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Biomedical subjects

O Westphal

Publications and source records attributed to O Westphal.

At least 19 recordsLinked to original sources
PubMed2004

Characterization of an interaction between fetal hemoglobin and lipid A of LPS resulting in augmented induction of cytokine production in vivo and in vitro.

A previously described extract of sheep fetal liver was reported to reverse many of the cytokine changes associated with aging in mice, including an augmented spleen cell ConA-stimulated production of IL-4 and decreased production of IL-2. Similar effects were not seen with adult liver preparations. These changes were observed in various strains of mice, including BALB/c, DBA/2 and C57BL/6, using mice with ages ranging from 8 to 110 weeks. Preliminary characterization of this crude extract showed evidence for the presence of Hb gamma chain, as well as of lipid A of LPS. We show below that purified preparations of sheep fetal Hb, but not adult Hb, in concert with suboptimally stimulating doses of LPS (lipid A), cooperate in the regulation of production of a number of cytokines, including TNFalpha and IL-6, in vitro. Furthermore, isolated fresh spleen or peritoneal cells from animals treated in vivo with the same combination of Hb and LPS, showed an augmented capacity to produce these cytokines on further culture in vitro. Evidence was also obtained for a further interaction between CLP, LPS and fetal Hb itself in this augmented cytokine production. These data suggest that some of the functional activities in the fetal liver extract reported earlier can be explained in terms of a novel immunomodulatory role of a mixture of LPS (lipid A) and fetal Hb.

Animals↗
PubMed2004

Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty.

BACKGROUND: Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotrophin-releasing hormone (GnRH) analogues. During such treatment, decreased growth velocity is frequent. AIM: To study whether the addition of growth hormone (GH) to GnRH analogue treatment improves final height in girls with early or precocious puberty. METHODS: Forty-six girls with early or precocious puberty (age < or =9.5 y) adopted from developing countries were randomized for treatment for 2-4 y with GnRH analogue, or with a combination of GH and GnRH analogue. RESULTS: During treatment, the mean growth velocity in the GH/GnRH analogue group was significantly higher compared to the control group. Combined GH/GnRH analogue treatment resulted in a higher final height: 158.9 cm compared to 155.8 cm in the GnRH analogue-treated group. Three out of 24 girls (13%) in the combined group and nine of the 22 girls (41%) treated with GnRH analogue alone attained a final height below -2 standard deviation scores (SDS). CONCLUSION: The difference between the two groups is statistically significant, and possibly of clinical importance. A future challenge is to identify a subgroup with clinically significant advantage of GH addition to GnRH analogue treatment. Being very short on arrival in Sweden and being short and young at start of treatment are possible indicators.

Adoption↗
PubMed2001

Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity.

Dyschondrosteosis (DCO; also called Léri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.

Blotting, Southern↗
PubMed2000

Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia.

Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequencing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients was carefully determined. Three novel mutations in DCO patients were found: (1) a deletion of one base (de1272G) (according to GenBank accession nos. Y11536, Y11535), resulting in a premature stop codon at position 75 of the amino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitution. These substitutions segregate with the DCO phenotype and affect evolutionarily conserved homeodomain residues, based on a comparison of homeobox containing proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mutations are pathogenic. The phenotype of our patients with DCO and HCH varied from mild to severe shortness and body disproportion. These results further support clinical and genetic heterogeneity of dyschondrosteosis and hypochondroplasia.

Amino Acid Sequence↗
PubMed2000

Children with septo-optic dysplasia - how to improve and sharpen the diagnosis.

The data in this article are based on investigations performed in 25 children with suspected septo-optic dysplasia (SOD). There are many signs and methods that help in the diagnosis of SOD. In particular, the ocular fundus, abnormalities of the hypothalamo-pituitary axis and other midline brain structures should be described. In order to achieve a more holistic and functional diagnosis, the degree of neurological, neuropsychiatric and psychological involvement should also be stated. It has been suggested that SOD is associated with autosomal recessive inheritance, and it can be speculated that it is the result of genetic and environmental influences early in gestation. An early diagnosis can favourably influence the outcome of the affected child.

Blindness↗
PubMed1999

Prevalence of coeliac disease in Turner syndrome.

This study was undertaken to investigate the prevalence of coeliac disease in children and adolescents with Turner syndrome. Eighty-seven children and adolescents with Turner syndrome were screened for IgA-antiendomysium antibodies (EMA) and IgA-antigliadin antibodies (AGA), 5% (4/87) being found to be EMA-positive, and 15% (13/87) to have AGA levels above normal. Of the 10 patients who were either AGA- or EMA-positive and further investigated with intestinal biopsy, four manifested villous atrophy (i.e. all three of the EMA-positive patients, but only one of the seven AGA-positive patients). The results suggest EMA-positivity to be a good immunological marker for use in screening for coeliac disease, and such screening to be justified in patients with Turner syndrome.

