SHOX gene in Leri-Weill syndrome and in idiopathic short stature.
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Female↗
Biomedical subjects
S Bernasconi
Publications and source records attributed to S Bernasconi.
Rhabdomyoma of a rare type in a child: case report and literature review.
We describe a 9-year-old boy who presented with dyspnea and with a neck mass which was initially described as a thyroid nodule. At the end of the diagnostic-therapeutic research this mass was finally diagnosed as an adult rhabdomyoma originating from the mediastinum. This is an extremely rare tumor which is usually found in the adult population.
Child↗
Leptin inhibits steroid biosynthesis by human granulosa-lutein cells.
Absence of leptin secretion compromises reproductive function and fertility in the ob/ob mouse which, when given leptin, shows a rise in serum LH levels and becomes fertile. Recently, the long and active isoform of the leptin receptor was detected in the ovary, indicating that leptin may also show direct gonad-related activity. To examine this, we studied the effect of graded doses of human leptin on estradiol (E2) and progesterone (P4) concentrations in the culture media of human granulosa-lutein cells obtained from follicular fluid of women undergoing in vitro fertilization. We also evaluated the mRNA expression of steroidogenic acute regulatory protein (StAR), aromatase, and cytochrome P450 17alpha (CYP17) in these cells at baseline and after exposure to leptin. Estradiol levels were significantly decreased in the media 24 hours after incubation of the cells with increasing hLeptin concentrations (10(-11) - 10(-7) mol/l). The maximal 30% decrease in E2 production was caused by the 10(-9) mol/l hLeptin concentration; however, P4 levels in the media were not influenced by leptin. Exposure of granulosa-lutein cells to 10(-9) mol/l hLeptin did not produce any measurable changes on StAR, aromatase, or CYP17 mRNA expression. When hLeptin (10(-9) mol/l) was co-incubated with increasing concentrations of hCG (1.25 - 10 mlU/ml), IGF-II (15-60 ng/ml) or 1-6 desaminated IGF-II (deslGF-II; 15-60 ng/ml), it did not modify the elevation of E2 concentrations caused by each of the different stimuli. We conclude that leptin suppresses E2 secretion by human granulosa-lutein cells but does not impair the stimulatory effects of hCG and IGFs on these cells. Leptin may play a minor, but direct regulatory role on unstimulated human ovarian steroidogenesis by interfering with either the translational or post-translational steps of the baseline CYP17 and/or aromatase synthesis and/or the activation of the enzymes.
Adult↗
Interactions of leptin and thyrotropin 24-hour secretory profiles in short normal children.
Thyroid hormones and leptin have effects on similar aspects of body homeostasis, such as energy expenditure, thermogenesis, and metabolic efficiency. Thus, the cross-talk between the thyrostat and the lipostat might play a crucial role in the maintenance of body homeostasis. To investigate the relationship between the hypothalamic-pituitary-thyroid (HPT) axis and leptin under physiological conditions, we evaluated the pulsatility and circadian rhythmicity and time-cross-correlated the 24-h secretory patterns of leptin and TSH in 12 short normal prepubertal children (6 girls and 6 boys). In both male and female subjects, leptin was secreted in a pulsatile and circadian fashion, with a nocturnal leptin surge that was more pronounced in males than in females. Mean 24-h leptin levels and total area under the curve were significantly higher in girls than in boys. This was mainly due to the nighttime mean leptin levels and total area under the curve, which were higher than those in boys. The cross-correlated 24-h leptin and TSH levels revealed significant positive and negative correlations. The positive one, of leptin over TSH, suggests a positive feedback regulation by leptin on the HPT axis, which might play an important role in triggering the neuroendocrine response to starvation, including decreased thyroid hormone levels. The negative correlation, of TSH over leptin, could explain the compensatory changes in adipocyte metabolism, and indirectly in circulating leptin levels, in response to alterations in thyroid status. In conclusion, we suggest that under baseline physiological conditions, the HPT axis has a prevailing inhibitory effect on leptin secretion, whereas leptin has a prevailing positive effect on the HPT axis. The sexual dimorphism in leptin levels does not seem to influence in a major way the interactions between the HPT axis and leptin.
Body Height↗
Leptin, cortisol, and GH secretion interactions in short normal prepubertal children.
