observed. The mean estimated height gain, defined as the difference between predicted and actual adult height was 6.2 ± 8.7 cm using the average tables of Bayley and Pinneau, and 0.3 ± 8.6 cm using the BA advance adjusted tables. Regional differences in height gain were observed between the different countries, reflecting different local practices. Conclusion: We conclude that GnRHa treatment in boys results in a FH close to target height.
Effects of Sex Hormones and Their Balance on the Proliferation of Rat Vascular Endothelial Cells
Authors: Liu Jianguo , Wu Saizhu , Wei Heming , Zhou Kexiang , Ruan Yunjun , Lai Wenyan
Published: April 2003

Objective: To investigate the adjustment of estrogen, progesterone and testosterone on the proliferation of female and male rat vascular endothelial cells (VECs) separately. Methods: Rat lung VECs were cultured according to the block explanting method. MTT assay was used to measure the proliferation of VECs. Results: 17β-Estradiol (E2) at 3 × 10–8 and 3 × 10–7 M accelerated the proliferation of female rat VECs (p < 0.01). E2 at 3 × 10–9, 3 × 10–8 and 3 × 10–7 M accelerated the proliferation of male rat VECs (p < 0.05). Tamoxifen, the estrogen receptor antagonist, could block the effect of estrogen on the proliferation of VECs. Testosterone at 3 × 10–8 and 3 × 10–7 M significantly increased the proliferation of male rat VECs (p < 0.05), but had no effect on female rat VECs. Progesterone at 10–9 and 10–8 M had no effect on female rat VECs alone. When the ratio of E2 to progesterone was 3/10, the proliferation of female rat VECs was accelerated (p < 0.05). When the ratio of E2 to testosterone was 1/1, the proliferation of female rat VECs was also hastened (p < 0.05). However, when the ratio was reduced to 1/100, the hastening effect disappeared. Conclusion: Estrogen can speed up the proliferation of female and male rat VECs, while progesterone has no effect on female rat VECs alone. The balance of the ratio of E2 to testosterone, E2 to progesterone may play an important role in the proliferation of female rat VECs.
Mixed Gonadal Dysgenesis and Precocious Puberty
Authors: Iliev D.I. , Ranke M.B. , Wollmann H.A.
Published: April 2003

A girl aged 5 years and 6 months presented with premature thelarche in our outpatient clinic. During long-term observation, we recorded growth acceleration, advanced bone age, and elevated oestradiol levels which together were taken to confirm the diagnosis of precocious puberty. The patient was successfully treated with a gonadotropin-releasing hormone agonist, but in view of the poor growth prognosis, recombinant human growth hormone was administered concurrently. At the age of 9 years and 6 months a mild clitoris enlargement and conspicuous muscle development without any further signs of virilization were noticed. Laboratory findings showed high values for testosterone and normal basal values for 17-hydroxyprogesterone and dehydroepinadrosterone sulphate. Explorative laparotomy revealed a gonadoblastoma arising from testicular structures on the left, a female streak gonad on the right side, and normal uterus and fallopian tubes. The karyotype was 46,XY/45,X. These findings confirmed the diagnosis of mixed gonadal dysgenesis with testosterone-producing gonadoblastoma.
Circulating Tumor Necrosis Factor-Alpha Production during the Progression of Rat Endotoxic Sepsis
Authors: Xuan Dawei , Nicolau David P. , Nightingale Charles H. , Quintiliani Richard
Published: April 2003

The endotoxin-mediated tumor necrosis factor-α (TNF-α) induction was investigated in a rat endotoxin septic shock model. Rats were challenged intravenously with lethal doses of endotoxin. Circulating endotoxin and TNF-α concentrations were measured over various times following endotoxin administration. A derivative of human immunoglobulin G, 5S-IgG, was administered at various times relative to endotoxin dosing to test its anti-endotoxin activity. Results showed that endotoxin challenge initiated substantial amounts of TNF-α release into the rat circulatory system leading to death. A temporal pattern of TNF-α increases following endotoxin administration was observed; the rat plasma TNF-α level rapidly increased 60 min after endotoxin injection, peaked around 120 min and returned to low levels by 240 min. A rapid clearance pattern of endotoxin was also observed in rats. 5S-IgG exhibited its moderate anti-endotoxin activity by partially suppressing the endotoxin-mediated TNF-α release and decreasing the overall mortality only when given before triggering of TNF-α induction. However, this inhibitory effect of 5S-IgG on endotoxin-mediated TNF-α release and the resultant protective effect against endotoxin lethality rapidly diminished when 5S-IgG was administered after the occurrence of TNF-α induction. Collectively, these results suggest that the timing of the anti-endotoxin treatment is critical in achieving its effectiveness and imply that the endotoxin levels after the onset of the cytokine cascade is of questionable significance.
New Targets and Drugs in Cancer Chemotherapy
Authors: Szekeres Thomas , Novotny Ladislav
Published: April 2003

