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Biomedical subjects

J M Wit

Publications and source records attributed to J M Wit.

At least 73 records · Page 4Linked to original sources
PubMed2001

Dehydroepiandrosterone sulfate treatment for atrichia pubis.

OBJECTIVE: To evaluate the efficacy of oral dehydroepiandrosterone sulfate (DHEAS) treatment for atrichia pubis in female adolescents. STUDY DESIGN: Two XY female adolescents with 17-hydroxylase deficiency and 2 XX females with panhypopituitarism presenting with atrichia pubis were treated with a daily dosage of DHEAS 10 mg/m2 body surface in addition to their regular substitution therapy. The dosage was increased according to clinical response. Pubic hair stages, growth and serum DHEAS were evaluated and in 1 case also serum IGFs and IGFBPs. RESULTS: A dosage of 10 mg/m2 for 1 year led to serum DHEAS levels at the lower limit of the normal range. 15 mg/m2 was needed to achieve pubic hair stage 4-5 and axillary hair in patients with 17-hydroxylase deficiency. In panhypopituitarism, pubic hair developed at a slower pace and reached stage 4 on a dosage of 25-30 mg/m2. Baseline serum IGF-I SDS was -0.67 and did not change on the initial dosage of DHEAS, in combination with submaximal estrogen substitution (10 microg ethinyl estradiol). On the combination of 15 mg/m2 DHEAS and full estrogen substitution, IGF-I SDS increased to an average of -0.15. IGFBP-3 SDS increased from 1.4 to a mean of 2.6 in the first year, and went back to 1.4 in the second year. IGFBP-6 SDS was low at baseline (-2.5) and rose to -1.9 and -1.7 IGF-II and IGFBP-1 showed an irregular pattern. CONCLUSIONS: Oral administration of DHEAS in a dosage of 15 mg/m2 o.d. is an efficacious treatment for atrichia pubis. For females with a panhypopituitarism a higher dosage appears needed. Given this and other biological actions of DHEAS, substitution therapy with DHEAS or DHEA to females with adrenal androgen deficiency appears rational.

Administration, Oral↗
PubMed2001

Pubertal development in The Netherlands 1965-1997.

We investigated pubertal development of 4019 boys and 3562 girls >8 y of age participating in a cross-sectional survey in The Netherlands and compared the results with those of two previous surveys. Reference curves for all pubertal stages were constructed. The 50th percentile of Tanner breast stage 2 was 10.7 y, and 50% of the boys had reached a testicular volume of 4 mL at 11.5 y of age. Median age at menarche was 13.15 y. The median age at which the various stages of pubertal development were observed has stabilized since 1980. The increase of the age at stage G2 between 1965 and 1997 is probably owing to different interpretations of its definition. The current age limits for the definition of precocious are close to the third percentile of these references. A high agreement was found between the pubic hair stages and stages of pubertal (genital and breast) development, but slightly more in boys than in girls. Menarcheal age was dependent on height, weight, and body mass index. At a given age tall or heavy girls have a higher probability of having menarche compared with short or thin girls. A body weight exceeding 60 kg (+1 SDS), or a body mass index of >20 (+1 SDS), has no or little effect on the chance of having menarche, whereas for height such a ceiling effect was not observed. In conclusion, in The Netherlands the age at onset of puberty or menarche has stabilized since 1980. Height, weight, and body mass index have a strong influence on the chance of menarche.

Adolescent↗
PubMed2001

Growth hormone (GH) secretion in patients with an inactivating defect of the GH-releasing hormone (GHRH) receptor is pulsatile: evidence for a role for non-GHRH inputs into the generation of GH pulses.

GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10-20 pulses in each 24-h cycle. The exact roles in pulse generation played by somatostatin, GHRH, and the recently isolated GH-releasing peptide, Ghrelin, are not fully elucidated. To investigate the GHRH-mediated GH secretion in human, we investigated pulsatile, entropic, and 24-h rhythmic GH secretion in two young adults (male, 24 yr; female, 23 yr) from a Moroccan family with a novel inactivating defect of the GHRH receptor gene. Data were compared with values in age- and gender-matched controls. Plasma GH concentration were measured by a sensitive immunofluorometric assay, with a detection limit of 0.01 mU/L. All plasma GH concentrations in the female patient were measurable; in the male patient 30 of 145 samples were at or below the detection limit. GH secretion was pulsatile, with 21 and 23 secretory episodes/24 h in the male and female patients, respectively. The fraction of basal to total GH secretion was raised in both patients by 0.18 and 0.15, respectively. The total 24-h GH production rate was greatly diminished; in the male patient it was 6.9 mU/L (normal values for his age, 26--63 mU/L), and in the female patient it was 4.2 mU/L (normal values for her age, 96--390 mU/L). The nyctohemeral plasma GH rhythm was preserved (P < 0.001), with normal acrophases (0430 and 0218 h in the male and female, respectively). Approximate entropy was greatly elevated in both subjects (0.82 in the male and 1.17 in the female; upper normal values for age and gender, 0.24 and 0.59, respectively). Intravenous injection of 50 microg GHRH failed to increase the plasma GH concentration in both patients, but 100 microg GH-releasing peptide-2 elicited a definite increase (male patient, 0.13 to 1.74 mU/L; female patient, 0.29 to 0.87 mU/L). Both patients had a partial empty sella on magnetic resonance imaging scanning. In summary, the present studies in two patients with a profound loss of function mutation of the GHRH receptor favor the view that in the human the timing of GH pulses is primarily supervised by intermittent somatostatin withdrawal, and the amplitude of GH pulses is driven by GHRH. In addition, we infer that effectual GHRH input controls the GH cell mass and the orderliness of the secretory process.

Adult↗
PubMed2001

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation.

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment.

Adolescent↗
PubMed2001

Isolated GH deficiency with dominant inheritance: new mutations, new insights.

Autosomal dominantly inherited isolated GH deficiency is caused by mutations of GH-1 that alter the normal structure of GH. We studied 16 familial cases and 1 sporadic case with isolated GH deficiency type II from 1 Dutch and 4 German families by direct sequencing of PCR-amplified genomic DNA and ectopic transcript analysis of lymphocyte mRNA. In addition, the clinical data of the affected individuals were analyzed. Two previously reported mutations and 1 novel splice site mutation in intron III of GH-1 (+1G to C and +1G to A; new, +2T to C) were detected that cause exon 3 skipping. We also discovered a novel G6191 to T missense mutation in exon 4 of GH-1 that changes valine 110, which is highly conserved in mammalian and several nonmammalian GH, to phenylalanine. Splicing of the primary RNA transcript was not affected by this mutation, which is very likely to alter the normal GH structure at the protein level. The onset of growth failure was earlier, and the degree was more severe in affected children with GH-1 splice site mutations compared with those in children with the GH-1 missense mutation. In addition, the severity of the phenotype was variable, even within the same family. The age at diagnosis was between 0.8-9.6 yr (median, 5.1 yr); height at diagnosis was between -2.5 and -8.1 SD score (median, -4.0). Most of the children were lean at diagnosis, with a body mass index ranging from -1.7 to +3.3 SD score (median, -0.5). The 5 affected adults had final heights between -1.8 and -4.5 SD score (median, -3.6), centripetal obesity, and muscular hypotrophy. Before therapy, IGF-I and IGF-binding protein-3 serum levels of all affected children were severely diminished (<<5th percentiles for age). The maximum GH peak in a total of 25 stimulation tests was between 0.1-5.0 microg/liter (median, 0.9), indicating severe GH deficiency. The height of the adenohypophysis studied by magnetic resonance imaging was normal in 2 affected children and mildly decreased in 2 others. Substitution with GH resulted in good catch-up growth in all treated children. Children with severe GH and IGF-I deficiencies, but normal size of the adenohypophysis should be examined for GH-1 splice site and missense mutations. The observed discrepancy between the very homogeneous hormone data proving severe GH and IGF-I deficiencies and the high variability of growth failure even within the same family suggests that the onset and predominance of GH-dependent growth during infancy are individually different and modified by as yet unknown factors.

Age Determination by Skeleton↗
PubMed2001

The estrogen receptor in the growth plate: implications for pubertal growth.

It is well established that estrogen is essential for statural growth during puberty, but until recently it was generally accepted that the role of estrogen was negligible during puberty in boys. Clinical findings in three male patients, one with an inactivating mutation in the estrogen receptor and two with P-450 aromatase deficiency, have, however, advanced our knowledge of the role of estrogen in the male. It has become apparent that estrogen (1) initiates the pubertal growth spurt, (2) causes growth plate fusion at the end of puberty, and (3) augments accrual of bone during puberty. Two estrogen receptors (alpha and beta) mediate the actions of estrogen, and the presence of both has been demonstrated in the growth plate. The mechanism by which estrogen acts locally on the growth plate, however, remains largely unknown. With the recent development of knockout models for both estrogen receptors, attempts are being made to unravel the local actions of estrogen in order to characterize further their roles in the regulation of longitudinal growth.