The hormonal regulation of the ob gene and leptin secretion in humans is still unclear. To investigate the interactions among leptin, cortisol, and GH, we analyzed and time-cross-correlated their spontaneous 24-h secretion in 12 short normal prepubertal children of both sexes (6 females and 6 males). Time-cross-correlation analyses demonstrated that leptin and cortisol were correlated in both a negative and positive fashion. The negative correlation, with cortisol leading leptin by 4 and 3 h for boys and girls, respectively, might reflect the stimulatory effect of CRH on the sympathetic system, which inhibits leptin secretion; the positive correlation, with leptin leading cortisol by 6 and 5 h for boys and girls, respectively, might reflect a direct effect of leptin on CRH secretion in the hypophyseal portal system. Time-cross-correlation analyses also showed a strong positive correlation between GH and leptin concentrations, with GH leading leptin by 5 and 2 h for boys and girls, respectively, suggesting a possible direct leptin-releasing effect of GH on adipocytes. We conclude that cross-correlation analyses of 24-h hormone secretions under baseline physiological conditions suggest that the hypothalamic-pituitary-adrenal axis might have a prevailing inhibitory effect on leptin secretion, whereas leptin might exert a positive effect on the hypothalamic-pituitary-adrenal axis. The relation between GH and leptin could be a direct one and characterized prevalently by a positive effect of GH on leptin secretion. Further investigations using different experimental systems are needed to ascertain the validity of these mathematically educed conclusions.
Body Height↗
Current concepts in tall stature and overgrowth syndromes.
In this overview an update is given on the pathogenesis, classification and differential diagnosis of overgrowth syndromes. In addition, height prognosis and therapeutic modalities available for managing mainly constitutional tall stature are discussed. Constitutional tall stature comprises normal variants in which one or both parents are tall. Primary disorders may have a prenatal onset and may be of chromosomal or genetic origin. Secondary overgrowth syndromes are most often the result of hormonal disturbances. Height prediction plays a key role in the management of tall children. Prediction equation models have been developed based on the growth data of healthy tall children. There is general agreement that a favourable effect on reducing ultimate height is obtained using high doses of sex steroids (girls 100-300 microg ethinyloestradiol; boys testosterone (T) ester depot preparations 250-1000 mg/month), the height reduction being greater when the treatment is started at a lower chronological and/or bone age. An alternative is the induction of puberty with low doses of sex steroids (girls 5-50 microg ethinyloestradiol; boys T esters 25-50 mg/m2/3 wk). In addition orthopaedic procedures have been suggested, but there is limited experience. Although psychosocial factors constitute the main reason for treating tall stature, extensive psychological investigations before or during height limiting therapy are lacking. Moreover, there are no objective data indicating lifelong psychosocial damage resulting from being tall.
Adolescent↗
Serum activin A levels in males and females during pubertal development.
Activin A is a dimeric protein composed of two beta A-subunits protein of the transforming growth factor-beta (TGF-beta) family. This protein is synthesized by a variety of organs. A sensitive and specific assay for bioactive dimeric activin A has recently been developed, to measure circulating levels in adult women and men, giving a new insights into the possible physiological role of this protein in the reproductive axis and/or in other functions. The aim of the present study was to evaluate serum dimeric activin A levels in boys and girls during pubertal development. The study was performed on a group of children (n = 54) aged between 6 and 18 years at different Tanner stages. Serum levels of activin A were measured using a specific and sensitive two-site ELISA. Serum activin A levels were not significantly different at various Tanner stages (Tanner I, 0.36 +/- 0.02 ng/ml; Tanner II, 0.33 +/- 0.02 ng/ml; Tanner III, 0.35 +/- 0.03 ng/ml; Tanner IV, 0.41 +/- 0.04 ng/ml; Tanner V, 0.35 +/- 0.05 ng/ml; p > 0.01). No difference between male and female children was observed. In conclusion, the lack of significant differences in activin A serum levels according to the Tanner stages or to gender demonstrates that this protein is not involved in the endocrine modifications during pubertal development and that its measurement may not provide a sensitive new tool for determining gonadal maturity at puberty.
Activins↗
Unicondylar femoral fractures: therapeutic strategy and long-term results. A review of 23 patients.
Unicondylar femoral fractures account for 0.65% of all femoral fractures; they have not been studied extensively in the orthopedic literature. Usually occurring following sports trauma or traffic accidents, these fractures involve the lateral condyle three times more frequently than the medial condyle. Conservative or surgical treatment has been advocated, depending on the fracture type. From 1986 to 1999, 19 patients with unicondylar femoral fractures were surgically treated at our institution: there were 15 males and 4 females, aged 36.2 years on average. According to the AO-ASIF classification, there were 7 B1, 6 B2 and 6 B3 fractures. We used Herbert screws in six cases, Barr screws together with cancellous screws in two, cannulated screws in five, cancellous screws alone in four, a compression screw and plate in one and a T-plate in one. In the same period of time, four patients were treated conservatively with a cast. Sixteen patients treated surgically were evaluated with a mean follow-up of 60 months, using Shatzker and Lambert's criteria: six results were rated as excellent, five good, four fair and one poor, while conservative treatment gave three fair and one poor results. In conclusion, we think that open reduction and internal fixation are essential in the treatment of such fractures.