Cancer is still the number two cause of death in highly developed countries. Due to increased life expectancy, the number of cancer cases has also increased, and it is not likely that the incidence of this often fatal illness will decrease in the near future. Breast cancer, for instance, strikes 1 of 8 women in the industrialized world. Incidence of lung cancer increases due to smoking, while that of colon cancer increases with age. These are only a few examples highlighting the growing importance of strategies effective for cancer treatment. Despite surgical treatment and irradiation, chemotherapy remains one of the important means to treat cancer. Although many institutions and companies have tried to establish new treatment strategies such as immunotherapy or vaccination, the conventional chemotherapy still remains an important treatment option. In this review, we present an overview of new and innovative treatment strategies for cancer chemotherapy. A number of new targets as well as anticancer compounds are introduced and though we are well aware of the fact that the list is incomplete, we hope to be able to provide insight into this rapidly developing field.
Vitamin K1 Prevents the Effect of Hypoxia on Phenylephrine-Induced Contraction in the Carotid Artery
Authors: Tirapelli Carlos R. , Mingatto Fábio E. , de Oliveira Ana M.
Published: April 2003

The purpose of the present study was to investigate the effects of vitamin K1 on vascular smooth muscle contractility in response to phenylephrine (Phe) during hypoxia. Rat carotid rings were placed in an organ chamber containing Krebs’ solution. The rings were subjected to hypoxia by changing the gas from 95% O2:5% CO2 to a mixture containing 95% N2:5% CO2. Concentration response curves for Phe were determined before, during, and after exposure to hypoxia. Endothelium-intact rings were incubated with vitamin K1 for 10 min in normoxic conditions before being subjected to hypoxia. In another set of experiments, endothelium-intact rings were incubated with NG-nitro-L-arginine methyl ester (L-NAME), indomethacin or a combination of these drugs for 30 min. In endothelium-intact rings, hypoxia caused significant reductions in Emax (from 0.97 ± 0.03 to 0.61 ± 0.04 g/mg; mean ± SEM) and pD2 values (from 8.26 ± 0.07 to 7.67 ± 0.10). Removal of a functional endothelium effectively prevented the hypoxia-induced reduction in Emax values, but not in pD2 values (from 9.14 ± 0.10 to 8.70 ± 0.11). Pretreatment with vitamin K1 at 3 concentrations (5 × 10–8, 5 × 10–7, 5 × 10–6 mol/l) prevented the inhibitory effect of hypoxia in intact rings. Exposure of endothelium-intact rings to L-NAME plus indomethacin also inhibited the hypoxic effect. Our results show that vitamin K1 prevents the deleterious vascular effects induced by hypoxia, probably due to its action on endothelial cells.
Smoking during Pregnancy: A Way to Transfer the Addiction to the Next Generation?
Authors: Hellström-Lindahl Ewa , Nordberg Agneta
Published: April 2003

Many epidemiological studies support a relationship between maternal smoking during pregnancy and adverse neurobehavioral effects later in life. Prenatal exposure to tobacco seems to increase the risks for cognitive deficits, attention deficit/hyperactivity disorder, conduct disorder, criminality in adulthood and a predisposition in the offspring to start smoking and alcohol abuse. Nicotine readily crosses the placenta and the fetuses of mothers who smoke are exposed to relatively higher nicotine concentrations than their mothers. In the fetal brain nicotine can activate nicotinic receptors which play an important role during development of the brain. A direct specific action on the developing human brain is plausible during the major part of the prenatal life, since the nicotinic receptors are already present in the brain during the first trimester.
Clinical Evaluation of Anaphylactic Reactions to Intravenous Corticosteroids in Adult Asthmatics
Authors: Nakamura Hideyo , Matsuse Hiroto , Obase Yasushi , Mitsuta Kazuko , Tomari Shinya , Saeki Sachiko , Kawano Tetsuya , Kondo Yuki , Machida Ikuko , Shimoda Terufumi , Asai Sadahiro , Kohno Shigeru
Published: April 2003

Background: Corticosteroids form an important component of the treatment of acute asthma. Systemic anaphylactic reactions to intravenous corticosteroids have been reported, although their incidence is extremely rare. Objectives: To determine the clinical features and underlying mechanisms of anaphylactic reactions to intravenous corticosteroids in adult asthmatics. Subjects and Methods: The clinical features of 7 adult asthmatics (4 males, 3 females, mean age 39.4 ± 16.9 years), who had developed systemic anaphylactic reactions to intravenous administration of corticosteroids for the treatment of acute asthma, were studied retrospectively on the basis of their medical records. Skin tests using various injectable steroid preparations were performed in 3 cases to determine the mechanism of this reaction. Results: Systemic anaphylactic reactions to intravenous administration of corticosteroids occurred in severe atopic asthmatics with previous exposure to parenteral corticosteroids, irrespective of age and gender. Aspirin-intolerant asthma was identified in only 3 subjects. In all cases, anaphylactic reactions were induced following intravenous administration of succinate-containing corticosteroid preparations, i.e. hydrocortisone and methylprednisolone. Administration of phosphate-containing corticosteroids, i.e. dexamethasone and betamethasone, was safe and resulted in a resolution of anaphylactic symptoms. Immunological examination with skin tests suggested that anaphylactic reactions were an IgE-mediated hypersensitivity. Conclusions: Intravenous injection of succinate-containing corticosteroids in high-risk asthmatics should be performed slowly by drip injection under continuous monitoring. Once anaphylactic reactions occur, it is important to stop the injection immediately and to use conventional medication for anaphylaxis.
Renal Prostacyclin Biosynthesis in a Baboon Model of Shiga Toxin Mediated Hemolytic Uremic Syndrome
Authors: Siegler Richard L. , Pysher Theodore J. , Tesh Vernon L. , Taylor Fletcher B.
Published: April 2003

