bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Systemic Administration of Human Recombinant Interleukin-1β Induces a Dose-Dependent Fall in Circulating Parathyroid Hormone in Rats
Authors: Lippuner K. , del Pozo E. , MacKenzie A. , Jaeger Ph.
Published: April 2003

The synergism/antagonism between interleukin (IL)-1β and parathyroid hormone (PTH) has been the subject of in vitro and in vivo work, but a possible direct action of the cytokine on PTH release has not been reported. We have investigated the effect of a continuous infusion of human recombinant IL-1β (rIL-1β) on circulating PTH during a 14-day period in 7-week-old female rats. This time interval was chosen in order to exclude initial hypercalcemia and to enable data collection under steady-state conditions. Five groups of 20 animals each had miniosmotic pumps (Alzet 2002, 200 µl) implanted subcutaneously and primed to release either distilled water (controls) or 100, 500, 1,000 and 2,000 ng/24 h of rIL-1β. Blood was drawn on days 1 and 14 for PTH, corticosterone and Ca2+ determinations. Adequate biological activity of the infused rIL-1β was supported by elevated rectal temperature records and significant elevations of plasma corticosterone on day 14. The 100-ng dose had no effect but 500–2,000 ng rIL-1β/24 h significantly reduced plasma PTH in a dose-dependent manner down to 54% of basal value (20.4 ± 1.1 vs. 15.3 ± 1.4 pg/ml for 500 ng, p < 0.005; 20.5 ± 1.3 vs 12.3 ± 1.1 for 1,000 ng, p < 0.001, and 19.5 ± 2.0 vs. 10.6 ± 1.1 pg/ml for 2,000 ng, p < 0.0008). Despite these findings, no differences in blood Ca2+ could be detected between treated animals and controls. The following conclusions can be inferred from the foregoing: Systemic administration of rIL-1β to rats induced a dose-dependent fall in circulating PTH without altering calcemia, calling into question the biological relevance of the former finding. Although the recorded PTH depression may indeed not have been severe enough to cause hypocalcemia, it can be hypothesized that osteoclast activation by rIL-1β would enhance bone mineral release into the pool compensating for depressed PTH activity.
Use of the New US90 Standards for TW-RUS Skeletal Maturity Scores in Youths from the Italian Population
Authors: Vignolo M. , Naselli A. , Magliano P. , Di Battista E. , Aicardi M. , Aicardi G.
Published: April 2003

Recently, 1997, Tanner and co-workers provided a new scale converting TW-RUS standard maturity scores to skeletal age for European North American youths (US90). The aim of the present study was to test if the accuracy of TW-RUS bone age assessments in the Italian population could be improved by evaluating the estimates obtained with this new scale in comparison with other standards (UK60: original British series, B70: Belgian series and S80: Spanish series). 1,831 hand-wrist radiographs (Italian healthy subjects aged from 8 to 16.8 years) were evaluated. The US90 reference values are resulted the most suitable TW-RUS standards. Therefore, it seems useful to update the reference values of TW-RUS SMS in Italian youths, using this new scale.
Effects of Glycyrrhizin on Production of Vascular Aldosterone and Corticosterone
Authors: Wu Pingsheng , Zhang Yongsheng , Liu Yili , Wang Xuan , Guo Zhigang , Zhang Yuanhui , Liang Xinwei , Lai Wenyan
Published: April 2003

This study is to confirm the role of glycyrrhizin on blood pressure and to test the effects of glycyrrhizin on production of vascular aldosterone and corticosterone in rats. Male Wistar rats received glycyrrhizin (Sigma) 200 mg/kg/day p.o. for 5 weeks, and blood pressure was monitored by a pressure transducer. Systolic blood pressure significantly increased in Wistar rats treated with glycyrrhizin compared to that without glycyrrhizin. Mesenteric artery perfusion ex vivo and pressor responses to norepinephrine were performed. The pressor responses to norepinephrine in mesenteric arteries treated with glycyrrhizin were significantly increased. The perfusate from the mesenteric arteries was collected and applied to a Sep-Pak C 18 cartridge column, used for reverse-phase high-performance liquid chromatography, and measured for both aldosterone and corticosterone by radioimmunoassay. Levels of aldosterone were decreased but those of corticosterone increased in perfusate from arteries treated with glycyrrhizin. RT-PCR showed that glycyrrhizin inhibited the expression of 11β- HSD2 and CYP11B2 mRNA in mesenteric arteries. These results confirm that glycyrrhizin is able to induce hypertension, and provide evidence that it inhibits the transcriptions of both 11β-HSD2 and CYP11B2 in the vasculature, leading to lower aldosterone and higher corticosterone production in vessels, and increased vasoconstrictor responses to norepinephrine.
Bioactivity of Luteinizing Hormone during Normal Puberty in Girls and Boys
Authors: Schroor Eelco J. , van Weissenbruch Mirjam M. , Engelbregt Mia , Martens Frans , Meurs Jacoline M. , Wennink Johanna M.B. , Delemarre-van de Waal Henriette A.
Published: April 2003