Adolescent↗
Turner's syndrome.
Turner syndrome (TS) is the most common sex-chromosome abnormality in females. Short stature and hypogonadism are the classical clinical findings. The spontaneous final height (FH) ranges between 139 and 147 cm, representing a growth deficit of about 20 cm with respect to the unaffected population. GH therapy improves FH and should be started during childhood at a high dose of about 1 IU/kg/week (range 0.6-2 IU/kg/week). Some authors advocate combined therapy with an anabolic steroid at various doses (e.g. oxandrolone 0.05-0.1 mg/kg/day). This treatment results in a significantly increased FH, a large proportion of treated girls reaching a FH of more than 150 cm. Gonadal function is compromised during adolescence in about 80% of girls with TS, whilst in about 20% pubertal development occurs spontaneously. Oestrogen therapy should be started at the age of 13-14 years in hypogonadic patients; early onset of treatment (before 12 years) seems to compromise FH. Other concerns in these patients are fertility and osteopenia.
Adolescent↗
Central diabetes insipidus in children and young adults.
BACKGROUND: Central diabetes insipidus is rare in children and young adults, and up to 50 percent of cases are idiopathic. The clinical presentation and the long-term course of this disorder are largely undefined. METHODS: We studied all 79 patients with central diabetes insipidus who were seen at four pediatric endocrinology units between 1970 and 1996. There were 37 male and 42 female patients whose median age at diagnosis was 7.0 years (range, 0.1 to 24.8). All patients underwent magnetic resonance imaging (MRI) and periodic studies of anterior pituitary function. The median duration of follow-up was 7.6 years (range, 1.6 to 26.2). RESULTS: The causes of the central diabetes insipidus were Langerhans-cell histiocytosis in 12 patients, an intracranial tumor in 18 patients, a skull fracture in 2 patients, and autoimmune polyendocrinopathy in 1 patient; 5 patients had familial disease. The cause was considered to be idiopathic in 41 patients (52 percent). In 74 patients (94 percent) the posterior pituitary was not hyperintense on the first MRI scan obtained, and 29 patients (37 percent) had thickening of the pituitary stalk. Eighteen patients had changes in the thickness of the pituitary stalk over time, ranging from normalization (six patients) or a decrease in thickness (one patient) to further thickening (seven patients) or thickening of a previously normal stalk (four patients). Anterior pituitary hormone deficiencies, primarily growth hormone deficiency, were documented in 48 patients (61 percent) a median of 0.6 year (range, 0.1 to 18.0) after the onset of central diabetes insipidus. CONCLUSIONS: Most children and young adults with acquired central diabetes insipidus have abnormal findings on MRI scans of the head, which may change over time, and at least half have anterior pituitary hormone deficiencies during follow-up.
Adolescent↗
Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis.
The chimeric anti-CD20 MAb rituximab has recently become a treatment of choice for low-grade or follicular non-Hodgkin's lymphomas (FL) with a response rate of about 50%. In this report, we have investigated the mechanism of action of rituximab on 4 FL and 1 Burkitt's lymphoma (BL) cell lines, 3 fresh FL samples and normal B cells in vitro. Rituximab efficiently blocks the proliferation of normal B cells, but not that of the lymphoma lines. We did not detect significant apoptosis of the cell lines in response to rituximab alone. All cell lines were targets of antibody-dependent cellular cytotoxicity (ADCC). On the other hand, human complement-mediated lysis was highly variable between cell lines, ranging from 100% lysis to complete resistance. Investigation of the role of the complement inhibitors CD35, CD46, CD55, and CD59 showed that CD55, and to a lesser extent CD59, are important regulators of complement-mediated cytotoxicity (CDC) in FL cell lines as well as in fresh cases of FL: Blocking CD55 and/or CD59 function with specific antibodies significantly increased CDC in FL cells. We conclude that CDC and ADCC are major mechanisms of action of rituximab on B-cell lymphomas and that a heterogeneous susceptibility of different lymphoma cells to complement may be at least in part responsible for the heterogeneity of the response of different patients to rituximab in vivo. Furthermore, we suggest that the relative levels of CD55 and CD59 may become useful markers to predict the clinical response. (Blood. 2000;95:3900-3908)
Antibodies, Monoclonal↗
7,11-cyclobotryococca-5,12,26-triene, a novel botryococcene-related hydrocarbon occurring in natural environments
[formula: see text] With the unambiguous structural characterization of 7,11-cyclobotryococca-5,12,26-triene 1 by NMR, a novel C30 botryococcene-related hydrocarbon skeleton bearing a midchain five-membered ring has been identified in organic-rich sediments from Lake Cadagno (Switzerland). This compound may originate from the green alga Botryococcus braunii (race B) widespread in recent and past environments. Alternatively, it may also be a yet unreported lipid of green sulfur photosynthetic bacteria (Chlorobiaceae) or a microbial transformation product of the farnesol produced by the latter.