Background/Aims: Shiga toxin (Stx) and lipopolysaccharide (LPS) both participate in the pathogenesis of post-diarrheal (D+) hemolytic uremic syndrome (HUS), but little is known about factors that modulate the host response to these toxins. Prostacyclin (PGI2) is a potent renal vasodilator and inhibitor of platelet aggregation and adhesion. An inability to produce PGI2 in response to endothelial cell injury could drive the pathogenic cascade. We therefore used a baboon model of HUS to measure PGI2 production following the administration of Stx and LPS. Methods: Shiga toxin-1 (Stx-1), with and without LPS, was administered intravenously to baboons in various doses and schedules. 6-keto-PGF1α, the stable metabolite of PGI2, was measured by ELISA in the plasma and urine. Results: Plasma concentrations did not change significantly. Urine values increased significantly in some groups, but not in others, and HUS developed both in animals that did and did not exhibit a significant increase in urinary PGI2 production. Conclusions: Renal PGI2 biosynthesis appears to be affected by the dose and rate of Stx administration, and the timing of LPS infusion. PGI2 does not protect our primate model from developing HUS.
Sexual Activity of Women and Men One Year before a First Acute Myocardial Infarction
Authors: Drory Yaacov , Kravetz Shlomo , Hirschberger Gilad
Published: April 2003

A decrease in sexual activity after an acute myocardial infarction (AMI) for both women and men has been reported with one study suggesting that this reduction in sexual activity may precede rather than proceed the AMI. The present study compared the sexual activity of women and men before AMI to the sexual activity of a normative community sample of women and men, to examine whether the above reduction in sexual activity is especially characteristic of women and men who later incur an AMI. This study also investigated the association between selected medical and sociodemographic variables and sexual inactivity of women and men before an AMI. During an interview before discharge,138 women and 760 men who were hospitalized due to a first AMI responded to a question regarding the frequency of their sexual activity 1 year before the AMI. Their sociodemographic and medical background was obtained from the interview and the medical charts. When compared to a normative sample, only women reported significantly less sexual activity during the year before their AMI. These women were also found to be at a disadvantage when compared to men on many of the sociodemographic and medical variables shown to contribute to sexual inactivity for both men and women. However, the higher percent of sexual inactivity for women during the year before AMI may not only be due to women’s higher morbidity and lower sociodemographic status. Other variables not included in this study, but associated with gender, could account for this result.
The Spectrum of Contact Allergy in Elderly Patients with and without Lower Leg Dermatitis
Authors: Uter Wolfgang , Geier Johannes , Pfahlberg Annette , Effendy Isaak
Published: April 2003

Background: There is a strong influence of lower leg dermatitis on the spectrum of allergic contact sensitivity in elderly patients. Objective: To quantitatively assess the impact of this factor which confounds the age-related pattern of allergic contact sensitivity. Methods: Stratified analysis of allergic contact sensitivity data collected between 1996 and 1999 in the 32 centres of the Information Network of Departments of Dermatology (three age groups: ≤60, 61–75, ≧76 years), both as crude and as directly standardised (for sex and leg dermatitis) proportions. Results: Among the 36,070 patients tested with the German standard series, allergic contact sensitivity to neomycin, lanolin, cetostearylic alcohols, colophony, fragrance mix and balsam of Peru, among others, was (much) more common in the elderly, with proportions more or less affected by standardisation. Conclusion: The comparison of crude and standardised proportions provides evidence that allergic contact sensitivity to several allergens strongly depends not only on age itself, but on age-related and thus confounding co-morbidity.
Multiple Congenital Symmetric Skin Dimples
Authors: Virgili Annarosa , Tosti Giulio , Bettoli Vincenzo , Corazza Monica
Published: April 2003

Skin dimples are seldom observed in sites other than the face. We report on a male premature child who was seen at the age of 2 months for the evaluation of cutaneous depressions symmetrically located on the shoulders, elbows and in the sacral region. Skin dimples have sometimes been considered a benign autosomal dominant trait. However, several authors have reported these cutaneous defects in a variety of conditions like congenital syndromes, infections, inborn errors of metabolism and mechanical trauma. In our case, the aetiology is unknown, even though maternal drug or infective exposure can reasonably be excluded as well as traumatic events. At a 3-year follow-up, the patient shows a normal psychophysical development. This appears to be the first case of a child presenting congenital, symmetric dimples in three different areas.
Invasive Tricholemmal Carcinoma of the Nose
Authors: van Zele Dirk , Arrese Jorge E. , Heymans Olivier , Fissette Jean , Piérard Gérald E.
Published: April 2003