In order to evaluate the in vitro bioactivity of LH during normal puberty compared to LH immunoactivity measured in a highly sensitive immunoassay, blood plasma samples from healthy children were analyzed in a mouse Leydig cell assay (MLCA). Blood samples were obtained from 60 healthy girls and boys during normal pubertal development. Samples were taken on two occasions with a 1-year interval. Three daytime samples and three nighttime samples were analyzed. The correlation of the LH immunoradiometric assay (IRMA) activity with the LH activity in the MLCA varied from 0.60 to 0.96 in the different pubertal stages. During pubertal development, a gradually increase in the activity of LH in both the IRMA and MLCA was found. The ratio of the in vitro bioactivity compared to the immunoreactivity (B/I ratio) did not change significantly during puberty: it was 0.84 (SD 0.58) and 0.66 (SD 0.40) during the first and second sampling period in girls and 0.88 (SD 0.38) and 0.91 (SD 0.46, NS) in the boys. The B/I ratio of LH does not change during puberty. With a high sensitivity and specificity, measurement of LH by IRMA gives representative measurements of the LH in vitro bioactivity in children during pubertal development.
Comparison of Bone Metabolic Markers between Maternal and Cord Blood
Authors: Yamaga Akihiro , Taga Michiyoshi , Hashimoto Sakae , Ota Chitaru
Published: April 2003

We studied 41 normal pregnant women and their neonates in order to compare bone metabolism between them. We examined more specific bone formation markers (intact osteocalcin, bone-specific alkaline phosphatase) and a recently developed and more sensitive bone resorption marker (C-telopeptide of type I collagen; CTX) than previously available in maternal and umbilical cord venous blood taken at delivery. The concentrations of all markers of bone turnover, including CTX, in cord serum were significantly higher than those in maternal serum. There was no significant correlation between maternal and cord serum levels for any marker. These results indicate that fetal bone turnover is markedly enhanced compared with maternal bone turnover and is independent of maternal bone metabolism in late pregnancy.
Sera from Children with Type 1 Diabetes mellitus React against a New Group of Antigens Composed of Lysophospholipids
Authors: Bleich David , Polak Michel , Chen Songyuan , Swiderek Kristine M. , Lévy-Marchal Claire
Published: April 2003

Several autoantibodies related to Type 1 diabetes mellitus and their corresponding autoantigens have been previously identified. While peptide antigens are more widely recognized, lipid antigens like sulfatides and gangliosides are also known epitopes for the diabetic humoral immune response. Islet cell antibodies (ICA) in Type 1 diabetes are heterogeneous immunoglobulins directed against selected antigens in the islets of Langerhans. Moreover, ICA may be the best predictive marker of disease in family members of patients with Type 1 diabetes. The aims of this study were: (1) to purify lipids from porcine pancreas that contain ICA epitopes; (2) to characterize these lipid antigens, and (3) to use the purified lipids in an assay to detect antibodies in patients with Type 1 diabetes. A unique family of 4 lysophospholipids, 1 fully characterized as lysophosphatidylmyoinositol, partially inhibited ICA staining, and therefore, were considered to be candidate antigens for an ICA immunoassay. Using a dot blot immunoassay, we detected antibodies directed against these phospholipids in 28 out of 46 (61%) diabetic sera, while detecting only 1 false positive out of 28 nondiabetic sera (3.6%; p < 0.0001 comparing diabetic vs. nondiabetic serum). Therefore, lysophospholipid immunoassay positivity is present in sera of Type 1 diabetic patients. Furthermore, we detected 15 out of 23 ICA-negative diabetic sera (65.2%), showing that our phospholipid immunoassay does not correlate with ICA positivity.
Hypothyroid Myopathy with Unusually High Serum Creatine Kinase Values
Authors: Finsterer J. , Stöllberger C. , Grossegger C. , Kroiss A.
Published: April 2003

Depending on the degree of hormone deficiency, skeletal muscle involvement may occur in hypothyroidism. Usually, hypothyroid myopathy is associated with creatine kinase values <5,000 U/l. We report a 54-year-old man suffering from increasing fatigability, hoarseness, gait disturbances and a creatine kinase of 9,000 (normal: <80 U/l). He presented with bradyphrenia, macroglossia, dysarthria, myxedema, monoparesis, reduced deep tendon reflexes and stocking-type sensory disturbances. Free triiodthyronine was 0.25 pg/ml (normal: 0.6–1.9 pg/ml), free thyroxine <0.1 ng/dl (normal: 0.6–1.8 ng/dl) and the thyroid-stimulating hormone >48.0 (normal: 0.1–4.0 IU). Clinical neurologic examination and electromyography were compatible with myopathy and polyneuropathy. Other causes of myopathy, except hypothyroidism, were excluded. After L-thyroxine therapy (1.7 μg/kg BW/day) during 3 months, the patient’s symptoms and signs vanished, except for sensory disturbances, and creatine kinase values and electromyography became normal. Severe hypothyroidism may be associated with highly elevated creatine kinase and myopathy. Adequate therapy leads to complete recovery, including myopathy.
Sonography and Scintigraphy Are Necessary in Diagnostics of Cystic Thyroid Lesions
Authors: Vierhapper H. , Hülsmann M.
Published: April 2003

Thyroid sonography in an otherwise asymptomatic 50-year-old woman revealed a mainly cystic lesion within the right thyroid lobe. Thyroid 99Tc scan showed an enhanced uptake over the right thyroid lobe with suppressed activity over the remaining thyroid tissue. Following aspiration of 6 ml of cyst fluid, a solid lesion became apparent in the location of the original cyst corresponding to the scintigraphically detected autonomous adenoma. This case report emphasizes that ultrasonography and scintigraphy are complementary methods and should be used as such in the primary evaluation of thyroid nodules.
Gastrectomy and Osteomalacia: An Association Not to Be Forgotten
Authors: Efstathiadou Zoe , Bitsis Spiros , Tsatsoulis Agathocles
Published: April 2003