Animals↗
PubMed2000

[Implications of the Barker hypothesis for general practitioners].

The Barker hypothesis states that there are foetal origins of adult disease. The hypothesis is primarily based on epidemiological associations between indicators of foetal malnutrition and mortality and morbidity in adulthood. The first association reported was between birth weight and coronary heart disease. Similar associations were found between birth weight and stroke, hypertension, type 2 diabetes mellitus, insulin resistance, serum lipids, and premature pubarche. In non-industrialized countries the associations appear to be even stronger. Although the Barker hypothesis has been criticized, the evidence from epidemiological studies and animal experiments appears sufficient to test it further and to consider the possible consequences for the physician. The first consequence could be that in taking a medical history from adults the physician should collect information about intrauterine growth. To facilitate this, communication between obstetricians, specialists in preventive child health care and paediatricians on the one hand and general practitioners and physicians on the other ought to be improved. A low birth weight, particularly smallness for gestational age, can be communicated to the adult patient as a potential risk factor for the diseases mentioned above and an extra reason to abstain from smoking and to avoid overweight.

Adult↗
PubMed2000

Development and psychometric evaluation of the TAPQOL: a health-related quality of life instrument for 1-5-year-old children.

The 43-item TNO-AZL Preschool Children Quality of Life (TAPQOL) questionnaire was developed to meet the need for a reliable and valid instrument for measuring parent's perceptions of health-related quality of life (HRQoL) in preschool children. HRQoL was defined as health status in 12 domains weighted by the impact of the health status problems on well-being. The aim of this study was to evaluate the psychometric performance of the TAPQOL. A sample of 121 parents of preterm children completed the TAPQOL questionnaire (response rate 88%) as well as 362 parents of children from the general population (response rate 60%). On the base of Cronbach's alpha, item-rest correlation, and principal component analysis, the TAPQOL scales were constructed from the data for the preterm children sample. The psychometric performance of these scales was evaluated for both the preterm children sample and the general population sample. Cronbach's alpha ranged from 0.66 to 0.88 for the preterm children sample and from 0.43 to 0.84 for the general population sample. The unidimensionality of the separate scales was confirmed by principal component analysis for both the preterm children sample and the general population sample. Spearman's correlation coefficients between scales were, on average, low. T-tests showed that the very preterm children, the children with chronic diseases, the less healthy and the less happy children had lower mean scores on the TAPQOL scales than healthy children, indicating a worse quality of life. This study shows that the TAPQOL is a reliable and valid parent's perception of HRQoL in preschool children. More research is needed to evaluate the psychometric performance of the TAPQOL in different clinical populations.

Child, Preschool↗
PubMed2000

Health status development in a cohort of preterm children.

OBJECTIVE: To determine the impact of preterm birth on health status (HS) development at the ages of 5 and 10 years in a cohort of children born before term. SAMPLE: Six hundred eighty-eight children, born in 1983 with a gestational age of <32 weeks and a birth weight of <1500 g. DESIGN: Prospectively collected HS variables, obtained from the parents, were analyzed in a longitudinal perspective by using principal component analyses. RESULTS: One third of the sample had minor to severe HS problems at both ages of measurement. One third had problems on one assessment only. The remainder of the sample had no HS problems at either age. The analyses grouped the HS variables into 3 combinations. Problems in basic functioning, such as mobility or speech, decreased with age. Negative moods substantially increased, and concentration problems increased slightly. Specifically at risk were preterm born children with handicaps, boys, and children who were small for gestational age. CONCLUSION: According to the parents, one third of the cohort had no HS problems at either age. The pattern of HS problems of the preterm born children changed between 5 and 10 years of age.

Child↗
PubMed2000

Body index measurements in 1996-7 compared with 1980.