Adolescent↗
PubMed1999

Effect of growth hormone (GH) during puberty in GH-deficient children: preliminary results from an ongoing randomized trial with different dose regimens.

This paper reports results from an ongoing, randomized, multicentre national trial. The aim is to elucidate whether a dose of growth hormone (GH) of 0.2 IU/kg (0.07 mg/kg), given either as once-daily or twice-daily injections during puberty, is more effective than a once-daily dose of 0.1 IU/kg/day (0.03 mg/kg/day) in improving final height in children with GH deficiency (GHD). The twice-daily regimen comes closer to the spontaneous GH secretion pattern in puberty. Ninety-two children with GHD who had been receiving GH therapy for at least 1 year, and with spontaneous puberty or who were prepubertal and due to be started on replacement therapy to induce puberty, were randomly assigned to receive GH as follows: group A, 0.1 IU/kg/day (0.03 mg/kg/day), administered once daily; group B, 0.2 IU/kg/day (0.07 mg/kg/day), administered once daily; and group C, 0.2 IU/kg/day (0.07 mg/kg/day), divided into two equal injections given at 12-hour intervals. Pubertal height gain was 0.7, 0.7 and 1.3 SDS for groups A, B and C, respectively. The gain in height during puberty was thus most marked in group C. Mean final height, when corrected for parental height, was between 0 and 1 SDS in all treatment groups. All but seven children reached a final height within +/- 2 SD of the general population. There was a wide range of final heights in all three treatment groups. This variation in response suggests the need to individualize treatment in order to achieve an appropriate final height for most individuals.

Adolescent↗
PubMed1998

A fetal sheep liver extract reverses age-related increments in spontaneous and induced cytokine production by indirect environmental effects.

BALB/c, DBA/2 and C57BL/6 mice of different ages (ranging from 8 to 110 weeks of age) were used as spleen cell donors to assay cytokine production from ConA activated spleen and Peyer's Patch (PP) lymphocytes. As reported in an earlier publication, there was an age-related decline in IL-2 production in all strains, with a general increase in IL-4 and IL-10 production with age, this being particularly marked for PP cell preparations. Similar conclusions were reached from independent analysis of CD44hi and CD44lo cell populations in these groups (memory vs. naive cells, respectively). Interestingly, IL-6 production was dramatically increased (some 4-5-fold in the different strains) and significantly increased levels of IL-6 were detected in the serum of aged mice. A previously described sheep fetal liver extract was able to reverse, to varying degrees, these cytokine changes associated with aging. Interestingly, when cells from aged mice were adoptively transferred to lethally irradiated young (8 week) recipients, the cytokine production phenotype of cells harvested from recipient mice 3 weeks later was that of the aged donor, unless recipients were treated continually with extract. Treatment of the donor alone produced minimal changes in cytokine production 3 weeks following adoptive transfer. The effect of extract was reversed in treated aged mice by concomitant daily intravenous infusion of the competitive inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine (NMMA)), which also decreased the increased serum nitrate levels in mice treated with extract. Our data suggest an important role for reactive nitrogen products, themselves induced by fetal liver extract, in age-associated changes in cytokine production.

Adoptive Transfer↗
PubMed1998

Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial.

The aims of this study were to evaluate the efficacy and safety of different doses of growth hormone (GH) treatment in prepubertal short children born small-for-gestational-age (SGA). Forty-eight children born SGA from Sweden, Finland, Denmark and Norway were randomly allocated to three groups: a control group of 12 children received no treatment for 2 y, one group was treated with GH at 0.1 IU/kg/d (n=16), and one group was treated with GH at 0.2 IU/kg/d (n=20). In total 42 children completed 2 y of follow-up, and 24 children from the treated groups completed 3 y of treatment. Their mean (SD) age at the start of the study was 4.69 (1.61) y and their mean (SD) height was -3.16 (0.70) standard deviation scores (SDS). The children remained prepubertal during the course of the study. No catch-up growth was observed in the untreated group, but a clear dose-dependent growth response was found in the treated children. After the third year of treatment, the group receiving the higher dose of GH, achieved their target height. The major determinants of the growth response were the dose of GH used, the age at the start of treatment (the younger the child, the better the growth response) and the family-corrected individual height deficit (the higher the deficit, the better the growth response). Concentration of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 increased during treatment. An increase in insulin levels was found without negative effects on fasting glucose levels or glycosylated haemoglobin levels. GH treatment was well tolerated. In conclusion, short prepubertal children born SGA show a dose-dependent growth response to GH therapy, and their target height SDS can be achieved within 3 y of treatment given GH at 0.2 IU/kg/d. However, the long-term benefit of different regimens of GH treatment in children born SGA remains to be established.