Metabolic bone disease due to calcium and vitamin D malabsorption is a well-defined consequence of gastrectomy and to a lesser extent of pancreatic insufficiency. The diversity of its presentation, however, can be misleading, resulting in delayed diagnosis or a thorough investigation for possible underlying neoplasias being undertaken. We describe the case of a man with partial gastrectomy and pancreatectomy with osteomalacia and secondary hyperparathyroidism.
Aldosterone Synthase Deficiency Type I: Hormonal and Genetic Analyses of Two Cases
Authors: López-Siguero Juan P. , García-García Emilio , Peter Michael , Sippell Wolfgang G.
Published: April 2003

Two female infants with clinical and biochemical findings of mineralocorticoid deficiency are presented. Both cases were diagnosed with aldosterone synthase type-I deficiency by multisteroid analysis. Two different mutations were located in the CYP11B2 gene: two homozygous amino acid substitutions (E188D and V386A) in case 1, and one heterozygous substitution (L324Q) and one heterozygous stop mutation (Y265X) in case 2.
Macroprolactinemia in Childhood and Adolescence: A Cause of Asymptomatic Hyperprolactinemia
Authors: Fideleff H.L. , Ruibal G. , Boquete H. , Pujol A. , Sequera A. , Sobrado P.
Published: April 2003

Asymptomatic hyperprolactinemias associated with altered proportions of molecular forms of circulating prolactin (PRL) have been reported in adults. The scarce references available in children and adolescents prompted us to report our experience in the evaluation and follow-up of patients with macroprolactinemia. We studied 5 patients (1 male and 4 females) aged 11.6–18 years with incidentally discovered asymptomatic hyperprolactinemia. Patients underwent repeated evaluations for a period of 3 months to 8 years, and their PRL levels remained elevated (34.4–516 ng/ml). Structural variants of PRL ≥45 kD ranged between 58.9 and 78.6%. Chromatographic profiles showed increases in Big Big PRL in the 5 cases, ranging between 40 and 72% (normal: 9–21%), and in Big PRL in 3 cases, ranging between 30.0 and 32.6% (normal: 5–25%). Little PRL was decreased in all cases, ranging between 20.6 and 41.1% (normal: 50– 90%). In conclusion, upon detection of hyperprolactinemia with no clinical manifestations and no alteration of the remaining endocrine functions, macroprolactinemia should be considered as a possible diagnosis. The confirmed absence of functional alterations during the follow-up would favor a no-treatment approach and at the same time avoid repeating imaging studies.
N-Glycosylated Variants of Growth Hormone in Human Pituitary Extracts
Authors: García-Barros M. , Costoya J.A. , Ríos R. , Arce V.M. , Devesa J.
Published: April 2003

This study was designed to investigate the existence, in human pituitary extracts, of growth hormone (GH) variants not encoded by the hGH-N gene. Using anion exchange-fast protein liquid chromatography followed by SDS-PAGE, we isolated several basic forms of pituitary GH. Incubation of these basic forms with endoglycosidase F/N-glycosidase F revealed that two of them (about 34 and 12 kD) were N-glycosylated. In contrast, no changes were found when samples were incubated with the O-linked glycosylation-specific O-glycosidase. Since the GH-N molecule lacks consensus sequences for N-linked glycosylation, our findings suggest that GH genes other than hGH-N are expressed in the human pituitary gland.
G Protein Defects in Signal Transduction
Authors: Spiegel Allen M.
Published: April 2003

G proteins couple receptors for many hormones to effectors that regulate second messenger metabolism. Several endocrine disorders have been shown to be caused by either loss- or gain-of-function mutations in G proteins or G protein-coupled receptors. In pseudohypoparathyroidism type Ia (PHP Ia), there are generalized hormone resistance (parathyroid hormone [PTH], thyroid-stimulating hormone, gonadotropins) and associated abnormal physical features, Albright hereditary osteodystrophy. Subjects with PHP Ib are normal in appearance and show renal resistance to PTH. In McCune-Albright syndrome (MAS), subjects show autonomous endocrine hyperfunction associated with fibrous dysplasia of bone and skin hyperpigmentation. Germline loss-of-function mutations have been identified in the Gs-α gene in PHP Ia, and recent evidence suggests that the Gs-α gene is paternally imprinted in a tissue-specific manner. Abnormal imprinting of the Gs-α gene may be the cause of PHP Ib. MAS, in contrast, is caused by gain-of-function missense mutations of the Gs-α gene.
Selective Oestrogen Receptor Modulators
Authors: Burger Henry G.
Published: April 2003

Selective oestrogen receptor modulators (SERMs) are compounds which act like oestrogens in some target tissues but which antagonise their effects in others. The first example of a SERM (referred to as a first-generation compound) was tamoxifen, for which oestrogen-like agonist activity on bone was seen to occur simultaneously with oestrogen antagonist activity on the breast. An unwanted effect of tamoxifen was its oestrogen-like action on the endometrium. Second-generation compounds have since been developed, most notably raloxifene, which has oestrogen-like actions on bone, lipids and the coagulation system, and oestrogen antagonist effects on the breast and uterus. Raloxifene has undergone very extensive, prospective, placebo-controlled, randomised trial evaluation, in which anti-fracture efficacy (to date only for vertebral fracture) has been accompanied by a major reduction in the incidence of new breast cancer. The compound is similar to placebo in its uterine effects, and similar to oestrogen in causing a two- to threefold increase in the risk of venous thromboembolism. Its lipid effects are similar to those of oestrogen, except for a relatively small effect on high-density lipoprotein cholesterol, and no significant effect on triglycerides. Data on cardiovascular event rates are not yet available; data on cognitive function are preliminary and, to date, reassuring. The mechanisms by which the same compound can exert oestrogen agonist effects on one target and antagonist effects on another are still being clarified. Important aspects include the fact that the oestrogen receptor undergoes different conformational changes according to the ligand. Thus the crystal structure of oestradiol bound to the oestrogen receptor differs from that of raloxifene bound to the same receptor. The existence of two oestrogen receptor subtypes may also be relevant. Mechanisms include differing interactions with various domains of the oestrogen receptor, and tissue-specific recruitment of steroid receptor co-activators and co-repressors may underlie some of the tissue-specific effects. The SERMs may be the prototype for other selective steroid receptor modulators, for example the androgen and progesterone receptors. The development of tissue target-specific agents is an exciting advance in endocrine pharmacology and can be extended to agents, such as tibolone, which exert some of their tissue specificity through their metabolites.
Pituitary Surgery for the Management of Acromegaly
Authors: Laws Edward R. , Vance Mary Lee , Thapar Kamal
Published: April 2003