Tricholemmal carcinoma is a rare entity. It must be distinguished from the benign proliferating variant of the tricholemmal cyst. We report a case of tricholemmal carcinoma massively invading the nose. The neoplasm was excised surgically with a satisfactory outcome.
Cutaneous Mycobacterium chelonae Infection Extending Distally in a Hemodialysed Patient
Authors: Kolivras Athanassios , De Berdt Pierre-André , Theunis Anne , Hooghe Luc , De Maubeuge Josiane , Dratwa Max , Song Micheline
Published: April 2003

We report a case of a cutaneous Mycobacterium chelonae infection on the dorsum of the forearm of a patient undergoing chronic hemodialysis. The infection showed a linear and distal extension. This unusual distal dissemination was apparently secondary to a venous reflux, a circulatory repercussion of the patient’s arteriovenous fistula.
A Double-Blind Placebo-Controlled Study of Ketoconazole + Desonide Gel Combination in the Treatment of Facial Seborrheic Dermatitis
Authors: Piérard-Franchimont C. , Piérard G.E.
Published: April 2003

Background: The pathobiology of seborrheic dermatitis is rooted in a peculiar inflammatory reaction to Malassezia spp. Both topical corticosteroids and antifungals are routinely used with success, either singly or in combination. Objective: To assess the effect of a new combination therapy in this condition. Methods: Eighteen patients with facial seborrheic dermatitis were treated in a pilot double-blind trial with an anhydrous gel containing the combination of 2% ketoconazole and 0.05% desonide (n = 9) or the unmedicated gel (n = 9). The products were applied once daily for 3 consecutive weeks. Disease severity was assessed at the start and weekly during treatment, as well as 2, 4 and 8 weeks after the end of treatment or at the time of recurrence. The overall clinical assessments were performed using a visual analogue scale. Objective measurements included squamometry X after harvesting the stratum corneum and the erythema index yielded by narrow-band reflectance spectrophotometry. Data were evaluated in an intent-to-treat analysis. Results: The combination therapy yielded reductions in the overall clinical symptom severity of 49, 84 and 92% after 1, 2 and 3 weeks of treatment, respectively. The corresponding improvements with the placebo gel were significantly smaller (p < 0.01), reaching 23, 29 and 42% at successive 1-week intervals. At the end of the 3-week treatment, the clinical signs had completely subsided in 6/9 patients treated with the medicated gel and in only 1/9 patients using the placebo gel. Thus, the clinical response rate was significantly faster (p < 0.01) with the combination therapy than with the vehicle. Differences between the treatment groups using objective noninvasive assessments were also significantly (p < 0.01) in favor of the combination therapy. The squamometry X measurements showed 47, 67 and 74% improvements with the combination gel after 1, 2 and 3 weeks, respectively. The corresponding values with the placebo gel were 34, 46 and 53%, respectively. The erythema index was almost completely reduced to normal at week 2 of treatment in contrast with about 50% reduction with the unmedicated vehicle. None of the patients reported any side effects. Conclusion: The combination of ketoconazole with desonide in an anhydrous gel is well tolerated and proves to be significantly more effective than the vehicle for treating facial seborrheic dermatitis. The fast response to treatment and the limited additional improvement between weeks 2 and 3 of the treatment suggest that this combination product may be efficacious with once daily applications for 2 weeks. These data call for expanded studies comparing each single compound, the vehicle and the combination therapy.
Multiple HPV-Positive Basal Cell Carcinomas on the Abdomen in a Young Pregnant Woman
Authors: Sass U. , Theunis A. , Noël J.C. , André J. , Song M.
Published: April 2003

Basal cell carcinoma (BCC) is the most common malignant skin tumour. In the last few years, the incidence of multiple BCC has also increased in young patients. We describe the clinical case of a young 29-year-old woman who developed 7 BCC on her abdomen during her first pregnancy and 4 other similar tumours 2 years later during her second pregnancy, all located on the abdomen. Polymerase chain reaction revealed the presence of numerous human papillomavirus DNA sequences. To our knowledge, such a clinical presentation has not been previously reported. Different physiopathological considerations are discussed.
Natural History of 70 Fetuses with a Prenatally Diagnosed Orofacial Cleft
Authors: Bergé Stefaan J. , Plath Hanno , von Lindern Jens J. , Appel Thorsten , Niederhagen Bernd , van de Vondel Patricia T. , Hansmann Manfred
Published: April 2003