Body Height↗
PubMed1997

Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus.

BACKGROUND: Good glycaemic control in insulin-dependent diabetes mellitus (IDDM) to prevent complications may be difficult to achieve during adolescence, because abnormalities in production of growth hormone or insulin-like growth-factor-I (IGF-I) can lead to lower insulin sensitivity. Recombinant human IGF-I (rhIGF-I) given as an adjunct to insulin therapy in IDDM, might improve glycaemic control in adolescents; we investigated the effects of the addition of IGF-I in a randomised, double-blind, placebo-controlled trial. METHODS: 53 patients with IDDM (26 male, 27 female) with a median age of 16.1 years (range 10.8-20.6) and diabetes of more than 2 years' duration were randomly assigned subcutaneous rhIGF-I (20 or 40 microg/kg daily [n=18, n=18, respectively]) or placebo (n=17), both in addition to multiple-injection insulin therapy for 24 weeks. The primary endpoint, glycated haemoglobin (HbA1c) and routine biochemistry were measured every 4 weeks. Retinal photographs and glomerular-filtration rates were assessed at base line and at the end of the study. Data were analysed by intention to treat. FINDINGS: With a dose of 40 microg/kg rhIGF-I daily, we found significant reductions in HbA1c compared with placebo (p=0.03), without changes in body-mass index, rate of hypoglycaemia, insulin dose, or circulating concentrations of IGF-binding proteins 1 and 3. The greatest median change in HbA1c of -0.6% (range -2.8 to -1.5%) was seen with rhIGF-I 40 microg/kg at week 12, but was not sustained at week 24. The greatest reductions in HbA1c at week 24 were seen among patients with the greatest changes in IGF-I concentrations (r=-0442, p=0.002). Retinal photographs, renal function (glomerular filtration rate and urinary albumin excretion), and routine biochemistry showed no adverse events. INTERPRETATION: Our data confirm that rhIGF-I as an adjunct to insulin therapy can improve HbA1c values in adolescents with IDDM without overt toxic effects, but they raise questions about whether these effects can be sustained in cases of poor compliance or reduced bioefficacy.

Adolescent↗
PubMed1997

Obese (ob) gene defects are rare in human obesity.

Our knowledge of the role of the recently cloned ob-protein (leptin) in the regulation of body fat stores is largely derived from experiments performed in mice. Different mouse models exhibit abnormalities in ob-gene expression, with extreme overexpression in mice which lack bioactive ob-protein, have nonfunctional ob-receptors or hypothalamic lesions, and undetectable expression in mice with suggested defects in regulatory elements. The aim of this study is to examine if defects, corresponding to those in mice, exist in human obesity. Adipose tissue was obtained from 94 adult obese subjects and from six children who had developed obesity after surgery in the hypothalamic region. Total RNA was isolated and ob-gene expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot. The coding region of the ob-gene was sequenced in both directions in the 94 obese adults. No mutations were detected in the coding region of the ob-gene and ob-gene expression was detectable in all subjects and none of the subjects had an extreme overexpression. There was no systematic increase in ob-expression in obese children with hypothalamic disease compared to their healthy brothers and sisters. These results show that severe abnormalities involving the ob-gene, analogous to those described in mouse models, are rare in human obesity. We therefore conclude that the cloning and subsequent analysis of the ob-gene has not provided information that can, by itself, explain the genetic component in the development of human obesity.

Adipose Tissue↗
PubMed1997

An antibody specific for interleukin-6 reverses age-associated changes in spontaneous and induced cytokine production in mice.

A number of quantitative and qualitative changes in the pattern of cytokine production have been reported to accompany the process of ageing in laboratory animals and in human populations, including an increase in serum levels of interleukin-1 (IL-1) and IL-6, as well as increased concanavalin A (ConA)-stimulated production of IL-4, IL-10 and transforming growth factor-beta (TGF-beta), and decreased production of IL-2 from cultured spleen cells. Increased IL-1 and IL-6 production is a feature of splenic adherent cells and peritoneal exudate cells taken from aged mice and stimulated with lipopolysaccharide in vitro. We have asked whether the altered production of lymphocyte-derived cytokines (IL-4, IL-2, TGF-beta) is itself a function of a primary alteration in IL-1/IL-6 production (from macrophage/monocytes) by infusing monoclonal antibodies to these cytokines prior to harvesting cells from aged mice and stimulating the cells in vitro. Anti-IL-6, but not anti-IL-1, reversed the age-associated alteration in lymphocyte cytokine production. The general pattern of cytokine production in aged mice is of a type-2 cytokine type, and thus these data are consistent with the idea that increased production of IL-6 in aged animals is causally implicated in this age-associated polarization to type-2 cytokine production.