Active acromegaly is almost always the result of a benign growth hormone (GH)-secreting adenoma of the pituitary gland. Because the same pituitary stem cell can produce both GH and prolactin (PRL), many acromegalic patients also have hyperprolactinemia. The advantages of surgical excision of pituitary adenomas associated with acromegaly include: (1) prompt decrease in GH; (2) reliable and immediate relief of the mass effect from the tumor (decompression of the optic nerves and chiasm), and (3) the opportunity to obtain tumor tissue for characterization and investigative study. Currently, more than 97% of operations for removal of pituitary tumors associated with acromegaly are done using the transsphenoidal approach rather than craniotomy. Technical advances to make the surgery safer continue to evolve, and include endoscopic approaches, computer-guided image-based intraoperative visualization, and intraoperative magnetic resonance imaging. Criteria for satisfactory remission of acromegaly after surgery are the same as those used for medical management. They include normal insulin-like growth factor (IGF)-I and suppression of GH to undetectable levels (<1.0 ng/ml) during an oral glucose tolerance test (OGTT). Data from a recent series of 86 patients operated upon for acromegaly at the University of Virginia and followed for more than 1 year have been reviewed. In patients receiving surgery as the initial procedure, 67% had a normal IGF-I, and 52% suppressed to <1.0 ng/ml in an OGTT. There was one true recurrence of disease diagnosed 81 months after surgery. Results are best in patients with noninvasive microadenomas. Gamma knife radiosurgery has been a valuable adjunct in those patients who fail to achieve postoperative remission. Pathological evaluation of the tumors revealed that 16% expressed GH only, 25% stained for GH and glycoprotein hormones (follicle stimulating hormone, thyroid hormone, thyroid stimulating hormone, α-subunit), 21% for GH and PRL, and 33% for GH, PRL and glycoprotein hormones. There was one acidophil stem cell tumor and 10% had the mammosomatotroph subtype. This contemporary series was free of mortality or serious complications. One patient had a transient cerebrospinal fluid leak and 3 developed transient SIADH with hyponatremia. Surgical treatment remains an important aspect of the combined management of patients with acromegaly.
Growth Hormone-Releasing Hormone: Past and Present
Authors: Sassolas Geneviève
Published: April 2003

The discovery of hypothalamic hypophysiotropic factors confirmed the hypothesis of Green and Harris in the late 1940s. These hormones were isolated from their eutopic site of production (the hypothalamus) with the exception of growth hormone (GH)-releasing hormone (GHRH), which was isolated from an ectopic, tumoral site of production and found to be responsible for acromegaly. Following the isolation, characterization and synthesis of human GHRH, clinical studies were performed and are described below. Circulating levels of GHRH can be measured and provide the basis for the diagnosis of acromegaly related to the ectopic, tumoral production of GHRH. At present, GHRH is used as a test of GH secretion mainly as an adjunct to other agents which modify somatostatin status, or to GH-releasing peptides. Its therapeutic potential in children and the elderly is still under investigation. The role of GHRH in the pulsatile secretion of GH is described.
Usefulness of HMG-CoA Reductase Inhibitor in Japanese Hyperlipidemic Women within Seven Years of Menopause
Authors: Ohta Hiroaki , Masuda Asako , Fuyuki Takahisa , Sugimoto Itaru , Suda Yoshio , Makita Kazuya , Takamatsu Kiyoshi , Horiguchi Fumi , Nozawa Shiro
Published: April 2003

Objective: To assess the therapeutic value of treatment with an HMG-CoA reductase inhibitor in women with hypoestrogenic hyperlipidemia caused by menopause. Design: Fifty-six women with total cholesterol (TC) levels of 220 mg/dl or more who were within 7 years of menopause were randomly assigned to receive an HMG-CoA reductase inhibitor (pravastatin 10 mg/day; treated group, 26 patients) or no medical treatment (nontreated group, 30 patients) in this 6-month nonblinded prospective trial. Results: In the treated group, the mean (SD) TC levels decreased significantly from 254.5 ± 22.3 mg/dl at baseline to 204.7 ± 22.2 mg/dl (19.6%), and the mean low-density lipoprotein cholesterol (LDL-C) level decreased significantly from 146.7 ± 30.5 to 104.3 ± 22.5 mg/dl (28.9%); the mean arteriosclerotic index decreased significantly from 2.98 to 2.08 (30.2%). There were no significant changes in either triglyceride levels or high-density lipoprotein cholesterol (HDL-C) levels. In the nontreated group, there were no significant changes in the TC, HDL-C, LDL-C, or triglyceride levels; there was also no change in the arteriosclerotic index. After 6 months, the TC level, LDL-C level, and arteriosclerotic index were significantly lower in the treated group compared with the nontreated group (p < 0.01). Conclusions: The results indicate that the HMG-CoA reductase inhibitor lowered TC and LDL-C levels and was useful in the treatment of hypoestrogenic hyperlipidemia for periods of at least 6 months.
Perceived versus Measured Height
Authors: Hunt Linda , Hazen Rebecca A. , Sandberg David E.
Published: April 2003