Objective: This study is an analysis of neonatal outcome in 70 fetuses diagnosed over a 10-year period as having cleft lip with or without cleft palate (CL-P) by ultrasonographic examination. Methods: We describe the natural history of these 70 fetuses with orofacial clefts and select those who may be candidates for fetal surgery. The sonograms of 70 fetuses with orofacial clefts were evaluated for the nature of the CL-P and for the nature of the associated anomalies. Additionally, karyotyping was performed in 63 of 70 patients (90%). Results: The frequency of additional anomalies and the mortality rate varied with the type of cleft. Also, the frequency and type of chromosomal abnormalities varied with the type of cleft. The overall mortality rate was 63% (n = 44). 3 of the surviving 26 fetuses had severe associated anomalies. In 13 of the remaining 23 cases, the fetal age at diagnosis (≧22 weeks) excluded the fetuses from the potential benefits of fetal intervention. Conclusion: Of 70 fetuses with prenatally diagnosed orofacial clefts, only 10 (14%) were candidates for fetal CL-P surgery.
Preterm Premature Rupture of Membrane and Twin-to-Twin Transfusion Syndrome before 20 Weeks: A Favourable Outcome
Authors: Gire C. , Nicaise C. , ShoJaï R. , Chau C. , Boubli L. , d’Ercole C.
Published: April 2003

We describe a monochorionic twin gestation with a severe twin-to-twin transfusion syndrome associated with a preterm premature rupture of membranes at 20 weeks of gestation in the polyhydramniotic sac. The pregnancy was managed expectantly and outcome was favourable for the 2 neonates. We discuss how these two severe pathologies seem to counteract each other by compensations of their symptoms.
Clinical Assessment and Serum Hormonal Profile in Prepubertal Hypertrichosis
Authors: Gryngarten M. , Bedecarràs P. , Ayuso S. , Bergadà C. , Campo S. , Escobar M.E.
Published: April 2003

Twenty-two prepubertal girls with hypertrichosis were studied and compared to 10 prepubertal normal girls. Hypertrichosis was assessed according to a score that considers the amount and the distribution of vellus hair in androgen- and non-androgen-sensitive areas. Serum androgen profile and free androgen index (FAI) were determined in both groups. The hypertrichosis score was higher in patients than in the normal girls. Testosterone levels and FAI were increased in patients when compared to control; 3α-androstanediol glucuronide levels above 2 SD from the control mean were found in 10 girls and all hormonal parameters falling in the normal range were found in 4 girls. The new score designed to assess the degree of hypertrichosis was useful to differentiate between normal and pathological hair growth. Although most of the girls with prepubertal hypertrichosis showed an increased androgen bio-availability, a slight increase in peripheral 5α-reductase activity and a completely normal androgen profile was also associated with a pathological hair growth.
Progesterone Receptor Isoforms, PR-B and PR-A, in Breast Cancer: Correlations with Clinicopathologic Tumor Parameters and Expression of AP-1 Factors
Authors: Bamberger Ana-Maria , Milde-Langosch Karin , Schulte Heinrich M. , Löning Thomas
Published: April 2003

In the present study, we used Western blot analysis to determine the expression of the progesterone receptor (PR) isoforms, PR-B and PR-A, in breast tumors (n = 53), and correlated the expression patterns of the two isoforms with the clinicopathological parameters of these tumors and with expression of the AP-1 family of transcription factors. Expression of the two PR isoforms correlated significantly with each other, indicating that the expression of the two isoforms is probably regulated in a correlated fashion. Expression of both isoforms correlated significantly with expression of the estrogen receptor (ER). Furthermore, expression of PR-B was found to correlate significantly with the absence of ErbB2/neu. For the AP-1 factors, Fra-1 expression showed an inverse correlation with PR-B expression. In contrast, expression of FosB correlated significantly with expression of both isoforms, and the association was stronger with PR-B expression. An analysis of the ratio of expression of the two isoforms showed that most of the tumors expressed PR-A levels which were equal or higher than the corresponding PR-B expression levels (together 94% of the analyzed tumors) indicating that, in mammary carcinomas, a predominance of the PR-A isoform over the PR-B isoform seems to be the case. While there was no statistically significant correlation with age, staging and histological type, expression of both isoforms correlated with a more differentiated phenotype (G1/G2 grading). However, this association was stronger for PR-B. Also, a PR-A ≤ PR-B expression level was associated with G1/G2 grading, while a PR-A > PR-B expression level showed an association with a more undifferentiated phenotype (G3 grading). The expression level of the two PR isoforms might prove to be of prognostic and/or predictive value, especially since the two isoforms have been shown to be functionally different and to modulate the response of tumor cells to progestins and antiprogestins differently.
Hormonal Regulation of Sodium-Dependent Phosphate Transport in Opossum Kidney Cells
Authors: Silverstein Douglas M. , Spitzer Adrian , Barac-Nieto Mario
Published: April 2003