OBJECTIVES: To compare the distribution of body mass index (BMI) in a national representative study in The Netherlands in 1996-7 with that from a study in 1980. METHODS: Cross sectional data on height, weight, and demographics of 14 500 boys and girls of Dutch origin, aged 0-21 years, were collected from 1996 to 1997. BMI references were derived using the LMS method. The 90th, 50th, and 10th BMI centiles of the 1980 study were used as baseline. Association of demographic variables with BMI-SDS was assessed by ANOVA. RESULTS: BMI age reference charts were constructed. From 3 years of age onwards 14-22% of the children exceeded the 90th centile of 1980, 52-60% the 50th centile, and 92-95% the 10th centile. BMI was related to region, educational level of parents (negatively) and family size (negatively). The -0.9, +1.1, and +2.3 SD lines in 1996-7 corresponded to the adult cut off points of 20, 25, and 30 kg/m(2) recommended by the World Health Organisation/European childhood obesity group. CONCLUSION: BMI age references have increased in the past 17 years. Therefore, strategies to prevent obesity in childhood should be a priority in child public health.

Adolescent↗
PubMed2000

Continuing positive secular growth change in The Netherlands 1955-1997.

Since 1858, an increase of mean stature has been observed in the Netherlands, reflecting the improving nutritional, hygienic, and health status of the population. In this study, stature, weight, and pubertal development of Dutch youth, derived from four consecutive nationwide cross-sectional growth studies during the past 42 y, are compared to assess the size and rate of the secular growth change. Data on length, height, weight, head circumference, sexual maturation, and demographics of 14,500 boys and girls of Dutch origin in the age range 0-20 y were collected in 1996 and 1997. Growth references for height and weight were constructed with a method that summarizes the distribution by three smooth curves representing skewness (L curve), the median (M curve), and coefficient of variation (S curve). The relationship between height and demographic variables was assessed by multivariate analysis. Reference curves for menarche and secondary sex characteristics were estimated by a generalized additive model using a logit transformation. A positive secular growth change has been present in the past 42 y for children, adolescents, and young adults of Dutch origin, although at a slower rate in the last 17 y. Height differences according to region, educational level of child and parents, and family size have remained. In girls, median age at menarche has decreased by 6 mo during the past four decades to 13.15 y. Environmental conditions have been favorable for many decades in the Netherlands, and the positive secular change in height has not yet come to a halt, in contrast to Scandinavian countries. Main contributors to the increase in height may be improved nutrition, child health, and hygiene, and a reduction of family size.

Adolescent↗
PubMed2000

Expression of Indian hedgehog, parathyroid hormone-related protein, and their receptors in the postnatal growth plate of the rat: evidence for a locally acting growth restraining feedback loop after birth.

A locally acting growth restraining feedback loop has been identified in the murine embryonic growth plate in which the level of parathyroid hormone-related peptide (PTHrP) expression regulates the pace of chondrocyte differentiation. To date, it is largely unknown whether this feedback loop also regulates the pace of chondrocyte differentiation in the growth plate after birth. We therefore characterized the spatio-temporal expression of Indian hedgehog (IHH), PTHrP, and their receptors in the postnatal growth plate from female and male rats of 1, 4, 7, and 12 weeks of age. These stages are representative for early life and puberty in rats. Using semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) on growth plate tissue, IHH and components of its receptor complex, patched (PTC) and smoothened (SMO), PTHrP and the type I PTH/PTHrP receptor messenger RNA (mRNA) were shown at all ages studied irrespective of gender. Using in situ hybridization, IHH, PTHrP, and PTH/PTHrP receptor mRNA were detected in prehypertrophic and hypertrophic chondrocytes in both sexes during development. In addition, especially in the younger age groups, faint expression of PTH/PTHrP receptor mRNA also was shown in stem cells and proliferative chondrocytes. Immunohistochemistry confirmed the observations made with in situ hybridization, by showing the presence of IHH, PTC, PTHrP, and PTH/PTHrP receptor protein in prehypertrophic and hypertrophic chondrocytes. In addition, staining for hedgehog, PTC, and PTHrP also was observed in growth plate stem cells. No differences in staining patterns were observed between the sexes. Furthermore, no mRNA or protein expression of the mentioned factors was detected in the perichondrium. Our data suggest that in contrast to the proposed feedback loop in the early embryonic growth plate, which requires the presence of the perichondrium, a feedback loop in the postnatal growth plate can be confined to the growth plate itself. In fact, two loops might exist: (1) a loop confined to the transition zone and early hypertrophic chondrocytes, which might in part be autocrine and (2) a loop involving the growth plate stem cells.

Animals↗
PubMed2000

Length velocity acceleration at 9 months of age in a representative birth cohort of Dutch infants.