The relationship between perceptions versus measured height and children’s psychosocial adaptation in a sample of medically referred youth with short stature was investigated. All children referred for a growth evaluation to one regional pediatric endocrinology clinic received a psychosocial screening assessment as a routine component of their initial visit. Data were collected for patients ages 4–18 years (n = 620) with heights ranging from –4.0 to –1.1 SD for age- and gender-adjusted population norms. Patients (8 years and older) and in all cases a parent/guardian served as informant through paper-and-pencil questionnaires. Both children and parents overestimated the child’s height. Overestimations of height were associated with greater patient and parent satisfaction with stature. Perceived height was more strongly associated with psychosocial adaptation than was measured height. Clinical management decisions designed to enhance patient quality of life by increasing projected adult height through hormonal interventions should take into account both measured and perceived patient height.
Apparent Cortisone Reductase Deficiency: A Rare Cause of Hyperandrogenemia and Hypercortisolism
Authors: Biason-Lauber Anna , Suter Stephan L. , Shackleton Cedric H.L. , Zachmann Milo
Published: April 2003

A 55-year-old woman presented with androgenetic alopecia which had started at age 40. Her clinical history revealed that, unlike her younger sister, she was unable to conceive and was diagnosed as being sterile at age 30. At age 45, 21-hydroxylase deficiency (late-onset CAH) was assumed and glucocorticoid treatment suggested, but not initiated. There was slight hirsutism, but no other sign of virilization. Retesting of plasma steroids revealed elevated 17-OH-progesterone and free testosterone. Treatment with prednisone, cyproterone acetate, and spironolactone was started with significant clinical success. Surprisingly, the analyses of urinary steroid metabolites revealed a pattern that did not support the diagnosis of 21-hydroxylase deficiency (pregnanetriolone absent, pregnanediol, 17-OH-pregnanolone and pregnanetriol not increased). Abdominal CT showed bilateral adrenal hyperplasia and masses in both ovaries. Bilateral adnexectomy was performed, and cystic teratomas were diagnosed. Postoperative urinary steroid analyses showed a decreased tetrahydrocortisol/tetrahydrocortisone ratio (values around 0.08 as compared to age- and sex-matched controls with a ratio of about 0.5–0.8). Plasma cortisol appeared to be repeatedly elevated with exogenous sources excluded. Mass spectrometry showed that, while the tetrahydro metabolites were mainly cortisone-derived, the metabolites not reduced in A ring were mostly cortisol derivatives. This constellation clearly indicates cortisone reductase deficiency, a defect of hepatic 11β-hydroxysteroid dehydrogenase (11β-HSD1). This enzyme catalyzes the oxidation of cortisol to cortisone and the reduction of cortisone to cortisol. In contrast to the corresponding kidney enzyme (11β-HSD2), its primary activity is, however, reductive. Although this is only the fifth reported case of that defect, more attention should be paid to this condition in hyperandrogenic women, even if elevated 17-OH-progesterone and testosterone suggest a more frequent cause.
What Have Mast Cells To Do with Edema Formation, the Consecutive Repair and Fibrinolysis?
Authors: Valent Peter , Sillaber Christian , Baghestanian Mehrdad , Bankl Hans-C. , Kiener Hans P. , Lechner Klaus , Binder Bernd R.
Published: April 2003

Mast cells (MC) have been implicated in the activation of vascular endothelial cells, capillary leak formation, transmigration of white blood cells, and translocation of fibrinogen (and other plasma molecules) into the tissues, with consecutive edema formation. However, the mechanisms of repair that lead to tissue reconstitution after MC activation and edema formation have not been defined so far. In the present article, the possible contribution of MC to repair, in particular fibrinolysis, is discussed. Thus, accumulating evidence exists that human MC express and release the tissue-type plasminogen activator (tPA) in a constitutive manner. MC also express the urokinase receptor (uPAR) and heparin. Most importantly, however, MC lack plasminogen activator inhibitors (PAI-1, PAI-2, PAI-3). In line with this ‘pro-fibrinolytic’ profile of antigens, MC supernatants induce plasminogen-to-plasmin conversion and fibrin clot lysis in vitro. The c-kit ligand SCF upregulates uPAR expression, and the release of tPA from MC. These observations point to an important role of MC in endogenous fibrinolysis, a hitherto unrecognized (repair) function of this cell.
Intradermal Injection of Monocyte Chemoattractant Protein-1 Induces Emigration and Differentiation of Blood Monocytes in Rat Skin
Authors: Yamashiro Shigeo , Takeya Motohiro , Kuratsu Jun-ichi , Ushio Yukitaka , Takahashi Kiyoshi , Yoshimura Teizo
Published: April 2003