Journal Article↗
Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes.
IL-8 and related Glu-Leu-Arg (ELR+) CXC chemokines are potent chemoattractants for neutrophils but not for monocytes. IL-13 and IL-4 strongly increased CXCR1 and CXCR2 chemokine receptor expression in human monocytes, macrophages, and dendritic cells. The effect was receptor- and cell type-selective, in that CCRs were not increased and no augmentation was seen in neutrophils. The effect was rapid, starting at 4 h, and concentration dependent (EC50 = 6.2 and 8.3 ng/ml for CXCR1 and CXCR2, respectively) and caused by new transcriptional activity. IL-13/IL-4-treated monocytes showed increased CXCR1 and CXCR2 membrane expression. IL-8 and related ELR+ chemokines were potent and effective chemotactic agents for IL-13/IL-4-treated monocytes, but not for untreated mononuclear phagocytes, with activity comparable to that of reference monocyte attractants, such as MCP-1. In the same cells, IL-8 also caused superoxide release. Macrophages and dendritic cells present in biopsies from Omenn's syndrome and atopic dermatitis patients, two Th2 skewed pathologies, expressed IL-8 receptors by immunohistochemistry. These results show that IL-13 and IL-4 convert IL-8 and related ELR+ chemokines, prototypic neutrophil attractants, into monocyte chemotactic agonists, by up-regulating receptor expression. Therefore, IL-8 and related chemokines may contribute to the accumulation and positioning of mononuclear phagocytes in Th2-dominated responses.
Antigens, CD↗
Redox regulation of chemokine receptor expression.
Cytokines and reactive oxygen intermediates (ROI) are frequent companions at sites of acute inflammation. We have shown previously that in human monocytes, bacterial lipopolysaccharide, IL-1, and tumor necrosis factor-alpha induce a rapid down-regulation of the monocyte chemotactic protein-1 receptor CCR2 (CC chemokine receptor-2). These stimuli also induce production of ROI. In this paper, we investigate the influence of antioxidants and/or ROI on chemokine-receptor expression. In human monocytes, the antioxidant pyrrolidine dithiocarbamate (PDTC) rapidly inhibited CCR2 (95-100% of inhibition) and CCR5 (77-100% of inhibition) mRNA expression by strongly decreasing transcript stability. CCR2 half-life was decreased from 1.5 h to 45 min; CCR5 half-life was decreased from 2 h to 70 min. This inhibitory activity also included CXCR4 (CXC chemokine receptor-4) but not CXCR2 receptor and, although to a lesser extent, was shared by the antioxidants N-acetyl-l-cysteine and 2-mercaptoethanol. In contrast, the ROI-generating system xanthine/xanthine oxidase increased CCR5 and CXCR4 mRNA expression and counteracted the inhibitory effect of PDTC. Accordingly, H(2)O(2) and the glutathione-depleting drug buthionine sulfoximine increased to different extents CCR2, CCR5, and CXCR4 mRNA expression. The PDTC-mediated inhibition of CCR5 and CXCR4 mRNA expression was associated with decreased chemotactic responsiveness (>90% inhibition) and with a marked inhibition of surface-receptor expression. In contrast, xanthine/xanthine oxidase opposed the bacterial lipopolysaccharide- and tumor necrosis factor-alpha-mediated inhibition of CCR5 and CXCR4 mRNA expression and increased both the CCR5 surface expression and the cell migration (3-fold) in response to macrophage inflammatory protein-1beta. These results suggest that the redox status of cells is a crucial determinant in the regulation of the chemokine system.
Acetylcysteine↗
Genetic modification of human T cells with CD20: a strategy to purify and lyse transduced cells with anti-CD20 antibodies.