Aging↗
PubMed1996

Improved final height in girls with Turner's syndrome treated with growth hormone and oxandrolone.

The spontaneous growth process in Turner's syndrome is characterized by a progressive decline in height velocity during childhood and no pubertal growth spurt. Therefore, therapy aimed at improving height during childhood as well as increasing final height is desirable for most girls with Turner's syndrome. Forty-five girls with Turner's syndrome, 9-16 yr of age (mean age, 12.2 yr), were allocated to three study groups. Group 1 (n = 13) was initially treated with oxandrolone alone; after 1 yr of treatment, GH without (group 1a; n = 6) or with (group 1b; n = 7) ethinyl estradiol was added. Group 2 (n = 17) was treated with GH plus oxandrolone. Group 3 (n = 15) was treated with GH, oxandrolone, and ethinyl estradiol. The dosage were: GH, 0.1 IU/kg.day; oxandrolone, 0.05 mg/kg.day; and ethinyl estradiol, 100 ng/kg.day. A height of 150 cm or more was achieved in 61%, 75%, and 60% of the girls in groups 1, 2, and 3, respectively. The most impressive increase in height was seen in group 2. In this group the mean final height was 154.2 cm (SD = 6.6), which is equivalent to a mean net gain of 8.5 cm (SD = 4.6) over the projected final height. In group 3, in which ethinyl estradiol was included from the start of therapy, the initially good height velocity decelerated after 1-2 yr of treatment. Their mean final height was 151.1 (SD = 4.6) cm, equivalent to a mean net gain of 3.0 cm (SD = 3.8). A similar growth-decelerating effect of ethinyl estradiol was seen in group 1b. We conclude that in girls with Turner's syndrome who are older than 9 yr of age, treatment with GH in combination with oxandrolone results in significant growth acceleration, imitating that in normal puberty, leading to a more favorable height during childhood. This mode of treatment also results in a significantly increased final height, permitting a great number of the girls to attain a final height of more than 150 cm. However, early addition of estrogen decelerates the height velocity and reduces the gain in height.

Adolescent↗
PubMed1995

Thyroid autoantibodies, Turner's syndrome and growth hormone therapy.

The prevalence of thyroid autoantibodies, i.e. thyroglobulin antibodies and antibodies to thyroid peroxidase, was analyzed in 89 girls, aged 3-16 years (mean age 10 years), with Turner's syndrome. The analyses were performed before the start of growth-promoting treatment and during a follow-up period of 1-5 years. The patients were divided into four groups according to karyotype as follows: group 1, 45, X (n = 63); group 2 with structural abnormalities of the X chromosome (n = 10); group 3 with mosaicism but no structural abnormalities of the X chromosome (n = 10); and group 4, with isochromosome X of the long arm (n = 12): 199 healthy girls aged 12 years, served as controls. Thyroid autoantibodies were demonstrated in 46 of 89 (52%) patients with Turner's syndrome compared with 34 of 199 (17%) age-matched control girls (p < 0.001), thus confirming the relationship between thyroid abnormalities and Turner's syndrome. There was also an increase in the prevalence of thyroid antibodies with age. Simultaneous presence of both autoantibodies was significantly more frequent in group 1 (45, X) and group 4 (isochromosome X of the long arm) than in group 3 (mosaicism) (p = 0.04 and p < 0.002, respectively) and significantly more frequent in group 4 than in group 1 (p < 0.05). During 12-60 months of growth-promoting treatment, no increase in the prevalence of thyroid antibodies was observed. The findings demonstrate the importance of continuous monitoring of thyroid function in girls with Turner's syndrome.

Adolescent↗
PubMed1995

Normal growth and growth disorders in children.

Growth in children is influenced by innumerable factors, and to achieve optimal final height, the child has to be healthy, its nutrition sufficient, and the psychosocial environment stimulating and positive. During the 1st year of life nutritional factors and thyroid hormone seem to be the most important regulators of growth; during the following years growth hormone increases in importance. Puberty and its timing are factors of greatest importance during the 2nd decade of life; disturbances in puberty will compromise final height. Increased understanding of factors influencing growth and increased access to growth hormone and analogs of hormone that influence the timing of puberty have made it possible to increase final height in some groups of patients predisposed to short stature.

Adolescent↗