Background: Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant for blood monocytes in vitro. Recent studies in MCP-1-transgenic mice revealed that the local production of MCP-1 caused monocyte infiltration. However, the kinetics of monocyte infiltration after the production of MCP-1 or the amount of MCP-1 necessary for monocyte recruitment are not known. Methods: We purified recombinant rat MCP-1 expressed in COS-7 cells, and injected it into rat skin. The infiltrating cells were examined by immunohistochemistry and ultrastructural peroxidase cytochemistry. Results: Rat recombinant MCP-1 had a molecular mass of approximately 30 kD and exhibited the peak monocyte chemotactic activity at 10–9 M. One microgram of MCP-1 caused intra- and extravascular accumulation of mononuclear cells 3 h after injection. The cells were ED1+, indicating they were blood monocytes. The infiltration of mononuclear cells peaked at 12–24 h, and most of them were TRPM-3+ and ED3+, characteristic to exudate macrophages. None of the cells expressed ED2 or Ki-M2R antigens, markers for resident macrophages, until 3 days after injection. There was no uptake of [3H]thymidine by the infiltrating cells. Ultrastructural peroxidase cytochemistry confirmed that the infiltrating cells were monocytes and exudate macrophages. The number of OX8+ lymphocytes also peaked at 12 h, consisting of approximately 9% of the total infiltrating cells. Conclusion: These results indicate that MCP-1 attracts blood monocytes as early as 3 h and the infiltrating monocytes differentiate into exudate macrophages in loco. However, this effect was transient and the infiltration of monocytes did not result in tissue damage.
Tumor Necrosis Factor α Is Necessary for Granulocyte-Macrophage-Colony-Stimulating-Factor-Induced Eosinophil Transendothelial Migration
Authors: Erger Rochelle A. , Casale Thomas B.
Published: April 2003

Background: We have previously shown that granulocyte macrophage-colony stimulating factor (GM-CSF) was capable of inducing eosinophil migration across naked filters but not endothelial monolayers. Tumor necrosis factor α (TNF-α) has been shown to be a key factor in granulocyte adhesion and transendothelial migration. Methods: We, therefore, pretreated human umbilical vein endothelial cell (HUVEC) monolayers with TNF-α and studied whether TNF-α could support GM-CSF-induced eosinophil transendothelial migration. Results: We found that TNF-α supported GM-CSF-induced eosinophil transendothelial migration and that this process was: (1) dependent upon GM-CSF and TNF-α dose; (2) time-dependent; (3) not due to TNF-α having a chemotactic effect itself; (4) not due to TNF-α-induced soluble factor production by endothelium, and (5) inhibitable by actinomycin D. We next studied the specificity of this response. Neutrophils did not migrate across TNF-α-pretreated endothelium in response to GM-CSF. TNF-α pretreatment of A549 human type-II-like epithelial lung cells (A549) did not support GM-CSF-induced transepithelial migration. Neither interleukin (IL)-1 nor GM-CSF pretreatment of the HUVEC supported GM-CSF-induced transendothelial migration. However, IL-5 induced eosinophil migration through naked filters as well as TNF-α-pretreated HUVEC in a manner analogous to GM-CSF. Antibodies to ICAM-1, but not VCAM-1 significantly inhibited this response. Although IL-1 did not support GM-CSF-induced eosinophil transendothelial migration, IL-1 and TNF-α induced equivalent expression of ICAM-1 on HUVEC. Conclusion: Thus, TNF-α-supported eosinophil transendothelial migration in response to GM-CSF (and IL-5) is dependent upon ICAM-1, and is both specific and complex.
Synthesis of Basic Fibroblast Growth Factor by Murine Mast CellsRegulation by Transforming Growth Factor Beta, Tumor Necrosis Factor Alpha, and Stem Cell Factor
Authors: Qu Zhenhong , Huang Xiaona , Ahmadi Proochista , Stenberg Paula , Liebler Janice M. , Le Anh-Chi , Planck Stephen R. , Rosenbaum James T.
Published: April 2003

Background: Mast cells (MC) are involved in a wide spectrum of disorders characterized by neovascularization and fibroproliferation. We and others recently reported that human MC are a source of basic fibroblast growth factor (b FGF-2), a potent angiogenic and mitogenic polypeptide, in several disease conditions, such as chronic inflammation, hemangioma, and benign cutaneous mastocytosis. These findings suggest that FGF-2 may be an important mediator of cell proliferation and angiogenesis associated with MC. Since MC are heterogeneous across species, it is unknown whether FGF-2 expression is a feature common to all MC, or whether FGF-2 expression by MC can be regulated. We therefore examined FGF-2 expression by MC in mouse tissue and MC lines. Methods: Immunostaining, RT-PCR, ELISA, immunoblot and Northern blot analyses were employed to study four murine MC lines for FGF-2 expression and its regulation by transforming growth factor-β (TGF-β), stem cell factor (SCF), and tumor necrosis factor-α (TNF-α). Results: Mouse tissue MC and three of four murine MC lines (CFTL-12, CFTL-15, ABFTL-3) express FGF-2 as judged by immunostaining, ELISA, Western blot and Northern blot analyses, and reverse transcription-polymerase chain reaction. While TNF-α appeared to downregulate FGF-2 mRNA levels, treatment with SCF or TGF-β resulted in an increase in the expression of FGF-2 at mRNA level which can be attenuated by TNF-α. However, the concurrent increase in FGF-2 protein was negligible, possibly due to immaturity of these cell lines. Conclusion: Expression of FGF-2 may be a ubiquitous feature of MC in other species in addition to humans, and can be selectively regulated by SCF, TGF-β and TNF-α.
Levels of IgG Subclasses in Active and Inactive Cases in the Disease Spectrum of Leprosy
Authors: Beuria M.K. , Parkash Om , Joshi B. , Mohanty K.K. , Katoch K. , Sengupta U.
Published: April 2003

The present study was carried out to establish the role of IgG subclasses in leprosy. IgG subclasses to Mycobacterium leprae sonicated antigens (MLSA) and phenolic glycolipid-I (PGL-I) were determined in 124 patients with active leprosy across the disease spectrum and in 76 cases with inactive disease after completion of chemotherapy. IgG2 antibodies were found to be the predominant subclass across the disease spectrum. Lepromatous patients showed elevated levels of IgGI. IgG3 antibody levels were higher in lepromatous than that in tuberculoid patients. Patients with erythema nodosum leprosum showed a significant fall in IgG3 antibody to MLSA. While chemotherapy induced a reduction in IgG1, IgG2 and IgG3 to PGL-I in almost all types of leprous patients, for MLSA the reduction was noticed for these subclasses only in lepromatous patients. IgG4 responses to these antigens were low through out the disease spectrum and did not alter with chemotherapy.
Eosinophil Granulocyte Interaction with Serum-Opsonized Particles: Binding and Degranulation Are Enhanced by Tumor Necrosis Factor Alpha
Authors: Egesten Arne , Blom Michaela , Calafat Jero , Janssen Hans , Knol Edward F.
Published: April 2003