There are multiple regulators of renal proximal tubule sodium-dependent phosphate (Na+-Pi) transport, including 1,25-dihydroxyvitamin D (1,25-Vit. D), parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), and arachidonic acid (AA) and/or its metabolites. The purpose of our studies was to determine whether the effect of these factors on Pi transport is synergistic or antagonistic. The control solution or the substances were added independently or coincidentally to opossum kidney (OK) cells before incubation for 4 h. 1,25-Vit. D (10–8M) had no significant effect on Pi transport (↑6.8%; p = 0.8). PTH (10–7M) significantly inhibited Pi transport by 39.6% (p < 0.0001). IGF-1 (10–8M) stimulated Pi transport by 19.6% (p < 0.0001). The AA metabolite 20-HETE (10–7M) had no significant impact on Pi transport (⇓6.4; p = 0.3). The combined effect of 1,25-Vit. D and PTH was no different from PTH alone (p = 0.2). Likewise, addition of either 1,25-Vit. D or 20-HETE to IGF-1 failed to affect the magnitude of the increase on Pi transport induced by IGF-1 alone (p = 0.4, p = 0.6, respectively). The combination of 20-HETE and PTH was not different from that observed with PTH alone (p = 0.9). We conclude that in OK cells, PTH inhibits whereas IGF-1 stimulates Pi transport into OK cells. The effects of each of these hormones are independent and unaffected by either 1,25-Vit. D or 20-HETE.
Insulin Resistance and Insulin Sensitizers
Authors: Stumvoll Michael , Häring Hans
Published: April 2003

Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-α and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) γ is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in β-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARγ-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance.
Growth Hormone Receptor Signalling and Actions in Bone Growth
Authors: Kelly Paul A. , Finidori Joëlle , Moulin Stéphanie , Kedzia Cécile , Binart Nadine
Published: April 2003

Growth hormone (GH) acts by binding to a membrane receptor that is part of the cytokine receptor superfamily. Ligand binding induces receptor dimerization leading to activation of the associated tyrosine kinase, Janus kinase (Jak) 2. Transphosphorylation of Jak2 occurs followed by tyrosine phosphorylation of the receptor, and numerous cytoplasmic proteins. Among these are the signal transducers and activators of transcription (Stat) proteins, as well as adaptor proteins leading to the activation of the Ras/mitogen-activated protein (MAP) kinase and the phosphatidyl-inositol-3′-kinase (PI 3-kinase) pathways. Activation of the GH receptor system is relatively transient, with several mechanisms being involved in down-regulation: internalization and degradation of the receptor and recruitment of phosphatases or specific inhibitors of the Jak–Stat pathway, the suppressors of cytokine signalling (SOCS) proteins. Finally, the use of the GH receptor knock-out mouse model has allowed us to dissect the role of this hormone in post-natal body growth and homeostasis.
The Ontogeny of Growth Hormone Sensitivity
Authors: Parks John S.
Published: April 2003

For many years it was believed that the growth hormone (GH) axis does not play a role in growth before birth or during the first year after birth. More recently, however, studies of genetic disorders of growth have led to developments in our understanding of the onset of GH sensitivity and the relationships between the maternal and fetal GH axes. Many children whose GH deficiency (GHD) is diagnosed in late childhood have a good rate of growth in their first year of life. This can be explained when one considers the differences between pituitary and hypothalamic GHD. Many children in whom GHD is diagnosed later in childhood have hypothalamic GHD, which may be masked in the first year of life by a relative lack of somatostatin secretion. Genetic defects in the GH axis lead to a slight degree of growth retardation at birth, consistent with growth impairment in the third trimester only. Conversely, a boy with a deletion in the insulin-like growth factor I (IGF-I) gene showed severe growth retardation at birth, indicating a role for IGF-I during the second and third trimesters. From these results, there are two possible models for the relationship between IGF-I production and other components of the maternal–fetal GH axis: independence of the IGF-I axis from somatotropic influences during the second trimester or, alternatively, redundancy of somatotropic hormones and their receptors. From reports of individuals with naturally occurring mutations that eliminate contributors to the GH axis, redundancy does indeed appear to be a feature of the maternal–fetal GH axis, with GH sensitivity arising around mid-gestation.
Growth Hormone Insensitivity: Pathophysiology, Diagnosis, Clinical Variation and Future Perspectives
Authors: Savage Martin O. , Burren Christine P. , Blair Joanne C. , Woods Katie A. , Metherell Louise , Clark Adrian J.L. , Camacho-Hübner Cecilia
Published: April 2003

The study of genetic growth hormone (GH) insensitivity is an evolving field. GH insensitivity syndrome (GHIS), otherwise known as Laron syndrome, is a heterogeneous disorder. Biochemical features consist of severe insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) deficiency and elevated GH secretion. In a heterogeneous ‘European’ cohort of GHIS patients, features varied from classical to moderate abnormalities of phenotype and endocrine disturbance. A study of facial features within this series showed that a mild subgroup existed with normal facies, mild short stature and moderate biochemical abnormalities. Overlap with idiopathic short stature (ISS) exists, with heterozygous mutations of the GH receptor demonstrated to cause impaired growth. This ‘partial’ GHIS has not yet been defined endocrinologically. GH sensitivity, measured by IGF-I and IGFBP-3 responses in the IGF-I generation test, may reveal abnormalities in ISS, although it is likely that the dose of recombinant human GH and frequency of sampling in the test need to be modified.
Growth Hormone Insensitivity Syndromes: Lessons Learned and Opportunities Missed
Authors: Rosenfeld Ron G. , Buckway Caroline K.
Published: April 2003