According to the ICP (infancy-childhood-puberty) growth model, statural growth can be divided into three partially superimposed components assumed to represent different physiologic mechanisms. This model predicts a sudden acceleration of length velocity (LV) at the onset of the childhood component around 9 months. The existence of such an infancy-childhood growth spurt has not yet been firmly corroborated by epidemiological studies. In the present study length measurements were made at the target ages of 1, 3, 6, 9, 12, 15, 18 and 24 months in a birth cohort of 2034 infants. In order to check whether length growth showed a continuous smooth pattern, different mathematical models were fitted to the individual growth curves. The models included Count and Guo functions, 5th order polynomial and combinations of 5th order polynomial with the logarithmic term of the Count function and the square root term of the Guo function. We showed that in boys and girls there is a small but systematic lack of fit of the mathematical modeling, due to a sudden acceleration of LV around 9 months. In addition there was an increase in variation of attained length at this age. Comparison of unbalanced ANOVA models with and without addition of dummy variables for the target ages confirmed that there was an acceleration around 9 months that, if corrected for, leads to a significantly improved model fit (likelihood ratio test p < 0.0001). In absolute terms of LV, the misfit at 9 months was not greater than 0.5 cm/year on average. We conclude that the results of this study support the existence of a late infancy growth spurt. In our opinion, however, the magnitude of the phenomenon does not legitimate construction and use of discontinuous growth references such as the ICP reference.

Aging↗
PubMed2000

The use of GH as pharmacological agent (minireview).

Growth hormone (GH) has been traditionally used a drug for substitution therapy of GH deficiency, but since the wide availability of biosynthetic GH it has also been used as a pharmacological agent. In this report the presently available data are reviewed.

Bone Diseases↗
PubMed1999

Effects of total-body irradiation on growth, thyroid and pituitary gland in rhesus monkeys.

PURPOSE: To investigate the effect of total-body irradiation (TBI) on growth, thyroid and pituitary gland in primates. METHODS AND MATERIALS: Thirty-seven rhesus monkeys (mean age 3.1+/-0.6 years) received either a low-dose (4-6 Gy) TBI (n = 26) or high-dose (7-12 Gy) TBI (n = 11) and were sacrificed together with 8 age-matched controls after a post-irradiation interval of 5.9+/-1.5 years. Anthropometric data were collected: thyroid and pituitary glands were examined; serum levels of thyroid stimulating hormone (TSH), free thyroxin (FT4), insulin-like growth factor-I (IGF-I) and its binding protein-3 (IGFBP-3) were measured. RESULTS: Decrease in final height due to irradiation could not be demonstrated. There was a dose-dependent decrease in body weight, ponderal index, skinfold thickness and thyroid weight. The latter was not accompanied by elevation of TSH or decrease in FT4. Structural changes in the thyroid gland were found in 50% of the irradiated animals. Levels of IGF-I and IGFBP-3 did not differ between the dose groups, but the high-dose group had a lower IGF-1/IGFBP-3 ratio. CONCLUSION: Total body irradiation had a negative effect on body fat. There was no evidence of (compensated) hypothyroidism, but dose-dependent decrease in thyroid weight and changes in follicular structure suggest some effect of TBI on the thyroid gland. The decreased IGF-I/IGFBP-3 ratio in the high-dose group can indicate that the somatotrophic axis was mildly affected by TBI. These results show that TBI can have an effect on the physical build and thyroid gland of primates even in the absence of cytostatic agents or immunosuppressive drugs.

Animals↗
PubMed1999

A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty.

Herein, we report mutation analysis of the LH receptor gene in 17 males with LH-independent precocious puberty, of which 8 were familial and 9 had a negative family history. A total of 7 different mutations (all previously reported) were detected in 12 patients. Among 10 European familial male-limited precocious puberty (FMPP) patients who had a LH receptor gene mutation, none had the Asp578Gly mutation, which is responsible for the vast majority of cases in the U.S. The restricted number of activating mutations of the LH receptor observed in this and other studies of FMPP strongly suggests that an activating phenotype is associated with very specific sites in the receptor protein. Clinical follow-up of the 5 patients who did not have LH receptor mutations shows that such cases most likely do not have true FMPP. LH receptor mutation analysis provides a sensitive tool for distinguishing true FMPP from other causes of early-onset LH-independent puberty in males.

Amino Acid Sequence↗