Eosinophils participate in the inflammatory response seen in allergy and helminthic infestation. Their release of granule-bound cationic proteins may play a role in these diseases. Therefore, we investigated mechanisms involved in the release of eosinophil cationic protein (ECP). Serum-opsonized zymosan was phagocytosed by eosinophils, and ECP was released into the phagosomes as judged by immunoelectron microscopy. Degranulation to the external milieu was induced by serum-opsonized, non-phagocytosable Sephadex beads (SOS), and ECP release was determined by use of an enzyme-linked immunosorbent assay. CD11b, CD18, and CD32 monoclonal antibodies inhibited degranulation, demonstrating dependence on complement receptor type 3 (CR3), and the low-affinity Fc receptor for IgG. Tumor necrosis factor-α (TNF-α) and interleukin (IL)-5 both rapidly enhanced the binding of eosinophils to serum-opsonized zymosan, and also the release of ECP upon interaction with SOS. The cytokine-induced increase in ECP release was inhibited by the phospholipase A2 (PLA2) inhibitor mepacrine, indicating an involvement of PLA2 in the enhanced response but not in baseline degranulation. Autocrine stimulation by the platelet-activating factor (PAF) is unlikely since the PAF receptor antagonist WEB 2086 did not inhibit the enhanced response. In conclusion, the main signals for eosinophil degranulation on serum-opsonized particles are mediated by CR3 and receptors for immunoglobulins. As for IL-5, TNF-α changes eosinophil phenotype from a resting to an activated state.
Expression and Rapid Purification of an Aedes aegypti Salivary Allergen by a Baculovirus System
Authors: Xu Wenzong , Simons F.  Estelle R. , Peng Zhikang
Published: April 2003

Mosquito salivary proteins cause allergic reactions in humans. Recombinant salivary allergens will facilitate both the diagnosis and immunotherapy of mosquito allergy. The Aed a 1, a 68-kD apyrase in the saliva of Aedes aegypti, has been demonstrated to be an allergen which binds to the IgE of mosquito-allergic subjects. The baculovirus expression vector pBlueBacHis C equipped with an N-terminal histidine tag was used to express the Aed a 1 protein. The cDNA coding for the 3′ significant portion of Aed a 1 (Aed a 1 3′) (150–562 amino acid residues) was cloned into pBlueBacHis C. The rAed a 1 3′ protein expressed by recombinant baculovirus was verified by immunoblot using anti-Aed a 1 and anti-histidine antibodies, respectively. The histidine-tagged fusion protein was purified to apparent homogeneity from infected Sf 9 cells by Ni2+ resin affnity chromatography. Both immunoblot and ELISA showed that the purified rAed a 1 3′ binds to the IgE and IgG in mosquito allergic sera, indicating that the antigenicity of the rAed a 1 3′ is identical to the native Aed a 1 of Aedes aegypti saliva.
Molecular Cloning and Expression of Cynomolgus Monkey Interleukin -1β cDNA
Authors: Totsuka Kazuya , Takakura Haruka , Hashimoto Osamu , Tatsumi Masashi
Published: April 2003

The cynomolgus monkey cDNA encoding interleukin-1β (IL-1β) was molecularly cloned by the reverse transcription polymerase chain reaction from a cDNA library of adherent splenocytes stimulated with lipopolysaccharides. The sequence analysis showed that the monkey IL-1β cDNA encodes a protein of 268 amino acids and displays a high degree (90%) of homology with the human counterpart. Substitution of amino acids resides mainly in the leader sequences of IL-1β when compared with those of human IL-1β. This cloned monkey IL-1β cDNA was used to express in Escherichia coli as a fusion protein with thioredoxin and in insect cells infected with a recombinant baculovirus after molecular modification where monkey IL-1β signal sequences were placed prior to the mature sequences of IL-1β for efficient secretion in insect cells. Recombinant monkey IL-1β expressed in both systems was shown to react with rabbit antihuman IL-1β antiserum by Western blot analysis and to have the biological activity of IL-1β in a bioassay.
IgG Antibody Subclasses, Tumor Necrosis Factor and IFN-γ Levels in Patients with Type II Lepra Reaction on Thalidomide Treatment
Authors: Partida-Sanchez S. , Favila-Castillo L. , Pedraza-Sanchez S. , Gomez-Melgar M. , Saul A. , Estrada-Parra S. , Estrada-Garcia I.
Published: April 2003

A group of 9 Mexican lepromatous leprosy patients was studied at the beginning of a type II reaction (erythema nodosum leprosum, ENL) and after 1 or 2 months of thalidomide treatment. ENL patients at the onset of the reaction had slightly higher amounts of anti-Mycobacterium leprae IgG1 and IgG2 antibodies, compared to similar lepromatous patients that did not develop ENL. Neither these antibody levels nor IgM and the other IgG subclasses were importantly modified after thalidomide treatment. Serum TNF was significantly higher in the patients that developed ENL compared to those that did not develop the reaction. TNF levels were slightly decreased after 1 month of thalidomide treatment and significantly decreased after 2 months of treatment. Serum IFN-γ was significantly lower in patients at the onset of ENL and was increased after 1 and 2 months of thalidomide treatment.
Predominant Implication of IL-5 in Acute Eosinophilic Pneumonia: Comparison with Chronic Eosinophilic Pneumonia
Authors: Okubo Yoshio , Horie Shiro , Hachiya Tsutomu , Momose Tomoyasu , Tsukadaira Akihiro , Takashi Shuuji , Suzuki Jun-ichi , Isobe Mitsuaki , Sekiguchi Morie
Published: April 2003