The concept of growth hormone (GH) insensitivity has evolved since the condition was originally identified in 1966, and we now know that the primary defect involved is in the GH receptor. Cloning of the receptor molecule has led to great progress in our understanding of GH insensitivity (GHI) and its therapy, including the roles of GH and insulin-like growth factor I (IGF-I) in growth and development, and the relationships between height and serum levels of GH, IGF-I and their binding proteins. Despite the success of work on GHI and IGF-I, a number of opportunities have been missed in the past. The differences between the metabolic effects of GH and IGF-I are not fully understood, while measurements of IGF-I and IGF-binding protein 3 are perhaps not the ideal means of diagnosing GHI. Finally, the use of IGF-I to treat GHI has a number of limitations, and work is underway to develop alternative therapies.
Biochemical Markers of Individual Response to Growth Hormone Replacement in Adults
Authors: Monson John P.
Published: April 2003

Options for determining the response to growth hormone (GH) replacement in adults include symptomatic response, changes in body composition and measurement of biochemical markers of GH action. It has become apparent from various studies and during routine clinical practice that abnormal elevation of serum markers of GH action during GH therapy may not be associated with either adverse symptoms or abnormalities in body composition, thereby limiting the value of subjective assessment and physical characteristics as safety markers of over-treatment. Candidate biochemical markers include insulin-like growth factor I (IGF-I), IGF-binding protein 3 (IGFBP-3) and the acid-labile subunit (ALS), and markers of bone remodelling. No single measurement provides an ideal index of adequacy of GH replacement. Serum IGF-I has the greatest utility during GH dose titration as it is more sensitive to changes in GH status than IGFBP-3 and ALS, and is also more sensitive to excessive GH replacement. IGF-I, therefore, provides an important safety marker. Furthermore, changes in IGF-I correlate with improvements in body composition. Changes in circulating insulin and leptin occur during GH therapy, but are significantly influenced by changes in body fat and its distribution and do not provide useful information upon which to gauge responsiveness to GH. Markers of bone remodelling are an important indicator of GH action within individuals, but exhibit wide inter-individual variation which limits their usefulness in defining relative GH responsiveness.
Safety in Growth Hormone Replacement Therapy: A Matter of Varied Responsiveness?
Authors: Wilton Patrick
Published: April 2003

Many studies of dosing and pharmacokinetics in growth hormone (GH) replacement therapy have been conducted, whereas there have been few studies examining GH sensitivity and individual responses to GH. It is probable that sensitivity to GH in terms of beneficial effects will be different from sensitivity in terms of fluid retention. Several factors, including age, body mass index and GH-binding protein levels have been implicated in growth and metabolic responses to GH in children and adults, respectively. Fluid retention during GH replacement in adults has been linked to age, body mass and body mass index. These conclusions are broadly supported by data from KIMS (Pharmacia International Metabolic Database), which also show that women are more susceptible than men to symptoms of fluid retention during GH replacement. Very few children undergoing GH therapy experience fluid retention, and thus it is difficult to draw conclusions about sensitivity. In the future, multiple regression analysis may be a useful tool for fully understanding the factors involved in individual responses to GH replacement.
Sensitivity to Growth Hormone – The Perspective
Authors: Monson John P. , Rosenfeld Ron G.
Published: April 2003

This round table discussion addressed the utility of insulin-like growth factor I (IGF-I) as a predictor of growth hormone (GH) action, the relationship between IGF-I response to GH and growth response, the possibility of a spectrum of both GH sensitivity and IGF-I sensitivity, and an examination of the possible need to acknowledge indicators of GH action in children which are distinct from those in adults.
Insulin-Like Growth Factor I Measurement on Filter Paper Blood Spots
Authors: Jones Jennifer S.
Published: April 2003

The measurement of insulin-like growth factor I (IGF-I) from extracted whole dried blood spots on filter paper is a simple method allowing sample collection to be carried out by the patient at home. One drop of blood is applied to a filter card, air dried and posted to the laboratory. The IGF-I is dissociated from its binding protein by an acidification and neutralization procedure, and IGF-I is then measured by an enzyme-linked immunosorbent assay. Results from the analysis of IGF-I using blood spots on filter paper compared favourably with those from conventional methods, thus showing it to be an ideal and cost-effective technique for the measurement of IGF-I in both adults and children.
Free Insulin-Like Growth Factor I: Are We Hunting a Ghost?
Authors: Bang Peter , Ahlsén Maria , Berg Ulrika , Carlsson-Skwirut Christine
Published: April 2003

During the last decade, there has been an increasing number of publications reporting concentrations of free dissociable insulin-like growth factor I (IGF-I) in serum or plasma. The goal for attempting to measure free IGF-I in a serum sample in vitro has been to obtain information about the bioactivity of IGF-I in target tissues, and thus relate a measurable parameter to biological responses such as longitudinal growth or glucose disappearance rate. In this review, the serum free IGF-I approach is placed into a physiological perspective. In addition, methodological aspects are discussed and suggestions for the validation of free IGF-I assays are presented.
Determination of Insulin-Like Growth Factor I in Children: Normal Values and Clinical Use
Authors: Juul Anders
Published: April 2003