A retroviral vector has been constructed that contains the human CD20 cDNA under the control of the Moloney murine leukemia virus (Mo-MuLV) LTR. Freshly isolated mononuclear cells are infected for three consecutive days in the presence of PHA and hrlL-2, and a mean 15.9% of the cells (range, 6.5 to 31.7%) acquire a CD3+CD20+ phenotype. Transduced T lymphocytes grow and expand in vitro for up to 3 weeks like mock-infected cells and, as observed for the T lymphoblastoid CEM cell line, CD20 expression is maintained for several months with no change in the growth curve of the cells. CD20-expressing CEM and fresh T lymphocytes can be positively immunoselected on columns using different anti-CD20 antibodies. Exposure to monoclonal chimeric anti-CD20 IgG1(kappa) Rituximab antibody (Roche), in the presence of complement, results in effective and rapid killing of the transduced CD3+CD20+ human T cells in vitro. This approach represents a new and alternative method to gene manipulation with "suicide" genes for the production of drug-responsive T cell populations, a crucial step for the future management of graft-versus-host disease in bone marrow transplant patients.
Antibodies, Monoclonal↗
Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma.
Monocyte chemotactic protein-1 (MCP-1, CCL2) is an important determinant of macrophage infiltration in tumors, ovarian carcinoma in particular. MCP-1 binds the chemokine receptor CCR2. Recent results indicate that proinflammatory and anti-inflammatory signals regulate chemokine receptor expression in monocytes. The present study was designed to investigate the expression of CCR2 in tumor-associated macrophages (TAM) from ovarian cancer patients. TAM isolated from ascitic or solid ovarian carcinoma displayed defective CCR2 mRNA (Northern blot and PCR) and surface expression and did not migrate in response to MCP-1. The defect was selective for CCR2 in that CCR1 and CCR5 were expressed normally in TAM. CCR2 gene expression and chemotactic response to MCP-1 were decreased to a lesser extent in blood monocytes from cancer patients. CCR2 mRNA levels and the chemotactic response to MCP-1 were drastically reduced in fresh monocytes cultured in the presence of tumor ascites from cancer patients. Ab against TNF-alpha restored the CCR2 mRNA level in monocytes cultured in the presence of ascitic fluid. The finding of defective CCR2 expression in TAM, largely dependent on local TNF production, is consistent with previous in vitro data on down-regulation of chemokine receptors by proinflammatory molecules. Receptor inhibition may serve as a mechanism to arrest and retain recruited macrophages and to prevent chemokine scavenging by mononuclear phagocytes at sites of inflammation and tumor growth. In the presence of advanced tumors or chronic inflammation, systemic down-regulation of receptor expression by proinflammatory molecules leaking in the systemic circulation may account for defective chemotaxis and a defective capacity to mount inflammatory responses associated with advanced neoplasia.
Ascites↗
Inhibition of HMG-CoA reductase activity by hypercholesterolaemia reduces leukocyte recruitment and MCP-1 production.
To clarify the relationship between cholesterol homeostasis and inflammation we studied the effect of hypercholesterolaemia on in vivo cytokine production and leukocyte migration, in a murine model of local inflammation. Hypercholesterolaemia reduced of 40% the leukocyte recruitment by inhibiting interleukin-6 and monocyte chemotactic protein-1 production in the pouch exudate, without affecting vascular permeability or leukocytes motility.
Animals↗
Pyridostigmine and metoclopramide do not restore the TSH response to TRH inhibited by L-thyroxine treatment in children with goiter.
To define the role of somatostatin and dopamine in TSH suppression induced by L-thyroxine, 16 children (12 F, 4 M) on suppressive doses of L-thyroxine (3-4 microg/kg/day) for endemic goiter were studied. Firstly a conventional TRH test was performed in all subjects, in order to evaluate TSH, PRL and GH (basal study). A week later a second TRH test was carried out; one hour before the test, however, group A (9 patients) was given 60 mg pyridostigmine bromide po (pyridostigmine study) and group B (7 patients) 10 mg metoclopramide po (metoclopramide study). In the basal study, TSH was suppressed in both groups and levels did not increase following TRH administration, while PRL increased significantly and GH levels remained stable. In the pyridostigmine study, TSH levels did not increase following TRH administration, while PRL and GH levels were both significantly raised. In the metoclopramide study, TSH and GH levels were not raised following TRH administration, while a significantly greater increase of PRL was observed. In conclusion, suppressive doses of L-thyroxine inhibit the TSH response to TRH, while they do not seem to affect GH and PRL secretion. Somatostatin and/or dopamine do not seem to play a significant role in the L-thyroxine-induced TSH suppression.
Adolescent↗