Background: Acute eosinophilic pneumonia (AEP) is a rare disease with unknown etiology. To examine pathophysiology of AEP we measured the cell number of eosinophils and eosinophil active cytokines in the peripheral blood and bronchoalveolar lavage fluid (BALF) of AEP patients and compared the levels with those measured in chronic eosinophilic pneumonia (CEP) patients. Methods: Cell number of eosinophils in peripheral blood and BALF from patients with AEP (n = 3) and CEP (n = 3) were measured. Eosinophil active cytokines in serum and BALF from the patients were measured using ELISA. Results: Eosinophil cell number in peripheral blood was 274–1,377/mm3 in AEP and 526–2,500/mm3 in CEP. The percentages of BALF eosinophils were high in AEP and CEP. Eosinophilia disappeared after methylprednisolone pulse therapy (1 g for 3 days) in AEP, however the cell number of eosinophils gradually increased after methylprednisolone pulse therapy and then spontaneously decreased to within normal range without any further medication. The concentrations of IL-5 in AEP were very high in serum and in BALF, however the concentrations in CEP were low in serum and BALF. Conclusion: AEP is a disease in which eosinophil active cytokine IL-5 is predominantly involved; CEP is not. The factors involving eosinophil infiltration to inflammatory loci differ between AEP and CEP.
Oral Tolerance Is Not Influenced by Oral Application of Oil-Emulsified Proteins
Authors: Kaneko Tetsuo , Terasawa Yuka , Senou Yukiko , Nagata Masashi , Kuwata Tamotsu
Published: April 2003

A 2-week program of feeding protein antigens as an oil-in-water emulsion to naive mice elicited a significant serum IgG antibody response, whereas their aqueous preparations did not at all. The unresponsive immune state that had been developed after feeding aqueous antigen was not disturbed by subsequent oral challenge with the same antigen in the presence of oil. These results suggest that the principle of oral tolerance is a feasible strategy for prophylaxis of hypersensitization to protein antigens, where protein tolerogens, in this case, are to be given without any additives at their first introduction.
Bell Peppers (Capsicum annuum) Express Allergens (Profilin, Pathogenesis-Related Protein P23 and Bet v 1) Depending on the Horticultural Strain
Authors: Jensen-Jarolim Erika , Santner Brigitte , Leitner Agnes , Grimm Rudolf , Scheiner Otto , Ebner Christof , Breiteneder Heimo
Published: April 2003

Background: Little is known about the role of bell peppers in food allergy. We collected sera from 11 patients with food allergy to bell peppers to analyze bell pepper extracts for allergen composition. Methods: Proteins of mature fruits of eight horticultural strains of bell peppers were extracted and tested with patients’ sera for IgE binding and with monoclonal and polyclonal antibodies in immunoblot. Results: Profilin was detected in bell pepper extracts by an anti-celery profilin antibody. It showed high IgE binding activity in all extracts, which could be inhibited by recombinant birch pollen profilin. Anti-birch pollen monoclonal antibody BIP3, directed against birch pollen proteins between 30 and 69 kD, bound to bell pepper antigens of comparable molecular weights. A homologue of the major birch pollen allergen Bet v 1 was detected in four of eight horticultural strains of bell peppers, and was shown to bind IgE in 1 of the 11 patients. A 23-kD allergen of bell peppers was shown to correspond to the 23-kD major paprika allergen by IgE absorption experiments. Its N-terminal sequence showed 100% identity to P23 from tomatoes. Conclusion: The appearance of profilin in all and Bet v 1 in 50% of the tested horticultural strains indicates that bell peppers have to be considered potentially dangerous for Bet v 1- and profilin-sensitized patients. Moreover, in 4 of 8 horticultural strains of bell peppers a homologue of the osmotin-like protein P23 from tomatoes is responsible for substantial IgE binding. Contact with Bet v 1 and P23 homologues in bell peppers can therefore be minimized by avoidance of the respective horticultural strains.
Diesel Exhaust Inhalation Enhances Airway Hyperresponsiveness in Mice
Authors: Miyabara Yuichi , Ichinose Takamichi , Takano Hirohisa , Sagai Masaru
Published: April 2003

Background: Repeated intratracheal instillation of diesel exhaust particles and ovalbumin-induced airway hyperresponsiveness and airway inflammation in mice. However, the effects of daily inhalation of diesel exhaust may differ from the effects of direct instillation. Methods: Therefore, mice were exposed to diesel exhaust by inhalation 12 h per day for 3 months. Before the diesel exhaust exposure, ovalbumin was injected intraperitoneally as a sensitization. After 3 weeks of diesel exhaust exposure, these mice were challenged with ovalbumin every 3 week thereafter. Results: Diesel exhaust exposure with antigen challenge induced airway hyperresponsiveness and airway inflammation which was characterized by increased numbers of eosinophils and mast cells in lung tissue. The recruitment of inflammatory cells was accompanied by an increment in goblet cells on bronchial epithelium. Diesel exhaust exposure alone also enhanced airway hyperresponsiveness, but did not induce eosinophilic infiltration and/or an increment in goblet cells. Conclusion: Diesel exhaust inhalation enhanced airway hyperresponsiveness and airway inflammation caused by ovalbumin sensitization in mice.