Circulating insulin-like growth factor I (IGF-I) levels are stable throughout the day and correlate with pulsatile endogenous growth hormone (GH) secretion. A single measurement of IGF-I may, therefore, provide information on the GH secretory status of an individual. The clinical use of IGF-I determination in the evaluation of short stature in children suspected of GH deficiency will be discussed. Previous methodological problems have now mostly been overcome, and IGF-I can be determined in serum from healthy children, although concentrations exhibit large inter-individual variations relating to age, gender and pubertal maturation. These variations must be taken into account before IGF-I can be evaluated in a clinical situation, and before it can be stated whether a certain value is too low for a given age. The diagnostic sensitivities of IGF-I reported in relation to the outcome of GH provocative testing are variable (47–100%). This variability probably results from the use of different IGF-I assays, IGF-I reference ranges, and different GH testing procedures. When proper IGF-I assays and reference ranges are used, however, IGF-I determination results in valid diagnostic information regarding children exhibiting short stature. Thus, an IGF-I value should always be evaluated together with auxological information and GH testing results before a decision is taken on whether or not to start GH therapy.
Renoprotective Mechanisms of Angiotensin II Antagonism in Experimental Chronic Renal Failure
Authors: Uhlenius Nina , Miettinen Aaro , Vuolteenaho Olli , Tikkanen Ilkka
Published: April 2003

Aims: We investigated angiotensin II and nitric oxide-cGMP pathway in the development of hypertension and renal damage in chronic experimental nephritis. Methods: Rats with autoimmune nephritis were treated for 12 weeks with AT1 receptor antagonist L-158,809 and/or ACE inhibitor captopril given in drinking water. Blood pressure, urinary albumin, and urinary excretion of cGMP were measured. Renal density of ACE, AT1 and AT2 receptors was determined by quantitative in vitro autoradiography. Results: L-158,809, captopril, and their combination decreased blood pressure and normalised urinary albumin excretion rate in rats with nephritis. In L-158,809-treated rats, cGMP excretion was increased compared to the vehicle-treated nephritic group suggesting that the dysfunctional nitric oxide system may be activated by angiotensin antagonism. In nephritic rats, AT1 and AT2 receptor binding densities in renal medulla were decreased, cortical AT receptor expression remained unchanged. Following L-158,809 treatment, both AT1 and AT2 receptor binding was suppressed. Conclusion: Long-term blockade of AT1 receptors in chronic nephritis has beneficial effects both on albuminuria and blood pressure being as effective as ACE inhibition or their combination. The stimulatory effect of AT1 receptor antagonism on cGMP production was not mediated by AT2 receptor-dependent mechanisms suggesting that AT1 receptor blockade per se favours activation of humoral pathways that stimulate cGMP production and potentially contribute to renal protection in chronic nephritis.
Endothelial Nitric Oxide Synthase Affects the Progression of Autosomal Dominant Polycystic Kidney Disease
Authors: Reiterová Jana , Merta Miroslav , Tesař Vladimír , Štekrová Jitka
Published: April 2003

Background/Aim: The phenotypic variability of autosomal dominant polycystic kidney disease (ADPKD) cannot be explained only by various mutations of two known genes (PKD1 and PKD2), but the influence of other unknown factors should also be considered. Impairment of endothelial function has been observed in ADPKD patients. Our study tried to verify the hypothesis that endothelial nitric oxide synthase (ecNOS) gene polymorphisms in intron 4 could have some relevance to the progression of ADPKD. Methods: We examined 155 Czech patients with ADPKD (80 males, 75 females; mean age 43.4 ± 14.7 years) and 100 genetically unrelated healthy subjects (50 men, 50 women; mean age 51.2 ± 8.2 years). The genomic DNA was amplified by polymerase chain reaction and the products were separated on 1.5% agarose gel and visualised by ultraviolet transillumination. We compared subjects homozygous for the ecNOSb allele with subjects homozygous and heterozygous for the ecNOSa allele. Results: The frequencies of ecNOSb/b, ecNOSa/b and ecNOSa/a were 81% (81/100), 17% (17/100) and 2% (2/100), respectively, in the control group, 60% (30/50), 32% (16/50) and 8% (4/50), respectively, in ADPKD patients with end-stage renal failure (ESRF), and 68.5% (72/105), 28.6% (30/105) and 2.9% (3/105), respectively, in ADPKD patients with normal renal function. The two-tailed t test revealed that the frequency of the ecNOSa allele (ecNOSa/b and ecNOSa/a) in dialysed patients was significantly higher than in ADPKD patients with normal renal function (p < 0.05). Conclusion: The a allele of the ecNOS gene polymorphism showed a significantly higher incidence among patients with ESRF caused by ADPKD. The a allele might have a negative influence on the progression of ADPKD.